Modulation of androgen receptor expression

Abstract

Certain embodiments are directed to compounds and compositions targeted to human androgen receptor (AR) for inhibiting androgen receptor levels in a cell, which can be useful for methods of treating cancer and inhibiting cancer cell growth or proliferation.

Parent Case Text

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 14/050,574, filed Oct. 10, 2013, which claims the benefit of priority to U.S. Provisional Patent Application No. 61/712,780 filed Oct. 11, 2012; U.S. Provisional Patent Application No. 61/712,756 filed Oct. 11, 2012; U.S. Provisional Patent Application No. 61/723,701 filed Nov. 7, 2012; U.S. Provisional Patent Application No. 61/777,813 filed Mar. 12, 2103; U.S. Provisional Patent Application No. 61/777,851 filed Mar. 12, 2103 and U.S. Provisional Patent Application No. 61/777,895 filed Mar. 12, 2103. The entire text of the above-referenced patent applications is incorporated herein by reference in their entirety.

Description

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0212WOSEQ.txt created Sep. 17, 2013, which is approximately 556 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

Certain embodiments are directed to compounds and compositions targeted to human androgen receptor (AR) for inhibiting androgen receptor levels in a cell, which can be useful for methods of treating cancer and inhibiting cancer cell growth or proliferation.

BACKGROUND

Androgen receptor (AR) belongs to the superfamily of nuclear receptors and is activated by binding to its hormone ligands: androgen, testosterone, or DHT. Upon binding hormone ligand in the cytoplasm, androgen receptor trans-locates to the nucleus where it binds DNA and functions as a transcription factor to regulate expression of a number of target genes, such as prostate specific antigen (PSA) and TMPRSS2. Knudsen et al. (Trends Endocrinol Metab 21: 315-24, 2010) Bennett et al. (Int J Biochem Cell Biol. 42:813-827, 201).

Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT), also known as "chemical castration", is a first-line treatment strategy against hormone-sensitive, androgen-dependent prostate cancer that reduces circulating androgen levels and thereby inhibits AR activity. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance in which the disease progresses despite castrate levels of testosterone. This type of cancer is known as castrate-resistant prostate cancer (CRPC). There are a number of mechanisms underlying the development of castrate (castration) resistance including an increase in the expression of AR protein which can sensitize cells to low levels of androgen, AR mutations that can alter transactivation or sensitize AR to alternative ligands and the emergence of alternatively spliced forms of AR, which lack the ligand binding domain but can nevertheless act to promote tumour growth in the absence of ligand stimulation. Additionally prostate tumors may also synthesize their own androgens thereby increasing the local intra-tumoral testosterone levels available to activate the AR.

Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance in which the disease progresses despite castrate levels of testosterone. This type of cancer is known as castrate-resistant prostate cancer (CRPC) (Karantos et al., Oncogene advance online: 1-13, 2013). There are a number of mechanisms underlying the development of castration resistance including an increase in the expression of AR protein which can sensitize cells to low levels of androgen (Gregory et al., Cancer Res 61: 2892-2898, 2001; Linja et al., Cancer Res 61: 3550-3555, 2001), AR mutations that can alter transactivation or sensitize AR to alternative ligands (Scher et al., J Clin Oncol 23: 8253-8261, 2005) and the emergence of alternatively spliced forms of AR, which lack the ligand binding domain but can nevertheless act to promote tumour growth in the absence of ligand stimulation (Yingming et al., Cancer Res 73:483-489, 2013). Additionally prostate tumors may also synthesize their own androgens thereby increasing the local intratumoral testosterone levels available to activate the AR (Attard et al., Cancer Cell 16:458-462, 2009).

The fact that the androgen receptor remains active in castrate resistant prostate cancer has led to the development of new agents that inhibit the production of androgen ligands or block the actions of these ligands on the AR. These new agents include abiraterone acetate which inhibits 17-.alpha.-hydroxylase/17,20-lyase (CYP17) activity resulting in a reduction in residual androgens synthesized by the adrenals and in the prostate tumour itself deBono et al. (N Engl J Med 364: 1995-2006, 2011) and enzalutamide which prevents androgen ligand from binding to AR, translocating to the nucleus, and binding to DNA (Scher et al., N Engl J Med 367:1187-1197, 2012). A number of other androgen synthesis inhibitors or androgen receptor blockers are under development either pre-clinically or clinically and include for example, ARN509, ODM201, TOK001, VT464.

Although the activity of agents such as enzalutamide and abiraterone in CRPC is very encouraging, neither works in all patients and both are associated with the development of additional resistance through re-activation of the AR by the mechanisms described above (Yingming et al., Cancer Res 73:483-489, 2013). Thus, there is a continued need to identify alternative therapies for the treatment of CRPC, and in particular those that can either remove and/or inhibit the activity of all forms of AR including for example, wildtype, mutated and splice variant ARs.

The present invention provides antisense oligonclueotides which by virtue of their design and mode of action (base-pair with the AR RNA target and mediate its destruction by RNase H, an enzyme that destroys the RNA in a DNA/RNA duplex) are aimed at inhibiting the major forms of AR By targeting an appropriate region of the AR mRNA the antisense oligonucleotide will result in inhibition of the major forms (full length, splice variant and mutated forms) of androgen receptor proteins and therefore be suitable for the treatment of patients with CRPC.

Aside from prostate cancer, AR is also implicated as a factor in the progression of other tumours such as breast cancer. In breast cancer AR is expressed in 70-80% of tumours which are also ER positive and in 12% cases which are known as triple negative (no expression of ER, PR and HER2) (Hickey et al., Molecular Endocrinology 26: 1252-1267, 2012). In pre-clinical studies, the androgen receptor antagonist bicalutamide induces anti-proliferative responses in vitro in breast cancer cells and this is potentiated by addition of a Pi3K/mTOR inhibitor (Ni et al., Cancer Cell 20: 119-131, 2011). The 2nd generation anti-androgen, enzalutamide inhibits dihydrotestosterone (DHT) mediated proliferation in ER+/AR+ breast cancer cells and is as effective as tamoxifen at inhibiting estrogen-stimulated breast cancer tumour growth in pre-clinical models in vivo (Cochrane et al., Cancer Res 72(24 Supplement): P2-14-02, 2012). Enzalutamide also inhibits proliferation in HER2 + and triple-negative breast cancer cells. It appears that in situations where estrogen action is reduced (eg. long-term estrogen deprivation or absence of ER) AR levels increase and can become oncogenic. This would suggest that AR antagonists may be best positioned in triple negative or hormone resistant breast cancer settings (Hickey et al., Molecular Endocrinology 26: 1252-1267, 2012). AR targeted therapies are currently under investigation in clinical trials for breast cancer (NCT00468715, NCT01597193, NCT01381874, NCT00755886).

AR is also expressed in a variety of other tumours, including, but not limited to bladder, ovarian, gastric, lung and liver. Pre-clinical data support a similar role as in breast cancer, to promote tumour cell proliferation survival; thus blocking AR in these tumours could have therapeutic clinical benefit (Chang et al., Oncogene advance online: 1-10, 2013).

SUMMARY

Several embodiments provided herein relate to the discovery of compounds and compositions for inhibiting androgen receptor levels in a cell, which can be useful for methods of treating cancer and inhibiting proliferation or growth of cancer cells, such as prostate, breast, ovarian, gastric or bladder cancer or cancer cells.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms, such as "includes" and "included", is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Where permitted, all patents, applications, published applications and other publications, GENBANK Accession Numbers and associated sequence information obtainable through databases such as National Center for Biotechnology Information (NCBI) and other data referred to throughout in the disclosure herein are incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

"2'-O-methoxyethyl" (also 2'-MOE and 2'-O(CH.sub.2).sub.2--OCH.sub.3) refers to an O-methoxy-ethyl modification at the 2' position of a sugar ring, e.g. a furanose ring. A 2'-O-methoxyethyl modified sugar is a modified sugar.

"2'-MOE nucleoside" (also 2'-O-methoxyethyl nucleoside) means a nucleoside comprising a 2'-MOE modified sugar moiety.

"2'-substituted nucleoside" means a nucleoside comprising a substituent at the 2'-position of the furanosyl ring other than H or OH. In certain embodiments, 2' substituted nucleosides include nucleosides with bicyclic sugar modifications.

"3' target site" refers to the nucleotide of a target nucleic acid which is complementary to the 3'-most nucleotide of a particular antisense compound.

"5' target site" refers to the nucleotide of a target nucleic acid which is complementary to the 5'-most nucleotide of a particular antisense compound.

"5-methylcytosine" means a cytosine modified with a methyl group attached to the 5' position. A 5-methylcytosine is a modified nucleobase.

"About" means within .+-.7% of a value. For example, if it is stated, "the compounds affected at least about 70% inhibition of Androgen Receptor", it is implied that Androgen Receptor levels are inhibited within a range of 63% and 77%.

"Administration" or "administering" refers to routes of introducing an antisense compound provided herein to a subject to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

"Androgen-receptor positive" with respect to breast cancer or a breast cancer cell refers to a breast cancer or a breast cancer cell that expresses androgen receptor.

"Animal" refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

"Anti-androgenic agent" refers to a therapeutic compound or drug which is an androgen synthesis inhibitor or an androgen receptor blocker.

"Antisense activity" means any detectable or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid.

"Antisense compound" means an oligomeric compound that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

"Antisense inhibition" means reduction of target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.

"Antisense mechanisms" are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.

"Antisense oligonucleotide" means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.

"Base complementarity" refers to the capacity for the precise base pairing of nucleobases of an antisense oligonucleotide with corresponding nucleobases in a target nucleic acid (i.e., hybridization), and is mediated by Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen binding between corresponding nucleobases.

"Bicyclic sugar moiety" means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2'-carbon and the 4'-carbon of the furanosyl.

Also included within the definition of LNA according to the invention are LNAs in which the 2'-hydroxyl group of the ribosyl sugar ring is connected to the 4' carbon atom of the sugar ring, thereby forming a methyleneoxy (4-CH.sub.2--O-2') bridge to form the bicyclic sugar moiety. The bridge can also be a methylene (--CH.sub.2--) group connecting the 2' oxygen atom and the 4' carbon atom, for which the term methyleneoxy (4-CH.sub.2--O-2') LNA is used. Furthermore; in the case of the bicylic sugar moiety having an ethylene bridging group in this position, the term ethyleneoxy (4'-CH.sub.2CH.sub.2--O-2') LNA is used. .alpha.-L-methyleneoxy (4-CH.sub.2--O-2'), an isomer of methyleneoxy (4-CH.sub.2--O-2') LNA is also encompassed within the definition of LNA, as used herein.

"Cap structure" or "terminal cap moiety" means chemical modifications, which have been incorporated at either terminus of an antisense compound.

"Castrate-resistant prostate cancer" or "Castration-resistant prostate cancer" and prostate cancer cells refer to the reduction of sensitivity of prostate cancer and prostate cancer cells to androgen deprivation therapy or an anti-androgenic agent.

"cEt" or "constrained ethyl" means a bicyclic sugar moiety comprising a bridge connecting the 4'-carbon and the 2'-carbon, wherein the bridge has the formula: 4-CH(CH.sub.3)--O-2'.

"Constrained ethyl nucleoside" (also cEt nucleoside) means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH(CH.sub.3)--O-2' bridge.

"Chemically distinct region" refers to a region of an antisense compound that is in some way chemically different than another region of the same antisense compound. For example, a region having 2'-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2'-O-methoxyethyl modifications.

"Chimeric antisense compounds" means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits.

"Complementarity" means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid.

"Comprise," "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

"Contiguous nucleobases" means nucleobases immediately adjacent to each other.

"Deoxyribonucleotide" means a nucleotide having a hydrogen at the 2' position of the sugar portion of the nucleotide. Deoxyribonucleotides may be modified with any of a variety of substituents.

"Designing" or "Designed to" refer to the process of designing an oligomeric compound that specifically hybridizes with a selected nucleic acid molecule.

"Downstream" refers to the relative direction toward the 3' end or C-terminal end of a nucleic acid.

"Efficacy" means the ability to produce a desired effect.

"Estrogen-receptor (ER) positive" with respect to breast cancer or a breast cancer cell refers to breast cancer or a breast cancer cell that expresses estrogen receptor (ER).

"Estrogen-receptor (ER) negative" with respect to breast cancer or a breast cancer cell refers to breast cancer or a breast cancer cell that does not express estrogen receptor (ER).

"Expression" includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to the products of transcription and translation.

"Fully complementary" or "100% complementary" means each nucleobase of a first nucleic acid has a complementary nucleobase in a second nucleic acid. In certain embodiments, a first nucleic acid is an antisense compound and a target nucleic acid is a second nucleic acid.

"Gapmer" means a chimeric antisense compound in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the "gap" and the external regions may be referred to as the "wings."

"Her2/neu negative" with respect to breast cancer or a breast cancer cell refers to breast cancer or a breast cancer cell that does not express Her2/neu.

"Hybridization" means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligonucleotide and a nucleic acid target.

"Immediately adjacent" means there are no intervening elements between the immediately adjacent elements.

"Individual" means a human or non-human animal selected for treatment or therapy.

"Induce", "inhibit", "potentiate", "elevate", "increase", "decrease", upregulate", "downregulate", or the like, generally denote quantitative differences between two states.

"Inhibiting the expression or activity" refers to a reduction, blockade of the expression or activity and does not necessarily indicate a total elimination of expression or activity.

"Internucleoside linkage" refers to the chemical bond between nucleosides.

"Lengthened" antisense oligonucleotides are those that have one or more additional nucleosides relative to an antisense oligonucleotide disclosed herein.

"Linked deoxynucleoside" means a nucleic acid base (A, G, C, T, U) substituted by deoxyribose linked by a phosphate ester to form a nucleotide.

"Linked nucleosides" means adjacent nucleosides linked together by an internucleoside linkage.

"Mismatch" or "non-complementary nucleobase" refers to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second or target nucleic acid.

"Modified internucleoside linkage" refers to a substitution or any change from a naturally occurring internucleoside bond (i.e. a phosphodiester internucleoside bond).

"Modified nucleobase" means any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. An "unmodified nucleobase" means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).

"Modified nucleoside" means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase.

"Modified nucleotide" means a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, or modified nucleobase.

"Modified oligonucleotide" means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase.

"Modified sugar" means substitution and/or any change from a natural sugar moiety.

"Monomer" refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides, whether naturally occuring or modified.

"Motif" means the pattern of unmodified and modified nucleosides in an antisense compound.

"Natural sugar moiety" means a sugar moiety found in DNA (2'-H) or RNA (2'-OH).

"Naturally occurring internucleoside linkage" means a 3' to 5' phosphodiester linkage.

"Non-complementary nucleobase" refers to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization.

"Nucleic acid" refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

"Nucleobase" means a heterocyclic moiety capable of pairing with a base of another nucleic acid.

"Nucleobase complementarity" refers to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair.

"Nucleobase sequence" means the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification.

"Nucleoside" means a nucleobase linked to a sugar.

"Nucleoside mimetic" includes those structures used to replace the sugar or the sugar and the base and not necessarily the linkage at one or more positions of an oligomeric compound such as for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo or tricyclo sugar mimetics, e.g., non furanose sugar units. Nucleotide mimetic includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by --N(H)--C(.dbd.O)--O-- or other non-phosphodiester linkage). Sugar surrogate overlaps with the slightly broader term nucleoside mimetic but is intended to indicate replacement of the sugar unit (furanose ring) only. The tetrahydropyranyl rings provided herein are illustrative of an example of a sugar surrogate wherein the furanose sugar group has been replaced with a tetrahydropyranyl ring system. "Mimetic" refers to groups that are substituted for a sugar, a nucleobase, and/or internucleoside linkage. Generally, a mimetic is used in place of the sugar or sugar-internucleoside linkage combination, and the nucleobase is maintained for hybridization to a selected target.

"Nucleotide" means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside.

"Oligomeric compound" means a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of a nucleic acid molecule.

"Oligonucleoside" means an oligonucleotide in which the internucleoside linkages do not contain a phosphorus atom.

"Oligonucleotide" means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another.

"Phosphorothioate linkage" means a linkage between nucleosides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage is a modified inter-nucleoside linkage.

"Portion" means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense compound

"Progesterone receptor (PR) negative" with respect to breast cancer or a breast cancer cell refers to breast cancer or a breast cancer cell that does not express progesterone receptor (PR).

"Region" is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic.

"Ribonucleotide" means a nucleotide having a hydroxy at the 2' position of the sugar portion of the nucleotide. Ribonucleotides may be modified with any of a variety of substituents.

"Segments" are defined as smaller or sub-portions of regions within a target nucleic acid.

"Sites," as used herein, are defined as unique nucleobase positions within a target nucleic acid.

"Specifically hybridizable" refers to an antisense compound having a sufficient degree of complementarity between an antisense oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays and therapeutic treatments. "Stringent hybridization conditions" or "stringent conditions" refer to conditions under which an oligomeric compound will hybridize to its target sequence, but to a minimal number of other sequences.

"Subject" means a human or non-human animal selected for treatment or therapy.

"Synergy" or "synergize" refers to an effect of a combination that is greater than additive of the effects of each component alone.

"Target" refers to a protein, the modulation of which is desired.

"Target gene" refers to a gene encoding a target.

"Targeting" means the process of design and selection of an antisense compound that will specifically hybridize to a target nucleic acid and induce a desired effect.

"Target nucleic acid," "target RNA," "target RNA transcript" and "nucleic acid target" all mean a nucleic acid capable of being targeted by antisense compounds.

"Target region" means a portion of a target nucleic acid to which one or more antisense compounds is targeted.

"Target segment" means the sequence of nucleotides of a target nucleic acid to which an antisense compound is targeted. "5' target site" refers to the 5'-most nucleotide of a target segment. "3' target site" refers to the 3'-most nucleotide of a target segment.

"Treating cancer" refers to performing actions that lead to amelioration of cancer or of the symptoms accompanied therewith. The combination of said actions is encompassed by the term "treatment." Amelioration of cancer includes, but is not limited to, reducing the number of cancer cells in a subject or reducing the number of cancer cells in the subject. Said treatment as used herein also includes an entire restoration of the health with respect to cancer. It is to be understood that treatment as used in accordance with embodiments provided herein may not be effective in all subjects to be treated. However, a population of subjects suffering from cancer referred to herein can be successfully treated. In certain embodiments, "treating cancer" can be described by a number of different parameters including, but not limited to, reduction in the size of a tumor in a subject having cancer, reduction in the growth or proliferation of a tumor in a subject having cancer, preventing metastasis or reducing the extent of metastasis, and/or extending the survival of a subject having cancer compared to control. The cancer referred to in this definition can be any cancer including one selected from prostate cancer, breast cancer, ovarian cancer, gastric cancer and bladder cancer.

"Unmodified" nucleobases mean the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).

"Unmodified nucleotide" means a nucleotide composed of naturally occuring nucleobases, sugar moieties, and inter-nucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e. .beta.-D-ribonucleosides) or a DNA nucleotide (i.e. .beta.-D-deoxyribonucleoside).

"Upstream" refers to the relative direction toward the 5' end or N-terminal end of a nucleic acid.

Certain Embodiments

Certain embodiments provide methods, compounds, and compositions for inhibiting androgen receptor (AR) mRNA expression.

Certain embodiments provide antisense compounds or compositions targeted to an androgen receptor nucleic acid. In certain embodiments, the androgen receptor nucleic acid is the sequences set forth in GENBANK Accession No. NT_011669.17_TRUNC_5079000_5270000 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NM_000044.3 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No. NM_001011645.2 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. FJ235916.1 (incorporated herein as SEQ ID NO: 4), GENBANK Accession No. FJ235917.1 (incorporated herein as SEQ ID NO: 5), GENBANK Accession No. FJ235918.1 (incorporated herein as SEQ ID NO: 6), GENBANK Accession No. FJ235919.1 (incorporated herein as SEQ ID NO: 7), or GENBANK Accession No. FJ235920.1 (incorporated herein as SEQ ID NO: 8).

In certain embodiments, the compounds or compositions comprise a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to AR. The AR target can have a sequence recited in any one of SEQ ID NOs: 1-8 or a portion thereof or a variant thereof. In certain embodiments, the AR target can have a sequence of known AR splicing variants including, but are not limited to, AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, and AR-V7 (also referred to as AR3), which contain exons 1-3 but lack exons 4-8. AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, AR-V7, and additional splicing variants targetable by compounds provided herein are described in Hu et al., Cancer Res 2009; 69:16-22 and US Patent Application Publication No. US 2010/0068802, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the compounds or compositions comprise a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, one or more modified nucleosides in the wing segment have a modified sugar. In certain embodiments, the modified sugar is a bicyclic sugar. In certain embodiments, the modified nucleoside is an LNA nucleoside. In certain embodiments, the modified nucleoside is a 2'-substituted nucleoside. In certain embodiments, 2' substituted nucleosides include nucleosides with bicyclic sugar modifications. In certain embodiments, the modified nucleoside is a 2'-MOE nucleoside. In certain embodiments, the modified nucleoside is a constrained ethyl (cEt) nucleoside.

In certain embodiments, the compounds or compositions comprise a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence consisting of a nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, one or more modified nucleosides in the wing segment have a modified sugar. In certain embodiments, the modified sugar is a bicyclic sugar. In certain embodiments, the modified nucleoside is an LNA nucleoside. In certain embodiments, the modified nucleoside is a 2'-substituted nucleoside. In certain embodiments, 2' substituted nucleosides include nucleosides with bicyclic sugar modifications. In certain embodiments, the modified nucleoside is a 2'-MOE nucleoside. In certain embodiments, the modified nucleoside is a constrained ethyl (cEt) nucleoside.

In certain embodiments, the compounds or compositions targeted to androgen receptor comprise a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175, or a pharmaceutically acceptable salt thereof. In certain embodiments, the antisense compound targeted to human AR is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

In certain embodiments, the modified oligonucleotide comprises: a) a gap segment consisting of linked deoxynucleosides; b) a 5' wing segment consisting of linked nucleosides; and c) a 3' wing segment consisting of linked nucleosides. The gap segment is positioned between the 5' wing segment and the 3' wing segment and each nucleoside of each wing segment comprises a modified sugar.

In certain embodiments, the modified oligonucleotide consists of 20 linked nucleosides, the gap segment consisting of 10 linked deoxynucleosides, the 5' wing segment consisting of five linked nucleosides, the 3' wing segment consisting of five linked nucleosides, each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, each internucleoside linkage is a phosphorothioate linkage and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 10 linked deoxynucleosides, a 5' wing segment consisting of three linked nucleosides, a 3' wing segment consisting of three linked nucleosides, each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar, each internucleoside linkage is a phosphorothioate linkage and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 9 linked deoxynucleosides, a 5' wing segment consisting of three linked nucleosides, a 3' wing segment consisting of four linked nucleosides; the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 8 linked deoxynucleosides, a 5' wing segment consisting of five linked nucleosides, a 3' wing segment consisting of three linked nucleosides; the five linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 8 linked deoxynucleosides, a 5' wing segment consisting of four linked nucleosides, a 3' wing segment consisting of four linked nucleosides; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 8 linked deoxynucleosides, a 5' wing segment consisting of five linked nucleosides, a 3' wing segment consisting of three linked nucleosides; the five linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 7 linked deoxynucleosides, a 5' wing segment consisting of seven linked nucleosides, a 3' wing segment consisting of two linked nucleosides; the seven linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the two linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 7 linked deoxynucleosides, a 5' wing segment consisting of six linked nucleosides, a 3' wing segment consisting of three linked nucleosides; the six linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 7 linked deoxynucleosides, a 5' wing segment consisting of five linked nucleosides, a 3' wing segment consisting of four linked nucleosides; the five linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides, a gap segment consisting of 7 linked deoxynucleosides, a 5' wing segment consisting of four linked nucleosides, a 3' wing segment consisting of five linked nucleosides; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the five linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, the compounds or compositions targeted to androgen receptor comprise a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises a gap segment consisting of deoxynucleosides; a 5' wing segment; and a 3' wing segment, wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage. In certain embodiments, each cytosine of the modified oligonucleotide is a 5'-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 9 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 9 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 8 linked deoxynucleosides;

a 5' wing segment consisting of four linked nucleosides; and

a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 8 linked deoxynucleosides;

a 5' wing segment consisting of five linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the five linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 7 linked deoxynucleosides;

a 5' wing segment consisting of four linked nucleosides; and

a 3' wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the five linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 7 linked deoxynucleosides;

a 5' wing segment consisting of six linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the six linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 43, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 124, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 150, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 155, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 169, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, a compound targeted to androgen receptor comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 175, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5' wing segment consisting of three linked nucleosides; and

a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

In certain embodiments, an antisense compound or antisense oligonucleotide targeted to an androgen receptor nucleic acid is complementary within the following nucleotide regions of SEQ ID NO: 1: 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, 5521-5536, 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58724-58739, 58725-58740, 58725-58740, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 102156-102171, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 139682-139697, 139762-139777, 139782-139797, 144856-144871, 144938-144953, 148406-148421, 148443-148458, 148520-148535, 181695-181710, 182958-182973, or 183049-183064.

In certain embodiments, an antisense compound or antisense oligonucleotide targeted to an androgen receptor nucleic acid target the following nucleotide regions of SEQ ID NO: 1: 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, 5521-5536, 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58724-58739, 58725-58740, 58725-58740, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 102156-102171, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 139682-139697, 139762-139777, 139782-139797, 144856-144871, 144938-144953, 148406-148421, 148443-148458, 148520-148535, 181695-181710, 182958-182973, or 183049-183064.

In certain embodiments, antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid. In certain embodiments, such compounds or oligonucleotides targeted to a region of an androgen receptor nucleic acid have a contiguous nucleobase portion that is complementary to an equal length nucleobase portion of the region. For example, the portion can be at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases portion complementary to an equal length portion of a region recited herein. In certain embodiments, such compounds or oligonucleotide target the following nucleotide regions of SEQ ID NO: 1: 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, 5521-5536, 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58724-58739, 58725-58740, 58725-58740, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 102156-102171, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 139682-139697, 139762-139777, 139782-139797, 144856-144871, 144938-144953, 148406-148421, 148443-148458, 148520-148535, 181695-181710, 182958-182973, or 183049-183064.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within exon 1, for example within nucleotide regions 2863-5593 (exon 1) or 27672-27853 (exon 1B) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4047-4062, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, or 5521-5536.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within exon 2, for example within nucleotide regions 102087-102238 (exon 2) or 139551-139834 (exon 2c) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 2 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 102155-102170, 102156-102171, 139682-139697, 139762-139777, or 139782-139797.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within exon 3, for example within nucleotide regions 144841-144957 (exon 3), 148380-148594 (exon 3b), or 153504-154908 (exon 3d) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 3 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 144856-144871, 144938-144953, 148406-148421, 148443-148458, or 148520-148535.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within exon 7, for example within nucleotide region 181658-181815 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 7 of AR is complementary within nucleotide region 181695-181710 of SEQ ID NO: 1.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within exon 8, for example within nucleotide region 182517-189455 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 8 of AR is complementary within nucleotide regions 182958-182973 or 183049-183064 of SEQ ID NO: 1.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within intron 1, for example within nucleotide regions 5594-27671 or 27854-102086 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to intron 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58724-58739, 58725-58740, 58725-58740, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, or 67454-67469.

In certain embodiments, an antisense compound or antisense oligonucleotide provided herein targets AR within intron 2, for example within nucleotide regions 102239-139550 or 139835-144840 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to intron 2 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 114874-114889, 115272-115287, 115365-115380, or 134971-134986.

In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or antisense oligonucleotides, display at least 50% inhibition: 3099-3114, 3120-3135, 3351-3366, 3353-3368, 3361-3376, 3513-3528, 3519-3534, 3768-3783, 3799-3814, 3851-3866, 3888-3903, 4059-4074, 4534-4549, 4555-4570, 4571-4586, 4578-4593, 4655-4670, 4699-4714, 4750-4765, 4755-4770, 4865-4880, 5054-5069, 5060-5075, 5061-5076, 5062-5077, 5155-5170, 5265-5280, 5392-5407, 5448-5463, 5483-5498, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58735, 58720-58739, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58765, 58750-58769, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 102156-102171, 114874-114889, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 144856-144871, 181695-181710, 182958-182973, and 183049-183064.

In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or antisense oligonucleotides, display at least 60% inhibition: 3799-3814, 3851-3866, 3888-3903, 4059-4074, 4534-4549, 4555-4570, 4571-4586, 4578-4593, 4655-4670, 4699-4714, 4755-4770, 4865-4880, 5060-5075, 5061-5076, 5062-5077, 5155-5170, 5265-5280, 5392-5407, 5448-5463, 5483-5498, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 42017-42032, 56050-56065, 58719-58734, 58720-58735, 58720-58739, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58765, 58750-58769, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 67454-67469, 102156-102171, 115272-115287, 115365-115380, 144856-144871, 181695-181710, 182958-182973, and 183049-183064.

In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or antisense oligonucleotides, display at least 70% inhibition: 3799-3814, 3851-3866, 3888-3903, 4059-4074, 4534-4549, 4655-4670, 4699-4714, 4755-4770, 4865-4880, 5060-5075, 5062-5077, 5155-5170, 5265-5280, 5392-5407, 5448-5463, 5483-5498, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 33315-33330, 42017-42032, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 102156-102171, 115365-115380, 144856-144871, 181695-181710, 182958-182973, and 183049-183064.

In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or antisense oligonucleotides, display at least 80% inhibition: 3799-3814, 3851-3866, 3888-3903, 4059-4074, 4534-4549, 4655-4670, 4699-4714, 4755-4770, 4865-4880, 5060-5075, 5062-5077, 5155-5170, 5265-5280, 5392-5407, 5448-5463, 5483-5498, 8471-8486, 8638-8653, 9464-9479, 10865-10880, 11197-11212, 13189-13204, 16793-16808, 58719-58734, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 102156-102171, 144856-144871, 181695-181710, 182958-182973, and 183049-183064.

In certain embodiments, the following nucleotide regions of SEQ ID NO: 1, when targeted by antisense compounds or antisense oligonucleotides, display at least 90% inhibition: 4534-4549, 5060-5075, 5062-5077, 5155-5170, 5265-5280, 5448-5463, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 182958-182973, and 183049-183064.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 50% inhibition of an androgen receptor mRNA, ISIS IDs: 549332, 549334, 549338, 549347, 549358, 549360, 549361, 549362, 549366, 549371, 549372, 549374, 549377, 549379, 549380, 549381, 549387, 549390, 549414, 549432, 549434, 549457, 549458, 549459, 560071, 560098, 560099, 560100, 560131, 560132, 560133, 560137, 569213, 569215, 569216, 569220, 569222, 569223, 569227, 569228, 569229, 569236, 569238, 583559, 583567, 583608, 583609, 583613, 583635, 583638, 583662, 583795, 583796, 583799, 583834, 583919, 584145, 584148, 584149, 584152, 584157, 584158, 584162, 584163, 584165, 584166, 584167, 584168, 584179, 584180, 584183, 584184, 584192, 584233, 584242, 584245, 584263, 584269, 584274, 584312, 584329, 584361, 584465, 584465, 584468, 584469, 584469, 584495, 584495, 585233, 585259, 585262, 585263, 585264, 585265, 585268, 585269, 585271, 585274, 586124, 586224, 586224, 586225, 586225, 586227, and 586227.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 50% inhibition of an androgen receptor mRNA, SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 46, 49, 53, 54, 55, 57, 59, 63, 92, 93, 95, 101, 125, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, and 177.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 60% inhibition of an androgen receptor mRNA, ISIS IDs: 549332, 549334, 549338, 549347, 549358, 549360, 549361, 549362, 549366, 549371, 549372, 549374, 549377, 549379, 549380, 549381, 549387, 549390, 549414, 549432, 549434, 549457, 549458, 549459, 560071, 560098, 560099, 560100, 560131, 560137, 569213, 569216, 569222, 569228, 569236, 583795, 583796, 583799, 584145, 584148, 584149, 584152, 584157, 584158, 584162, 584163, 584165, 584166, 584167, 584168, 584179, 584180, 584183, 584184, 584192, 584233, 584242, 584245, 584274, 584312, 584361, 584468, 584469, 585233, 585259, 585262, 585263, 585264, 585265, 585268, 585269, 585274, 586124, 586224, 586225, and 586227.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 60% inhibition of an androgen receptor mRNA, SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 92, 93, 95, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 170, 171, 173, 175, and 176.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 70% inhibition of an androgen receptor mRNA, ISIS IDs: 549332, 549334, 549338, 549347, 549358, 549360, 549361, 549362, 549366, 549371, 549372, 549374, 549377, 549379, 549380, 549381, 549387, 549390, 549414, 549432, 549434, 549457, 549458, 549459, 560071, 560098, 560099, 560100, 560131, 560137, 569222, 584145, 584148, 584149, 584152, 584162, 584163, 584165, 584166, 584167, 584168, 584179, 584180, 584183, 584184, 584192, 584245, 584274, 584469, 585259, 585262, 585268, 585269, 586124, 586224, 586225, and 586227.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 70% inhibition of an androgen receptor mRNA, SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 148, 149, 150, 151, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 167, 170, and 176.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 80% inhibition of an androgen receptor mRNA, ISIS IDs: 549332, 549334, 549338, 549347, 549358, 549360, 549361, 549362, 549366, 549371, 549372, 549374, 549377, 549379, 549380, 549381, 549387, 549390, 549414, 549432, 549434, 549457, 549458, 549459, 560098, 560099, 560100, 560137, 584148, 584149, 584152, 584162, 584163, 584166, 584180, 586124, 586224, 586225, and 586227.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 80% inhibition of an androgen receptor mRNA, SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 43, 149, 150, 151, 154, 155, 157, and 161.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 90% inhibition of an androgen receptor mRNA, ISIS IDs: 549358, 549371, 549372, 549374, 549377, 549380, 549432, 549434, 549457, 549458, 549459, 560098, 560099, 560100, 560137, and 586224.

In certain embodiments, the following antisense compounds or antisense oligonucleotides target a region of an androgen receptor nucleic acid and effect at least a 90% inhibition of an androgen receptor mRNA, SEQ ID NOs: 16, 21, 22, 23, 24, 26, 33, 34, 35, 36, 37, 39, 40, and 41.

Percent inhibition of androgen receptor mRNA can be determined using standard methods known to those of skill in the art, such as described in Example 1.

It is understood that the sequence set forth in each SEQ ID NO in the examples contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Antisense compounds described by ISIS number (ISIS #) indicate a combination of nucleobase sequence, chemical modification, and motif.

In certain embodiments, the compounds or compositions as described herein are efficacious by virtue of having at least one of an in vitro IC.sub.50 of less than 250 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 65 nM, less than 60 nM, less than 55 nM, less than 50 nM, less than 45 nM, less than 40 nM, less than 35 nM, less than 30 nM, less than 25 nM, or less than 20 nM when delivered to HuVEC cells. In certain embodiments inhibition is measured with primer probe set RTS3559, as described herein.

In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having at least one of an increase an ALT or AST value of no more than 4 fold, 3 fold, or 2 fold over saline treated animals or an increase in liver, spleen, or kidney weight of no more than 30%, 20%, 15%, 12%, 10%, 5%, or 2%. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase of ALT or AST over saline treated animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase in liver, spleen, or kidney weight over saline treated animals.

In certain embodiments, an antisense compound provided herein targets an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of exons 4-8 encoding the ligand binding domain. An example of such an AR splicing variant includes, but is not limited to, AR-V7, which contains exons 1-3 but lacks exons 4-8. Additional examples of such AR splicing variants include, for example, AR3, AR4, AR4b, AR5, and AR6 (SEQ ID NOs: 4-8, respectively). In certain embodiments, an antisense compound targeted to AR upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain is capable of inhibiting androgen receptor levels to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176, which is targeted to exon 4 and corresponds to SEQ ID NO: 58 described in U.S. Pat. No. 7,737,125.

In certain embodiments, an antisense compound targets an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain. It will be understood that in certain embodiments an antisense compound can target an AR splicing variant that includes the entire or at least a functional portion of exon 1 encoding the N-terminal domain and the entire or at least a functional portion of exons 2 and 3 encoding the DNA binding domain, but does not include at least a functional portion of exon 4 encoding the short hinge region or at least a functional portion of exons 4-8 encoding the ligand binding domain. It is contemplated that certain AR splicing variants targeted by the antisense compounds provided herein substantially consisting of exons 1-3 may also include a non-functional portion of nucleic acid sequence from a genomic region or exons 4-8. It is contemplated that the splicing process may give rise to such AR splicing variants that retain DNA binding function but not ligand binding function. In certain embodiments, an antisense compound targeted to an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain, is capable of inhibiting growth or proliferation of prostate cancer cells that are castrate-resistant. In certain embodiments, an antisense compound targeted to an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain, is capable of inhibiting growth or proliferation of a prostate cancer cell resistant to a diarylhydantoin AR inhibitor of Formula XI to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176, which is targeted to exon 4 and corresponds to SEQ ID NO: 58 described in U.S. Pat. No. 7,737,125. In certain embodiments, an antisense compound provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 2, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within intron 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain.

In certain embodiments, an antisense compound provided herein is capable of reducing expression of both full-length AR and an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of any one of exons 4-8 encoding the ligand binding domain. In certain embodiments, such an antisense compound targets human androgen receptor upstream of the ligand binding domain. In certain embodiments, such antisense compounds target human androgen receptor upstream of the 3' end of exon 3. In certain embodiments, an antisense compound provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 2, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within intron 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain.

In certain embodiments, an antisense compound provided herein targets an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of exons 4-8 encoding the ligand binding domain. An example of such an AR splicing variant includes, but is not limited to, AR-V7, which contains exons 1-3 but lacks exons 4-8.

Certain embodiments are drawn to an antisense compound targeted to human androgen receptor (AR) upstream of the ligand binding domain that is capable of inhibiting growth or proliferation of the resistant prostate cancer cell to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176, which is targeted to exon 4 and corresponds to SEQ ID NO: 58 described in U.S. Pat. No. 7,737,125. In certain embodiments, an antisense compound targeted to human androgen receptor (AR) upstream of the ligand binding domain is targeted to a region of AR upstream of the 3' end of exon 3. In certain embodiments, an antisense compound provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 2, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within intron 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain.

In certain embodiments, the nucleobase sequence of a modified oligonucleotide provided herein is at least 70%, 75%, 80%, 85%, 90%, 95% or 100% complementary to any one of SEQ ID NOs: 1-8, as measured over the entirety of the modified oligonucleotide.

In certain embodiments, an antisense compound is a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence at least 90% complementary to any of SEQ ID NOs: 1-8 as measured over the entirety of said modified oligonucleotide.

In certain embodiments, an antisense compound is a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence 100% complementary to any of SEQ ID NOs: 1-8 as measured over the entirety of said modified oligonucleotide. In certain embodiments, a compound or modified oligonucleotide provided herein is single-stranded.

In certain embodiments, a modified oligonucleotide provided herein consists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 20 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, at least one internucleoside linkage of a modified oligonucleotide provided herein is a modified internucleoside linkage. In certain embodiments, each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleoside of the modified oligonucleotide comprises a modified sugar. In certain embodiments, at least one modified sugar comprises a 2'-O-methoxyethyl group (2'-O(CH.sub.2).sub.2--OCH.sub.3). In certain embodiments, the modified sugar comprises a 2'-O--CH.sub.3 group.

In certain embodiments, at least one modified sugar is a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a 4'-(CH.sub.2).sub.n--O-2' bridge, wherein n is 1 or 2. In certain embodiments, the bicyclic sugar comprises a 4'-CH.sub.2--O-2' bridge. In certain embodiments, the bicyclic sugar comprises a 4-CH(CH.sub.3)--O-2' bridge.

In certain embodiments, at least one nucleoside of a modified oligonucleotide provided herein comprises a modified nucleobase. In certain embodiments, the modified nucleobase is a 5-methylcytosine.

In certain embodiments, a modified oligonucleotide provided herein consists of a single-stranded modified oligonucleotide.

In certain embodiments, compounds or compositions provided herein comprise a salt of the modified oligonucleotide.

Compositions and Methods for Formulating Pharmaceutical Compositions

Antisense oligonucleotides may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

An antisense compound targeted to an androgen receptor nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense compound targeted to an androgen receptor nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the antisense compound is an antisense oligonucleotide provided herein.

Pharmaceutical compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense compound which are cleaved by endogenous nucleases within the body, to form the active antisense compound.

In certain embodiments, the compounds or compositions further comprise a pharmaceutically acceptable carrier or diluent.

Certain Indications

Certain aspects of the invention are directed to methods of treating cancer which comprises administering an antisense compound targeted to androgen receptor as provided herein. In certain embodiments, the cancer is AR positive. In certain embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer or gastric cancer. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Certain aspects are directed to an antisense compound targeted to androgen receptor provided herein for use in treating cancer. In certain embodiments, the cancer is AR positive. In certain embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer or gastric cancer. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Certain aspects are directed to use of an antisense compound targeted to androgen receptor provided herein for the manufacture of a medicament for treating cancer. In certain embodiments, the cancer is AR positive. In certain embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer or gastric cancer. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Certain aspects of the invention are directed to the use of an antisense compound targeted to human androgen receptor (AR) as described herein, for treating a cancer patient whose cancer has become resistant to treatment with an anti-androgenic agent (e.g. compound or drug). In certain embodiments, said cancer is prostate cancer. In certain embodiments, said patient is one that has, or whose cancer has, developed resistance to treatment with an agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound targets AR within exon 1, for example within nucleotide regions 2863-5593 (exon 1) or 27672-27853 (exon 1B) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, or 5521-5536. In certain embodiments, an antisense compound provided herein targets AR within exon 2, for example within nucleotide regions 102087-102238 (exon 2) or 139551-139834 (exon 2c) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 2 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 102155-102170, 102156-102171, 139682-139697, 139762-139777, or 139782-139797. In certain embodiments, an antisense compound provided herein targets AR within exon 3, for example within nucleotide regions 144841-144957 (exon 3), 148380-148594 (exon 3b), or 153504-154908 (exon 3d) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 3 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 144856-144871, 144938-144953, 148406-148421, 148443-148458, or 148520-148535. In certain embodiments, an antisense compound provided herein targets AR within intron 1, for example within nucleotide regions 5594-27671 or 27854-102086 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to intron 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58724-58739, 58725-58740, 58725-58740, 58725-58740, 58750-58769, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, or 67454-67469. In certain embodiments, an antisense compound provided herein targets AR within intron 2, for example within nucleotide regions 102239-139550 or 139835-144840 of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to intron 2 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 114874-114889, 115272-115287, 115365-115380, or 134971-134986. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

By resistant to treatment with a particular agent (e.g. compound or drug) is meant that the agent is less or no longer effective in halting the growth or spread of the cancer and so the patient, or their cancer, has become less responsive or sensitive to it over time. Typically such patient would be classed as resistant to said agent and would no longer be treated with such agent. A subject having prostate cancer resistant to an agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464 can include, for example, a patient who previously received said agent but whose prostate cancer has become less sensitive or responsive to a agent. For example, prostate cancer resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464, can include prostate cancer that has increased in tumor volume, metastasis, or progression despite treatment with the agent. In certain embodiments, prostate cancer resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464, can include prostate cancer that is refractory to the agent and is not decreasing in tumor volume, metastasis, or progression despite treatment. Several embodiments relate to a method of treating prostate cancer resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464, in a subject comprising identifying the subject as having prostate cancer resistant to the agent and administering to the subject an antisense compound targeted to human androgen receptor (AR) upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain, as described herein. Several embodiments relate to a method of treating prostate cancer resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464, in a subject comprising administering to a subject identified or diagnosed as having prostate cancer resistant to said anti-androgenic agent an antisense compound targeted to human androgen receptor (AR) upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain, as described herein. In certain embodiments, prostate cancer cells resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464, preferentially expresses an AR splicing variant over full-length AR.

Certain aspects of the invention are directed to a method of treating a patient suffering from prostate cancer wherein the patient has, or their cancer has, developed or become resistant to treatment with an anti-androgenic agent (compound or drug) comprising administering to said patient an antisense compound targeted to human androgen receptor (AR) as described herein. In certain embodiments, said patient is one that has developed resistance to treatment with an agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

A prostate cancer that has developed or become resistant to treatment with an anti-androgenic agent is referred to as castrate-resistant prostate cancer (CRPC). Thus, in several embodiments, a prostate cancer cell resistant to an anti-androgenic agent, such as MDV3100, was previously exposed to the inhibitor and has become less responsive or sensitive to it over time. For example, MDV3100 might initially inhibit prostate cancer cell growth or proliferation in the patient, but over time such inhibitory effect may be diminished when the cells become resistant to the inhibitor.

Certain aspects of the invention are directed to the use of an antisense compound targeted to androgen receptor provided herein for the manufacture of a medicament for treating cancer in a patient whose cancer has become become resistant to treatment with an anti-androgenic agent (compound or drug). In certain embodiments the cancer is prostate cancer. In certain embodiments, said patient is one that has, or whose cancer has, developed resistance to treatment with an agent selected from: MDV3100, ARN-059, ODM-201, abiraterone acetate, TOK001, TAK700 and VT464. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound is single-stranded. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Enzalutamide:

MDV3100, also known as enzalutamide (Xtandi.TM.) and by the IUPAC name 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida- zolidin-1-yl)-2-fluoro-N-methylbenzamide, is an androgen receptor ligand binding inhibitor belonging to the diarylhydantoin class of androgen receptor inhibitors represented by Formula XI. MDV3100 has the following chemical formula:

##STR00001##

MDV3100 and additional diarylhydantoin androgen receptor inhibitors suitable for use in certain embodiments provided herein are described in U.S. Pat. No. 7,709,517, US Patent Application Publication No. US20100172975 and US Patent Application Publication No. US20100210665, which are incorporated herein by reference in their entireties.

ARN-509:

##STR00002##

The compound of Formula XII, also known as ARN-509 and by the IUPAC name 4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3- .4]octan-5-yl)-2-fluoro-N-methylbenzamide, is an androgen receptor ligand binding inhibitor. ARN-509 and additional androgen receptor inhibitors suitable for use in certain embodiments provided herein are described in WO 2007126765, WO 2008119015 and US Patent Application Publication No. 2013/0116258, which are incorporated herein by reference in their entirety.

Abiraterone Acetate

The compound of Formula XIII, which is also known as Abiraterone acetate and ZYTIG-A.RTM. and by the IUPAC name [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,1- 4,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]acetate, is an androgen biosynthesis inhibitor and has the following chemical formula:

##STR00003##

The structure and synthesis of Abiraterone acetate is described in Potter et al., Journal of Medicinal Chemistry (38(13), 2463-71, 1995), which is incorporated herein by reference in its entirety.

Galeterone:

The compound of Formula XIV, which is also known as TOK-001 and Galeterone, and by the IUPAC name (3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,- 11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, has the following chemical formula:

##STR00004##

The structure and synthesis of TOK-001 is described in Handratta et al., (Journal of Medicinal Chemistry (2005), 48(8), 2972-84, 2005), which is incorporated herein by reference in its entirety:

Orteronel:

The compound of Formula XV, which is also known as TAK-700 and Orteronel and by the IUPAC name 6-[7(S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methylnapht- halene-2-carboxamide, is an androgen biosynthesis inhibitor and has the following chemical formula:

##STR00005##

The structure and synthesis of TAK-700 is described in Kaku et al., Bioorganic and Medicinal Chemistry (19(21), 6383-99, 2011).

Yin et al., (Int. J. Mol. Sci., 14(7):13958-13978, 2013) discusses recent progress with various pharmaceutical therapies, including ODM-21, VT464, ARN509, TAK700 and TOK-001, for castration-resistant prostate cancer.

Certain Combinations and Combination Therapies

In certain embodiments, a first agent comprising the compound described herein is co-administered with one or more secondary agents. In certain embodiments, such second agents are designed to treat the same disease, disorder, or condition as the first agent described herein. In certain embodiments, such second agents are designed to treat a different disease, disorder, or condition as the first agent described herein. In certain embodiments, a first agent is designed to treat an undesired side effect of a second agent. In certain embodiments, second agents are co-administered with the first agent to treat an undesired effect of the first agent. In certain embodiments, such second agents are designed to treat an undesired side effect of one or more pharmaceutical compositions as described herein. In certain embodiments, second agents are co-administered with the first agent to produce a combinational effect. In certain embodiments, second agents are co-administered with the first agent to produce a synergistic effect. In certain embodiments, the co-administration of the first and second agents permits use of lower dosages than would be required to achieve a therapeutic or prophylactic effect if the agents were administered as independent therapy.

In certain embodiments, one or more compounds or compositions provided herein are co-administered with one or more anti-androgenic agents. In certain embodiments, one or more compounds or compositions provided herein and one or more anti-androgenic agents, are administered at different times. In certain embodiments, one or more compounds or compositions provided herein and one or more anti-androgenic agents, are prepared together in a single formulation. In certain embodiments, one or more compounds or compositions provided herein and one or more anti-androgenic agents, are prepared separately. In certain embodiments, an anti-androgenic agent is selected from MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

Certain aspects of the invention are directed to the use of an antisense compound targeted to human androgen receptor (AR) as described herein in combination with an anti-androgenic agent. In particular embodiments such use is in a method of treating a patient suffering from cancer or in the manufacture of a medicament for treating cancer. In certain embodiments the cancer is selected from: prostate cancer, breast cancer, ovarian cancer, bladder cancer or gastric cancer. Particular classes of anti-androgenic agents are the second generation anti-hormonal agents such as: enzalutamide (MDV3100), ARN-059, ODM-201, abiraterone acetate, Galeterone (TOK001), orteronel (TAK700) and VT464 (see Yin et al. supra).

Certain aspects are drawn to a combination of an antisense compound targeted to human androgen receptor (AR) as described herein and an anti-androgenic agent, such as a second generation anti-hormonal agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

In certain embodiments, such a combination of an antisense compound targeted to androgen receptor (AR) as described herein and an anti-androgenic agent, such as a second generation anti-hormonal agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, is useful for inhibiting cancer cell growth or proliferation and/or treating cancer. In certain embodiments the cancer is selected from: prostate cancer, breast cancer, ovarian cancer, bladder cancer or gastric cancer. In certain embodiments the cancer is prostate cancer. In certain embodiments the cancer is breast cancer. In certain embodiments, an antisense compound targeted to AR as described herein and an anti-androgenic agent, such as a second generation anti-hormonal agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, synergize in combination to inhibit growth or proliferation of a cancer cell. In several embodiments, the cancer cell is a prostate cancer cell which is or has become castration-resistant. In various embodiments, the cancer cell is a prostate cancer cell which is or has become resistant to a second generation anti-hormonal agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, the antisense compound targeted to androgen receptor comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Several embodiments are drawn to a combination of an antisense compound targeted to human androgen receptor (AR) and a diarylhydantoin AR inhibitor of Formula XI, such as MDV3100. In several embodiments, a diarylhydantoin Androgen Receptor (AR) inhibitor is a compound of Formula XVI:

##STR00006##

wherein X is selected from the group consisting of trifluoromethyl and iodo, wherein W is selected from the group consisting of O and NR5, wherein R5 is selected from the group consisting of H, methyl, and

##STR00007## wherein D is S or O and E is N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or D is S or a and E-G together are C1-C4 lower alkyl, wherein R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group, wherein R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl, wherein R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, and wherein R3 is not methylaminomethyl or dimethylaminomethyl. R5 may be

##STR00008##

In certain embodiments, such a combination of an antisense compound targeted to androgen receptor (AR) and a diarylhydantoin AR inhibitor of Formula XVI, such as MDV3100, is useful for inhibiting prostate cancer cell growth or proliferation and/or treating prostate cancer. In certain embodiments, an antisense compound targeted to AR and a diarylhydantoin AR inhibitor of Formula XVI, such as MDV3100, synergize in combination to inhibit growth or proliferation of a prostate cancer cell. In several embodiments, the prostate cancer cell is castration-resistant. In various embodiments, the prostate cancer cell is resistant to a diarylhydantoin AR inhibitor of Formula XVI, such as MDV3100. In certain embodiments, the prostate cancer cell or castration-resistant prostate cancer cell preferentially expresses an AR splicing variant over full-length AR. In certain embodiments the antisense compound targeted to AR as described herein and the other anti-androgenic agent are used in combination treatment by administering the two agents simultaneously, separately or sequentially. In certain embodiments the two agents are formulated as a fixed dose combination product. In other embodiments the two agents are provided to the patient as separate units which can then either be taken simultaneously or serially (sequentially).

In certain embodiments, antisense compounds useful for inhibiting prostate cancer cell and/or castration-resistant prostate cancer cell growth or proliferation in combination with another anti-androgenic agent, such as a second generation anti-hormonal agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, target human androgen receptor upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 1, exon 2, exon 3, intron 1, or intron 2 as described herein.

In certain embodiments, an antisense compound provided herein targets an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of exons 4-8 encoding the ligand binding domain. An example of such an AR splicing variant includes, but is not limited to, AR-V7, which contains exons 1-3 but lacks exons 4-8. Additional examples of such AR splicing variants include, for example, AR3, AR4, AR4b, AR5, and AR6 (SEQ ID NOs: 4-8, respectively). In certain embodiments, the prostate cancer cell, which may be castration-resistant, preferentially expresses an AR splicing variant over full-length AR. In particular embodiments the prostate cancer cell is castration-resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464 In certain embodiments, an antisense compound targeted to AR upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain is capable of inhibiting growth or proliferation of a prostate cancer cell, including a castration-resistant prostate cancer cell, in combination with an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176, which is targeted to exon 4 and corresponds to SEQ ID NO: 58 described in U.S. Pat. No. 7,737,125, in combination with the same anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, the combination of an antisense compound as described herein and the anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, provides a synergistic (e.g. greater-than-additive) effect in inhibiting the growth or proliferation of a prostate cancer cell, such as a castration-resistant prostate cancer cell, compared to the antisense compound alone or the anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464 alone. Accordingly, in certain embodiments the amounts of either or both of the antisense compound and/or anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, when used in combination can be less than the corresponding amount of either the antisense compound alone or the anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, alone necessary to achieve an equivalent level of prostate cancer cell growth or proliferation inhibition.

In certain embodiments, an antisense compound provided herein useful for inhibiting prostate cancer cell and/or castration-resistant prostate cancer cell growth or proliferation in combination with an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, targets an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain. It will be understood that in certain embodiments an antisense compound can target an AR splicing variant that includes the entire or at least a functional portion of exon 1 encoding the N-terminal domain and the entire or at least a functional portion of exons 2 and 3 encoding the DNA binding domain, but does not include at least a functional portion of exon 4 encoding the short hinge region or at least a functional portion of exons 4-8 encoding the ligand binding domain. It is contemplated that certain AR splicing variants targeted by the antisense compounds provided herein substantially consisting of exons 1-3 may also include a non-functional portion of nucleic acid sequence from a genomic region or exons 4-8. It is contemplated that the splicing process may give rise to such AR splicing variants that retain DNA binding function but not ligand binding function. In certain embodiments, the prostate cancer cell, which may be castrate-resistant, preferentially expresses an AR splicing variant over full-length AR. In certain embodiments the prostate cancer cell is castrate-resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, an antisense compound provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 1, exon 2, exon 3, intron 1, or intron 2 as described herein.

In certain embodiments, an antisense compound targeted to an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain, is capable of inhibiting growth or proliferation of a prostate cancer cell, including a castration-resistant prostate cancer cell, in combination with a an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176, which is targeted to exon 4 and corresponds to SEQ ID NO: 58 described in U.S. Pat. No. 7,737,125, in combination with a the same anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, the combination of an antisense compound and anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, provides a synergistic (e.g. greater-than-additive) effect in inhibiting the growth or proliferation of a prostate cancer cell, such as a castration-resistant prostate cancer cell, compared to the antisense compound alone or the anti-androgenic agent alone. Accordingly, in certain embodiments the amounts of either or both of the antisense compound and/or anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, when used in combination can be less than the corresponding amount of either the antisense compound alone or anti-androgenic agent, alone necessary to achieve an equivalent level of prostate cancer cell growth or proliferation inhibition.

In certain embodiments, an antisense compound provided herein useful for inhibiting prostate cancer cell and/or castration-resistant prostate cancer cell growth or proliferation in combination with a anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464 is capable of reducing expression of both full-length AR and an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of any one of exons 4-8 encoding the ligand binding domain. In certain embodiments, such an antisense compound targets human androgen receptor upstream of the ligand binding domain. In certain embodiments, such antisense compounds target human androgen receptor upstream of the 3' end of exon 3. In certain embodiments, an antisense compound provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain.

In certain embodiments, there is provided a combination of an antisense compound targeted to human androgen receptor (AR) as described herein and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, wherein the antisense compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 12-179. In certain embodiments, there is provided a combination of an antisense compound targeted to human androgen receptor (AR) and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, wherein the antisense compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising any of SEQ ID NOs: 12-179. In certain embodiments, there is provided a combination of an antisense compound targeted to human androgen receptor (AR) and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, wherein the antisense compound comprises a modified oligonucleotide consisting of the nucleobase sequence of any of SEQ ID NOs: 12-179. In certain embodiments, there is provided a combination of an antisense compound targeted to human androgen receptor (AR) and a diarylhydantoin AR inhibitor of Formula XI, such as MDV3100, wherein the antisense compound comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175. In certain embodiments, there is provided a combination of an antisense compound targeted to human androgen receptor (AR) and a diarylhydantoin AR inhibitor of Formula XI, such as MDV3100, wherein the antisense compound targeted to androgen receptor is ISIS 560131, ISIS 569213, ISIS 569216, ISIS 569221, ISIS 569236, ISIS 579671, ISIS 586124, ISIS 583918, ISIS 584149, ISIS 584163, ISIS 584269, or ISIS 584468.

Several embodiments are drawn to a method of inhibiting prostate cancer cell growth or proliferation comprising contacting the prostate cancer cell with an antisense compound targeted to human androgen receptor (AR) and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, the antisense compound and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, synergize in combination to inhibit the growth or proliferation of the prostate cancer cell. In several embodiments, the prostate cancer cell is castration-resistant. In various embodiments, the prostate cancer cell is castration-resistant by being resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. In certain embodiments, the prostate cancer cell or castration-resistant prostate cancer cell preferentially expresses an AR splicing variant over full-length AR.

In certain aspects of any of the foregoing embodiments, antisense compounds useful for inhibiting prostate cancer cell growth or proliferation in combination with a diarylhydantoin AR inhibitor of Formula XVI, such as MDV3100, can target (i) human androgen receptor upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain or (ii) an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain; and/or is capable of (i) reducing expression of both full-length AR and an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of any one of exons 4-8 encoding the ligand binding domain; with the proviso that the antisense compounds do not have a nucleobase sequence consisting of any of SEQ ID NOs: 194-215 identified in Table A below.

TABLE-US-00001 TABLE A SEQ ID NO: Sequence 194 GAGAACCATCCTCACC 195 GGACCAGGTAGCCTGT 196 CCCCTGGACTCAGATG 197 GCACAAGGAGTGGGAC 198 GCTGTGAAGAGAGTGT 199 TTTGACACAAGTGGGA 200 GTGACACCCAGAAGCT 201 CATCCCTGCTTCATAA 202 TGGGGAGAACCATCCTCACCCTGC 203 TCCAGGACCAGGTAGCCTGTGGGG 204 TGTTCCCCTGGACTCAGATGCTCC 205 TGGGGCACAAGGAGTGGGACGCAC 206 TTCGGCTGTGAAGAGAGTGTGCCA 207 CGCTTTTGACACAAGTGGGACTGG 208 CATAGTGACACCCAGAAGCTTCAT 209 GAGTCATCCCTGCTTCATAACATT 210 CTGTGAAGAGAGTG 211 TGTGAAGAGAGT 212 TTGACACAAGTGGG 213 TGACACAAGTGG 214 TGACACCCAGAAGC 215 GACACCCAGAAG

In certain aspects of any of the foregoing embodiments, antisense compounds useful for inhibiting growth or proliferation of a prostate cancer cell resistant to anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, can target (i) human androgen receptor upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain or (ii) an AR splicing variant that has a functional DNA binding domain, but not a functional ligand binding domain; and/or is capable of (i) reducing expression of both full-length AR and an AR splicing variant that includes exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of any one of exons 4-8 encoding the ligand binding domain; or (ii) inhibiting growth or proliferation of the resistant prostate cancer cell to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176; with the proviso that the antisense compounds do not have a nucleobase sequence consisting of any of SEQ ID NOs: 194-215 described in U.S. Pat. No. 7,737,125 as SEQ ID NOs: 2-9, 49-50, 52-53, 55-56, and 86-93 (herein incorporated by reference), and identified in Table A.

Certain aspects are directed to methods of treating breast cancer and methods of inhibiting breast cancer cell growth or proliferation with an antisense oligonucleotide targeted to human androgen receptor (AR) as described herein. In certain embodiments, the breast cancer has one or more of the following characteristics: Androgen Receptor positive, dependent on androgen for growth, Estrogen Receptor (ER) negative, independent of estrogen for growth, Progesterone Receptor (PR) negative, independent of progesterone for growth, or Her2/neu negative. In certain embodiments, the breast cancer or breast cancer cell is apocrine.

Certain embodiments are drawn to a method of treating breast cancer in a subject comprising administering to the subject an antisense compound targeted to human androgen receptor (AR). Certain embodiments are drawn to a method of treating breast cancer in a subject comprising identifying a subject having breast cancer and administering to the subject an antisense compound targeted to human androgen receptor (AR), thereby treating the subject's breast cancer. Certain embodiments are directed to a method of inhibiting growth or proliferation of a breast cancer cell comprising contacting the breast cancer cell with an antisense compound targeted to human androgen receptor (AR). Certain embodiments relate to a method of inhibiting AR expression in a subject having or at risk of having breast cancer comprising identifying a subject breast cancer, and administering to the subject an antisense compound targeted to human AR, wherein the antisense compound inhibits AR expression in the subject.

In certain embodiments, the breast cancer or breast cancer cell has one or more of the following characteristics: Androgen Receptor positive, dependent on androgen for growth, Estrogen Receptor (ER) negative, independent of estrogen for growth, Progesterone Receptor (PR) negative, independent of progesterone for growth, or Her2/neu negative. In certain embodiments, the breast cancer or breast cancer cell is ER, PR, and HER2 triple negative and AR positive (ER-, PR-, HER2-, AR+). In certain embodiments, the breast cancer or breast cancer cell is ER negative and AR positive (ER-, AR+). In certain embodiments, the breast cancer or breast cancer cell is ER positive and AR positive (ER+, AR+).

In certain embodiments, the breast cancer or breast cancer cell is apocrine. Apocrine breast cancers are often "triple negative", meaning that the cells do not express ER, PR, or HER2 receptors, and usually, but not necessarily, AR positive. In certain embodiments, an apocrine breast cancer or breast cancer cell is ER, PR, and HER2 triple negative and AR positive (ER-, PR-, HER2-, AR+). In certain embodiments, an apocrine breast cancer or breast cancer cell is ER negative and AR positive (ER-, AR+). In certain embodiments, an apocrine breast cancer or breast cancer cell originates from the sweat gland of the breast. In certain embodiments, an apocrine breast cancer or breast cancer cell is a ductal cancer or cancer cell of the breast. In certain embodiments, an apocrine breast cancer can have any one or more of the following features: a large amount of eosinophilic granular cytoplasm, well-defined margins, large vesicular nuclei, a nuclear to cytoplasmic ratio of about 1:2, and/or accumulations of secreted granules in the apical cytoplasm known as apical snouts.

In certain embodiments, the breast cancer or breast cancer cell is an ER negative and AR positive (ER-, AR+) molecular apocrine breast cancer or breast cancer cell. In certain aspects, an ER negative and AR positive (ER-, AR+) molecular apocrine breast cancer or breast cancer cell can further be PR positive, PR negative, HER2 negative, or HER2 positive.

Breast cancer can be identified as positive or negative with respect to hormone receptors, such as ER, PR, or HER2 by standard histological techniques. For example, histological breast cancer samples can be classified as "triple negative" (ER-, PR-, HER2-) when less than 1% of cells demonstrate nuclear staining for estrogen and progesterone receptors, and immunohistochemical staining for HER2 shows a 0, 1-fold, or a 2-fold positive score and a FISH ratio (HER2 gene signals to chromosome 17 signals) of less than 1.8 according to the relevant ASCO and CAP guidelines. (Meyer, P. et al., PLoS ONE 7(5): e38361 (2012)).

In certain embodiments, an antisense compound useful for treating breast cancer or inhibiting growth or proliferation of a breast cancer cell target provided herein targets AR within exon 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within exon 1, for example within nucleotide regions 2863-5593 (exon 1) or 27672-27853 (exon 1B) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 3353-3368, 3361-3376, 3519-3534, 3735-3750, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3888-3903, 4047-4062, 4062-4077, 4109-4124, 4534-4549, 4537-4552, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4655-4670, 4750-4765, 4752-4767, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4872-4887, 4874-4889, 4876-4891, 4916-4931, 4918-4933, 5052-5067, 5054-5069, 5060-5075, 5061-5076, 5061-5076, 5062-5077, 5155-5170, 5265-5280, 5293-5308, 5392-5407, 5448-5463, 5483-5498, 5486-5501, or 5494-5509.

In certain embodiments, an antisense compound provided herein targets AR within exon 2, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound useful for treating breast cancer or inhibiting growth or proliferation of a breast cancer cell target provided herein targets AR within exon 2, for example within nucleotide regions 102087-102238 (exon 2) or 139551-139834 (exon 2c) of SEQ ID NO: 1. In certain embodiments, an antisense compound provided herein targeted to exon 2 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 102155-102170 or 102156-107171.

In certain aspects, an antisense compound useful for treating breast cancer or inhibiting growth or proliferation of a breast cancer cell provided herein targets AR within intron 1, which is upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, an antisense compound provided herein targets AR within intron 1, for example within nucleotide regions 5594-27671 or 27854-102086 of SEQ ID NO: 1. In certain aspects, an antisense compound provided herein targeted to intron 1 of AR is complementary within any of the following nucleotide regions of SEQ ID NO: 1: 5666-5681, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58735, 58721-58736, 58722-58737, 58723-58738, 58725-58740, 58750-58765, 58751-58766, 58752-58767, 58753-58768, 58754-58769, or 58755-58770.

In certain aspects of any of the foregoing embodiments, antisense compounds useful for treating breast cancer or inhibiting growth or proliferation of a breast cancer cell target human androgen receptor upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain. In certain embodiments, antisense compounds provided herein, including but not limited to those that target human androgen receptor upstream of the 3' end of exon 3 and/or upstream of the ligand binding domain, can treat breast cancer or inhibiting growth or proliferation of a breast cancer cell to a greater extent than an antisense compound targeted to the ligand binding domain, such as EZN-4176; with the proviso that the antisense compounds do not have a nucleobase sequence consisting of any of SEQ ID NOs: 194-215 described in U.S. Pat. No. 7,737,125 as SEQ ID NOs: 2-9, 49-50, 52-53, 55-56, and 86-93 (herein incorporated by reference), and identified in Table A.

Antisense Compounds

Oligomeric compounds include, but are not limited to, oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics, antisense compounds, antisense oligonucleotides, and siRNAs. An oligomeric compound may be "antisense" to a target nucleic acid, meaning that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding.

In certain embodiments, an antisense compound has a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted. In certain such embodiments, an antisense oligonucleotide has a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted.

In certain embodiments, an antisense compound is 10-30 subunits in length. In certain embodiments, an antisense compound is 12 to 30 subunits in length. In certain embodiments, an antisense compound is 12 to 22 subunits in length. In certain embodiments, an antisense compound is 14 to 30 subunits in length. In certain embodiments, an antisense compound is 14 to 20 subunits in length. In certain embodiments, an antisense compound is 15 to 30 subunits in length. In certain embodiments, an antisense compound is 15 to 20 subunits in length. In certain embodiments, an antisense compound is 16 to 30 subunits in length. In certain embodiments, an antisense compound is 16 to 20 subunits in length. In certain embodiments, an antisense compound is 17 to 30 subunits in length. In certain embodiments, an antisense compound is 17 to 20 subunits in length. In certain embodiments, an antisense compound is 18 to 30 subunits in length. In certain embodiments, an antisense compound is 18 to 21 subunits in length. In certain embodiments, an antisense compound is 18 to 20 subunits in length. In certain embodiments, an antisense compound is 20 to 30 subunits in length. In other words, such antisense compounds are from 12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to 20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linked subunits, respectively. In certain embodiments, an antisense compound is 14 subunits in length. In certain embodiments, an antisense compound is 16 subunits in length. In certain embodiments, an antisense compound is 17 subunits in length. In certain embodiments, an antisense compound is 18 subunits in length. In certain embodiments, an antisense compound is 20 subunits in length. In other embodiments, the antisense compound is 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. In certain such embodiments, the antisense compounds are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits in length, or a range defined by any two of the above values. In some embodiments the antisense compound is an antisense oligonucleotide, and the linked subunits are nucleotides.

In certain embodiments antisense oligonucleotides may be shortened or truncated. For example, a single subunit may be deleted from the 5' end (5' truncation), or alternatively from the 3' end (3' truncation). A shortened or truncated antisense compound targeted to an Androgen Receptor nucleic acid may have two subunits deleted from the 5' end, or alternatively may have two subunits deleted from the 3' end, of the antisense compound. Alternatively, the deleted nucleosides may be dispersed throughout the antisense compound, for example, in an antisense compound having one nucleoside deleted from the 5' end and one nucleoside deleted from the 3' end.

When a single additional subunit is present in a lengthened antisense compound, the additional subunit may be located at the 5' or 3' end of the antisense compound. When two or more additional subunits are present, the added subunits may be adjacent to each other, for example, in an antisense compound having two subunits added to the 5' end (5' addition), or alternatively to the 3' end (3' addition), of the antisense compound. Alternatively, the added subunits may be dispersed throughout the antisense compound, for example, in an antisense compound having one subunit added to the 5' end and one subunit added to the 3' end.

It is possible to increase or decrease the length of an antisense compound, such as an antisense oligonucleotide, and/or introduce mismatch bases without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of antisense oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Antisense oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the antisense oligonucleotides were able to direct specific cleavage of the target mRNA, albeit to a lesser extent than the antisense oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase antisense oligonucleotides, including those with 1 or 3 mismatches.

Gautschi et al. (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo.

Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase antisense oligonucleotides, and a 28 and 42 nucleobase antisense oligonucleotides comprised of the sequence of two or three of the tandem antisense oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase antisense oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase antisense oligonucleotides.

Certain Antisense Compound Motifs and Mechanisms

In certain embodiments, antisense compounds have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

Chimeric antisense compounds typically contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense compound may confer another desired property e.g., serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex.

Antisense activity may result from any mechanism involving the hybridization of the antisense compound (e.g., oligonucleotide) with a target nucleic acid, wherein the hybridization ultimately results in a biological effect. In certain embodiments, the amount and/or activity of the target nucleic acid is modulated. In certain embodiments, the amount and/or activity of the target nucleic acid is reduced. In certain embodiments, hybridization of the antisense compound to the target nucleic acid ultimately results in target nucleic acid degradation. In certain embodiments, hybridization of the antisense compound to the target nucleic acid does not result in target nucleic acid degradation. In certain such embodiments, the presence of the antisense compound hybridized with the target nucleic acid (occupancy) results in a modulation of antisense activity. In certain embodiments, antisense compounds having a particular chemical motif or pattern of chemical modifications are particularly suited to exploit one or more mechanisms. In certain embodiments, antisense compounds function through more than one mechanism and/or through mechanisms that have not been elucidated. Accordingly, the antisense compounds described herein are not limited by particular mechanism.

Antisense mechanisms include, without limitation, RNase H mediated antisense; RNAi mechanisms, which utilize the RISC pathway and include, without limitation, siRNA, ssRNA and microRNA mechanisms; and occupancy based mechanisms. Certain antisense compounds may act through more than one such mechanism and/or through additional mechanisms.

RNase H-Mediated Antisense

In certain embodiments, antisense activity results at least in part from degradation of target RNA by RNase H. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are "DNA-like" elicit RNase H activity in mammalian cells. Accordingly, antisense compounds comprising at least a portion of DNA or DNA-like nucleosides may activate RNase H, resulting in cleavage of the target nucleic acid. In certain embodiments, antisense compounds that utilize RNase H comprise one or more modified nucleosides. In certain embodiments, such antisense compounds comprise at least one block of 1-8 modified nucleosides. In certain such embodiments, the modified nucleosides do not support RNase H activity. In certain embodiments, such antisense compounds are gapmers, as described herein. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA-like nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides and DNA-like nucleosides.

Certain antisense compounds having a gapmer motif are considered chimeric antisense compounds. In a gapmer an internal region having a plurality of nucleotides that supports RNaseH cleavage is positioned between external regions having a plurality of nucleotides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment generally serves as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. In certain embodiments, the regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer may in some embodiments include .beta.-D-ribonucleosides, .beta.-D-deoxyribonucleosides, 2'-modified nucleosides (such 2'-modified nucleosides may include 2'-MOE and 2'-O--CH.sub.3, among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a constrained ethyl). In certain embodiments, nucleosides in the wings may include several modified sugar moieties, including, for example 2'-MOE and bicyclic sugar moieties such as constrained ethyl or LNA. In certain embodiments, wings may include several modified and unmodified sugar moieties. In certain embodiments, wings may include various combinations of 2'-MOE nucleosides, bicyclic sugar moieties such as constrained ethyl nucleosides or LNA nucleosides, and 2'-deoxynucleosides.

Each distinct region may comprise uniform sugar moieties, variant, or alternating sugar moieties. The wing-gap-wing motif is frequently described as "X-Y-Z", where "X" represents the length of the 5'-wing, "Y" represents the length of the gap, and "Z" represents the length of the 3'-wing. "X" and "Z" may comprise uniform, variant, or alternating sugar moieties. In certain embodiments, "X" and "Y" may include one or more 2'-deoxynucleosides. "Y" may comprise 2'-deoxynucleosides. As used herein, a gapmer described as "X-Y-Z" has a configuration such that the gap is positioned immediately adjacent to each of the 5'-wing and the 3' wing. Thus, no intervening nucleotides exist between the 5'-wing and gap, or the gap and the 3'-wing. Any of the antisense compounds described herein can have a gapmer motif. In certain embodiments, "X" and "Z" are the same; in other embodiments they are different. In certain embodiments, "Y" is between 8 and 15 nucleosides. X, Y, or Z can be any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 or more nucleosides.

In certain embodiments, the antisense compound targeted to an Androgen Receptor nucleic acid has a gapmer motif in which the gap consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 linked nucleosides.

In certain embodiments, the antisense oligonucleotide has a sugar motif described by Formula A as follows: (J).sub.m-(B).sub.n-(J).sub.p-(B).sub.r-(A).sub.t-(D).sub.g-(A).sub.v-(B)- .sub.w-(J).sub.x-(B).sub.y-(J).sub.z

wherein:

each A is independently a 2'-substituted nucleoside;

each B is independently a bicyclic nucleoside;

each J is independently either a 2'-substituted nucleoside or a 2'-deoxynucleoside; each D is a 2'-deoxynucleoside;

m is 0-4; n is 0-2; p is 0-2; r is 0-2; t is 0-2; v is 0-2; w is 0-4; x is 0-2; y is 0-2; z is 0-4; g is 6-14; provided that:

at least one of m, n, and r is other than 0;

at least one of w and y is other than 0;

the sum of m, n, p, r, and t is from 2 to 5; and

the sum of v, w, x, y, and z is from 2 to 5.

RNAi Compounds

In certain embodiments, antisense compounds are interfering RNA compounds (RNAi), which include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and/or sequester a target nucleic acid (thus, include microRNA/microRNA-mimic compounds). In certain embodiments, antisense compounds comprise modifications that make them particularly suited for such mechanisms.

i. ssRNA Compounds

In certain embodiments, antisense compounds including those particularly suited for use as single-stranded RNAi compounds (ssRNA) comprise a modified 5'-terminal end. In certain such embodiments, the 5'-terminal end comprises a modified phosphate moiety. In certain embodiments, such modified phosphate is stabilized (e.g., resistant to degradation/cleavage compared to unmodified 5'-phosphate). In certain embodiments, such 5'-terminal nucleosides stabilize the 5'-phosphorous moiety. Certain modified 5'-terminal nucleosides may be found in the art, for example in WO/2011/139702.

In certain embodiments, the 5'-nucleoside of an ssRNA compound has Formula IIc:

##STR00009## wherein:

T.sub.1 is an optionally protected phosphorus moiety;

T.sub.2 is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound;

A has one of the formulas:

##STR00010##

Q.sub.1 and Q.sub.2 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or N(R.sub.3)(R.sub.4);

Q.sub.3 is O, S, N(R.sub.5) or C(R.sub.6)(R.sub.7);

each R.sub.3, R.sub.4 R.sub.5, R.sub.6 and R.sub.7 is, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy;

M.sub.3 is O, S, NR.sub.14, C(R.sub.15)(R.sub.16), C(R.sub.15)(R.sub.16)C(R.sub.17)(R.sub.18), C(R.sub.15).dbd.C(R.sub.17), OC(R.sub.15)(R.sub.16) or OC(R.sub.15)(Bx.sub.2);

R.sub.14 is H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

R.sub.15, R.sub.16, R.sub.17 and R.sub.18 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

Bx.sub.1 is a heterocyclic base moiety;

or if Bx.sub.2 is present then Bx.sub.2 is a heterocyclic base moiety and Bx.sub.1 is H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

J.sub.4, J.sub.5, J.sub.6 and J.sub.7 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

or J.sub.4 forms a bridge with one of J.sub.5 or J.sub.7 wherein said bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR.sub.19, C(R.sub.20)(R.sub.21), C(R.sub.20).dbd.C(R.sub.21), C[.dbd.C(R.sub.20)(R.sub.21)] and C(.dbd.O) and the other two of J.sub.5, J.sub.6 and J.sub.7 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

each R.sub.19, R.sub.20 and R.sub.21 is, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

G is H, OH, halogen or O--[C(R.sub.8)(R.sub.6)].sub.n--[(C.dbd.O).sub.m--X.sub.1].sub.j--Z;

each R.sub.8 and R.sub.9 is, independently, H, halogen, C.sub.1-C.sub.6 alkyl or substituted C.sub.1-C.sub.6 alkyl;

X.sub.1 is O, S or N(E.sub.1);

Z is H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or N(E.sub.2)(E.sub.3);

E.sub.1, E.sub.2 and E.sub.3 are each, independently, H, C.sub.1-C.sub.6 alkyl or substituted C.sub.1-C.sub.6 alkyl;

n is from 1 to about 6;

m is 0 or 1;

j is 0 or 1;

each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ.sub.1, N(J.sub.1)(J.sub.2), .dbd.NJ.sub.1, SJ.sub.1, N.sub.3, CN, OC(.dbd.X.sub.2)J.sub.1, OC(.dbd.X.sub.2)N(J.sub.1)(J.sub.2) and C(.dbd.X.sub.2)N(J.sub.1)(J.sub.2);

X.sub.2 is O, S or NJ.sub.3;

each J.sub.1, J.sub.2 and J.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl; when j is 1 then Z is other than halogen or N(E.sub.2)(E.sub.3); and

wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid.

In certain embodiments, M.sub.3 is O, CH.dbd.CH, OCH.sub.2 or OC(H)(Bx.sub.2). In certain embodiments, M.sub.3 is O.

In certain embodiments, J.sub.4, J.sub.5, J.sub.6 and J.sub.7 are each H. In certain embodiments, J.sub.4 forms a bridge with one of J.sub.5 or J.sub.7.

In certain embodiments, A has one of the formulas:

##STR00011## wherein:

Q.sub.1 and Q.sub.2 are each, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or substituted C.sub.1-C.sub.6 alkoxy. In certain embodiments, Q.sub.1 and Q.sub.2 are each H. In certain embodiments, Q.sub.1 and Q.sub.2 are each, independently, H or halogen. In certain embodiments, Q.sub.1 and Q.sub.2 is H and the other of Q.sub.1 and Q.sub.2 is F, CH.sub.3 or OCH.sub.3.

In certain embodiments, T.sub.1 has the formula:

##STR00012## wherein:

R.sub.a and R.sub.c are each, independently, protected hydroxyl, protected thiol, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, protected amino or substituted amino; and

R.sub.b is O or S. In certain embodiments, R.sub.b is O and R.sub.a and R.sub.c are each, independently, OCH.sub.3, OCH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2.

In certain embodiments, G is halogen, OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, OCH.sub.2CH.sub.3, O(CH.sub.2).sub.2F, OCH.sub.2CHF.sub.2, OCH.sub.2CF.sub.3, OCH.sub.2--CH.dbd.CH.sub.2, O(CH.sub.2).sub.2--OCH.sub.3, O(CH.sub.2).sub.2--SCH.sub.3, O(CH.sub.2).sub.2--OCF.sub.3, O(CH.sub.2).sub.3--N(R.sub.10)(R.sub.11), O(CH.sub.2).sub.2--ON(R.sub.10)(R.sub.11), O(CH.sub.2).sub.2--O(CH.sub.2).sub.2--N(R.sub.10)(R.sub.11), OCH.sub.2C(.dbd.O)--N(R.sub.10)(R.sub.11), OCH.sub.2C(.dbd.O)--N(R.sub.12)--(CH.sub.2).sub.2--N(R.sub.10)(R.sub.11) or O(CH.sub.2).sub.2--N(R.sub.12)--C(.dbd.NR.sub.13)[N(R.sub.10)(R.sub.11- )] wherein R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are each, independently, H or C.sub.1-C.sub.6 alkyl. In certain embodiments, G is halogen, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CF.sub.3, OCH.sub.2--CH.dbd.CH.sub.2, O(CH.sub.2).sub.2--OCH.sub.3, O(CH.sub.2).sub.2--O(CH.sub.2).sub.2--N(CH.sub.3).sub.2, OCH.sub.2C(.dbd.O)--N(H)CH.sub.3, OCH.sub.2C(.dbd.O)--N(H)--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 or OCH.sub.2--N(H)--C(.dbd.NH)NH.sub.2. In certain embodiments, G is F, OCH.sub.3 or O(CH.sub.2).sub.2--OCH.sub.3. In certain embodiments, G is O(CH.sub.2).sub.2--OCH.sub.3.

In certain embodiments, the 5'-terminal nucleoside has Formula IIe:

##STR00013##

In certain embodiments, antisense compounds, including those particularly suitable for ssRNA comprise one or more type of modified sugar moieties and/or naturally occurring sugar moieties arranged along an oligonucleotide or region thereof in a defined pattern or sugar modification motif Such motifs may include any of the sugar modifications discussed herein and/or other known sugar modifications.

In certain embodiments, the oligonucleotides comprise or consist of a region having uniform sugar modifications. In certain such embodiments, each nucleoside of the region comprises the same RNA-like sugar modification. In certain embodiments, each nucleoside of the region is a 2'-F nucleoside. In certain embodiments, each nucleoside of the region is a 2'-OMe nucleoside. In certain embodiments, each nucleoside of the region is a 2'-MOE nucleoside. In certain embodiments, each nucleoside of the region is a cEt nucleoside. In certain embodiments, each nucleoside of the region is an LNA nucleoside. In certain embodiments, the uniform region constitutes all or essentially all of the oligonucleotide. In certain embodiments, the region constitutes the entire oligonucleotide except for 1-4 terminal nucleosides.

In certain embodiments, oligonucleotides comprise one or more regions of alternating sugar modifications, wherein the nucleosides alternate between nucleotides having a sugar modification of a first type and nucleotides having a sugar modification of a second type. In certain embodiments, nucleosides of both types are RNA-like nucleosides. In certain embodiments the alternating nucleosides are selected from: 2'-OMe, 2'-F, 2'-MOE, LNA, and cEt. In certain embodiments, the alternating modificatios are 2'-F and 2'-OMe. Such regions may be contiguous or may be interupted by differently modified nucleosides or conjugated nucleosides.

In certain embodiments, the alternating region of alternating modifications each consist of a single nucleoside (i.e., the patern is (AB).sub.xA.sub.y wheren A is a nucleoside having a sugar modification of a first type and B is a nucleoside having a sugar modification of a second type; x is 1-20 and y is 0 or 1). In certain embodiments, one or more alternating regions in an alternating motif includes more than a single nucleoside of a type. For example, oligonucleotides may include one or more regions of any of the following nucleoside motifs:

TABLE-US-00002 AABBAA; ABBABB; AABAAB; ABBABAABB; ABABAA; AABABAB; ABABAA; ABBAABBABABAA; BABBAABBABABAA; or ABABBAABBABABAA;

wherein A is a nucleoside of a first type and B is a nucleoside of a second type. In certain embodiments, A and B are each selected from 2'-F, 2'-OMe, BNA, and MOE.

In certain embodiments, oligonucleotides having such an alternating motif also comprise a modified 5' terminal nucleoside, such as those of formula IIc or IIe.

In certain embodiments, oligonucleotides comprise a region having a 2-2-3 motif Such regions comprises the following motif: -(A).sub.2-(B).sub.x-(A).sub.2-(C).sub.y-(A).sub.3-

wherein: A is a first type of modifed nucleosde;

B and C, are nucleosides that are differently modified than A, however, B and C may have the same or different modifications as one another;

x and y are from 1 to 15.

In certain embodiments, A is a 2'-OMe modified nucleoside. In certain embodiments, B and C are both 2'-F modified nucleosides. In certain embodiments, A is a 2'-OMe modified nucleoside and B and C are both 2'-F modified nucleosides.

In certain embodiments, oligonucleosides have the following sugar motif: 5'-(Q)-(AB).sub.xA.sub.y-(D).sub.z wherein:

Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or IIe;

A is a first type of modifed nucleoside;

B is a second type of modified nucleoside;

D is a modified nucleoside comprising a modification different from the nucleoside adjacent to it. Thus, if y is 0, then D must be differently modified than B and if y is 1, then D must be differently modified than A. In certain embodiments, D differs from both A and B.

X is 5-15; Y is 0 or 1;

Z is 0-4.

In certain embodiments, oligonucleosides have the following sugar motif: 5'-(Q)-(A).sub.x-(D).sub.z wherein:

Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or IIe;

A is a first type of modifed nucleoside;

D is a modified nucleoside comprising a modification different from A.

X is 11-30;

Z is 0-4.

In certain embodiments A, B, C, and D in the above motifs are selected from: 2'-OMe, 2'-F, 2'-MOE, LNA, and cEt. In certain embodiments, D represents terminal nucleosides. In certain embodiments, such terminal nucleosides are not designed to hybridize to the target nucleic acid (though one or more might hybridize by chance). In certain embodiments, the nucleobase of each D nucleoside is adenine, regardless of the identity of the nucleobase at the corresponding position of the target nucleic acid. In certain embodiments the nucleobase of each D nucleoside is thymine.

In certain embodiments, antisense compounds, including those particularly suited for use as ssRNA comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphoro-thioate internucleoside linkages. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 12 consecutive phosphoro-thioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3' end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3' end of the oligonucleotide.

Oligonucleotides having any of the various sugar motifs described herein, may have any linkage motif. For example, the oligonucleotides, including but not limited to those described above, may have a linkage motif selected from non-limiting the table below:

TABLE-US-00003 5` most linkage Central region 3`-region PS Alternating PO/PS 6 PS PS Alternating PO/PS 7 PS PS Alternating PO/PS 8 PS

ii. siRNA Compounds

In certain embodiments, antisense compounds are double-stranded RNAi compounds (siRNA). In such embodiments, one or both strands may comprise any modification motif described above for ssRNA. In certain embodiments, ssRNA compounds may be unmodified RNA. In certain embodiments, siRNA compounds may comprise unmodified RNA nucleosides, but modified internucleoside linkages.

Several embodiments relate to double-stranded compositions wherein each strand comprises a motif defined by the location of one or more modified or unmodified nucleosides. In certain embodiments, compositions are provided comprising a first and a second oligomeric compound that are fully or at least partially hybridized to form a duplex region and further comprising a region that is complementary to and hybridizes to a nucleic acid target. It is suitable that such a composition comprise a first oligomeric compound that is an antisense strand having full or partial complementarity to a nucleic acid target and a second oligomeric compound that is a sense strand having one or more regions of complementarity to and forming at least one duplex region with the first oligomeric compound.

The compositions of several embodiments modulate gene expression by hybridizing to a nucleic acid target resulting in loss of its normal function. In some embodiments, the target nucleic acid is Androgen Receptor. In certain embodiment, the degradation of the targeted Androgen Receptor is facilitated by an activated RISC complex that is formed with compositions of the invention.

Several embodiments are directed to double-stranded compositions wherein one of the strands is useful in, for example, influencing the preferential loading of the opposite strand into the RISC (or cleavage) complex. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In some embodiments, the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Certain embodiments are drawn to double-stranded compositions wherein both the strands comprises a hemimer motif, a fully modified motif, a positionally modified motif or an alternating motif Each strand of the compositions of the present invention can be modified to fulfil a particular role in for example the siRNA pathway. Using a different motif in each strand or the same motif with different chemical modifications in each strand permits targeting the antisense strand for the RISC complex while inhibiting the incorporation of the sense strand. Within this model, each strand can be independently modified such that it is enhanced for its particular role. The antisense strand can be modified at the 5'-end to enhance its role in one region of the RISC while the 3'-end can be modified differentially to enhance its role in a different region of the RISC.

The double-stranded oligonucleotide molecules can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide molecules can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e. each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double-stranded structure, for example wherein the double-stranded region is about 15 to about 30, e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 base pairs; the antisense strand comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof (e.g., about 15 to about 25 or more nucleotides of the double-stranded oligonucleotide molecule are complementary to the target nucleic acid or a portion thereof). Alternatively, the double-stranded oligonucleotide is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siRNA are linked by means of a nucleic acid based or non-nucleic acid-based linker(s).

The double-stranded oligonucleotide can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNAi.

In certain embodiments, the double-stranded oligonucleotide comprises separate sense and antisense sequences or regions, wherein the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der waals interactions, hydrophobic interactions, and/or stacking interactions. In certain embodiments, the double-stranded oligonucleotide comprises nucleotide sequence that is complementary to nucleotide sequence of a target gene. In another embodiment, the double-stranded oligonucleotide interacts with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene.

As used herein, double-stranded oligonucleotides need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non-nucleotides. In certain embodiments, the short interfering nucleic acid molecules lack 2'-hydroxy (2'-OH) containing nucleotides. In certain embodiments short interfering nucleic acids optionally do not include any ribonucleotides (e.g., nucleotides having a 2'-OH group). Such double-stranded oligonucleotides that do not require the presence of ribonucleotides within the molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. Optionally, double-stranded oligonucleotides can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions. As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics. For example, double-stranded oligonucleotides can be used to epigenetically silence genes at both the post-transcriptional level and the pre-transcriptional level. In a non-limiting example, epigenetic regulation of gene expression by siRNA molecules of the invention can result from siRNA mediated modification of chromatin structure or methylation pattern to alter gene expression (see, for example, Verdel et al., 2004, Science, 303, 672-676; Pal-Bhadra et al., 2004, Science, 303, 669-672; Allshire, 2002, Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237).

It is contemplated that compounds and compositions of several embodiments provided herein can target Androgen Receptor by a dsRNA-mediated gene silencing or RNAi mechanism, including, e.g., "hairpin" or stem-loop double-stranded RNA effector molecules in which a single RNA strand with self-complementary sequences is capable of assuming a double-stranded conformation, or duplex dsRNA effector molecules comprising two separate strands of RNA. In various embodiments, the dsRNA consists entirely of ribonucleotides or consists of a mixture of ribonucleotides and deoxynucleotides, such as the RNA/DNA hybrids disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. The dsRNA or dsRNA effector molecule may be a single molecule with a region of self-complementarity such that nucleotides in one segment of the molecule base pair with nucleotides in another segment of the molecule. In various embodiments, a dsRNA that consists of a single molecule consists entirely of ribonucleotides or includes a region of ribonucleotides that is complementary to a region of deoxyribonucleotides. Alternatively, the dsRNA may include two different strands that have a region of complementarity to each other.

In various embodiments, both strands consist entirely of ribonucleotides, one strand consists entirely of ribonucleotides and one strand consists entirely of deoxyribonucleotides, or one or both strands contain a mixture of ribonucleotides and deoxyribonucleotides. In certain embodiments, the regions of complementarity are at least 70, 80, 90, 95, 98, or 100% complementary to each other and to a target nucleic acid sequence. In certain embodiments, the region of the dsRNA that is present in a double-stranded conformation includes at least 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 75, 100, 200, 500, 1000, 2000 or 5000 nucleotides or includes all of the nucleotides in a cDNA or other target nucleic acid sequence being represented in the dsRNA. In some embodiments, the dsRNA does not contain any single stranded regions, such as single stranded ends, or the dsRNA is a hairpin. In other embodiments, the dsRNA has one or more single stranded regions or overhangs. In certain embodiments, RNA/DNA hybrids include a DNA strand or region that is an antisense strand or region (e.g, has at least 70, 80, 90, 95, 98, or 100% complementarity to a target nucleic acid) and an RNA strand or region that is a sense strand or region (e.g, has at least 70, 80, 90, 95, 98, or 100% identity to a target nucleic acid), and vice versa.

In various embodiments, the RNA/DNA hybrid is made in vitro using enzymatic or chemical synthetic methods such as those described herein or those described in WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. In other embodiments, a DNA strand synthesized in vitro is complexed with an RNA strand made in vivo or in vitro before, after, or concurrent with the transformation of the DNA strand into the cell. In yet other embodiments, the dsRNA is a single circular nucleic acid containing a sense and an antisense region, or the dsRNA includes a circular nucleic acid and either a second circular nucleic acid or a linear nucleic acid (see, for example, WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.) Exemplary circular nucleic acids include lariat structures in which the free 5' phosphoryl group of a nucleotide becomes linked to the 2' hydroxyl group of another nucleotide in a loop back fashion.

In other embodiments, the dsRNA includes one or more modified nucleotides in which the 2' position in the sugar contains a halogen (such as fluorine group) or contains an alkoxy group (such as a methoxy group) which increases the half-life of the dsRNA in vitro or in vivo compared to the corresponding dsRNA in which the corresponding 2' position contains a hydrogen or an hydroxyl group. In yet other embodiments, the dsRNA includes one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The dsRNAs may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the dsRNA contains one or two capped strands, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.

In other embodiments, the dsRNA can be any of the at least partially dsRNA molecules disclosed in WO 00/63364, as well as any of the dsRNA molecules described in U.S. Provisional Application 60/399,998; and U.S. Provisional Application 60/419,532, and PCT/US2003/033466, the teaching of which is hereby incorporated by reference. Any of the dsRNAs may be expressed in vitro or in vivo using the methods described herein or standard methods, such as those described in WO 00/63364.

Occupancy

In certain embodiments, antisense compounds are not expected to result in cleavage or the target nucleic acid via RNase H or to result in cleavage or sequestration through the RISC pathway. In certain such embodiments, antisense activity may result from occupancy, wherein the presence of the hybridized antisense compound disrupts the activity of the target nucleic acid. In certain such embodiments, the antisense compound may be uniformly modified or may comprise a mix of modifications and/or modified and unmodified nucleosides.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

Nucleotide sequences that encode human Androgen Receptor include, without limitation, the following: GENBANK Accession No. NT_011669.17_TRUNC_5079000_5270000 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NM_000044.3 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No. NM_001011645.2 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. FJ235916.1 (incorporated herein as SEQ ID NO: 4), GENBANK Accession No. FJ235917.1 (incorporated herein as SEQ ID NO: 5), GENBANK Accession No. FJ235918.1 (incorporated herein as SEQ ID NO: 6), GENBANK Accession No. FJ235919.1 (incorporated herein as SEQ ID NO: 7), and GENBANK Accession No. FJ235920.1 (incorporated herein as SEQ ID NO: 8).

Androgen Receptor mRNA encodes several functional domains. In certain embodiments, full-length Androgen Receptor mRNA includes exon 1 encoding the N-terminal domain, exons 2 and 3 encoding the DNA binding domain, exon 4 encoding the short hinge region, and exons 4-8 encoding the ligand binding domain.

In certain embodiments, Androgen Receptor splicing variants targetable by the antisense compounds provided herein include exon 1 encoding the N-terminal domain and exons 2 and 3 encoding the DNA binding domain, or functional portions thereof, but does not include at least a portion of exon 4 encoding the short hinge region or at least a portion of exons 4-8 encoding the ligand binding domain. Examples of such AR splicing variants include, but are not limited to, AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, and AR-V7 (also referred to as AR3), which contain exons 1-3 but lack exons 4-8. AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, AR-V7, and additional splicing variants targetable by the antisense compounds provided herein are described in Hu et al., Cancer Res 2009; 69:16-22 and US Patent Application Publication No. US 2010/0068802, each of which is incorporated herein by reference in its entirety. Further examples of such AR splicing variants targetable by the antisense compounds provided herein include, but are not limited to, AR3, AR4, AR4b, AR5, and AR6 (SEQ ID NOs: 4-8, respectively) as described in Guo et al., Cancer Res. 2009; 69: 2305-13, which is incorporated herein by reference in its entirety.

Hybridization

In some embodiments, hybridization occurs between an antisense compound disclosed herein and an Androgen Receptor. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Stringent conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art. In certain embodiments, the antisense compounds provided herein are specifically hybridizable with Androgen Receptor.

Complementarity

An antisense compound and a target nucleic acid are complementary to each other when a sufficient number of nucleobases of the antisense compound can hydrogen bond with the corresponding nucleobases of the target nucleic acid, such that a desired effect will occur (e.g., antisense inhibition of a target nucleic acid, such as an Androgen Receptor nucleic acid).

Non-complementary nucleobases between an antisense compound and an Androgen Receptor nucleic acid may be tolerated provided that the antisense compound remains able to specifically hybridize to a target nucleic acid. Moreover, an antisense compound may hybridize over one or more segments of an Androgen Receptor nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

In certain embodiments, the antisense compounds provided herein, or a specified portion thereof, are, or are at least, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to an Androgen Receptor nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of an antisense compound with a target nucleic acid can be determined using routine methods.

For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having four noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, the antisense compounds provided herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, an antisense compound may be fully complementary to an Androgen Receptor nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein, "fully complementary" means each nucleobase of an antisense compound is capable of precise base pairing with the corresponding nucleobases of a target nucleic acid. For example, a 20 nucleobase antisense compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the antisense compound. Fully complementary can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase antisense compound can be "fully complementary" to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase oligonucleotide is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the antisense compound. At the same time, the entire 30 nucleobase antisense compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the antisense compound are also complementary to the target sequence.

The location of a non-complementary nucleobase may be at the 5' end or 3' end of the antisense compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the antisense compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide.

In certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as an Androgen Receptor nucleic acid, or specified portion thereof.

In certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as an Androgen Receptor nucleic acid, or specified portion thereof.

The antisense compounds provided also include those which are complementary to a portion of a target nucleic acid. As used herein, "portion" refers to a defined number of contiguous (i.e. linked) nucleobases within a region or segment of a target nucleic acid. A "portion" can also refer to a defined number of contiguous nucleobases of an antisense compound. In certain embodiments, the antisense compounds, are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 9 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 10 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 15 nucleobase portion of a target segment. Also contemplated are antisense compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values.

Identity

The antisense compounds provided herein may also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific Isis number, or portion thereof. As used herein, an antisense compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the antisense compounds described herein as well as compounds having non-identical bases relative to the antisense compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the antisense compound. Percent identity of an antisense compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

In certain embodiments, the antisense compounds, or portions thereof, are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the antisense compounds or SEQ ID NOs, or a portion thereof, disclosed herein.

In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

In certain embodiments, a portion of the antisense oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

Modifications

A nucleoside is a base-sugar combination. The nucleobase (also known as base) portion of the nucleoside is normally a heterocyclic base moiety. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2', 3' or 5' hydroxyl moiety of the sugar. Oligonucleotides are formed through the covalent linkage of adjacent nucleosides to one another, to form a linear polymeric oligonucleotide. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside linkages of the oligonucleotide.

Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity.

Chemically modified nucleosides may also be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides.

Modified Internucleoside Linkages

The naturally occuring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodiester linkage. Antisense compounds having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over antisense compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.

Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known.

In certain embodiments, antisense compounds targeted to an Androgen Receptor nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage.

Modified Sugar Moieties

Antisense compounds can optionally contain one or more nucleosides wherein the sugar group has been modified. Such sugar modified nucleosides may impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense compounds. In certain embodiments, nucleosides comprise chemically modified ribofuranose ring moieties. Examples of chemically modified ribofuranose rings include without limitation, addition of substitutent groups (including 5' and 2' substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or C(R.sub.1)(R.sub.2) (R, R.sub.1 and R.sub.2 are each independently H, C.sub.1-C.sub.12 alkyl or a protecting group) and combinations thereof. Examples of chemically modified sugars include 2'-F-5'-methyl substituted nucleoside (see PCT International Application WO 2008/101157 Published on Aug. 21, 2008 for other disclosed 5',2'-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2'-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5'-substitution of a BNA (see PCT International Application WO 2007/134181 Published on Nov. 22, 2007 wherein 4'-(CH.sub.2)--O-2' (LNA) is substituted with for example a 5'-methyl or a 5'-vinyl group).

Examples of nucleosides having modified sugar moieties include without limitation nucleosides comprising 5'-vinyl, 5'-methyl (R or S), 4'-S, 2'-F, 2'-OCH.sub.3, 2'-OCH.sub.2CH.sub.3, 2'-OCH.sub.2CH.sub.2F and 2'-O(CH.sub.2).sub.2OCH.sub.3 substituent groups. The substituent at the 2' position can also be selected from allyl, amino, azido, thio, O-allyl, O--C.sub.1-C.sub.10 alkyl, OCF.sub.3, OCH.sub.2F, O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2--O--N(R.sub.m)(R.sub.n), O--CH.sub.2--C(.dbd.O)--N(R.sub.m)(R.sub.n), and O--CH.sub.2--C(.dbd.O)--N(R.sub.1)--(CH.sub.2).sub.2--N(R.sub.m)(R.sub.n)- , where each R.sub.1, R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl.

As used herein, "bicyclic nucleosides" refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleosides include without limitation nucleosides comprising a bridge between the 4' and the 2' ribosyl ring atoms. In certain embodiments, antisense compounds provided herein include one or more bicyclic nucleosides comprising a 4' to 2' bridge. Examples of such 4' to 2' bridged bicyclic nucleosides, include but are not limited to one of the formulae: 4'-(CH.sub.2)--O-2' (LNA); 4'-(CH.sub.2)--S-2; 4'-(CH.sub.2).sub.2--O-2' (ENA); 4-CH(CH.sub.3)--O-2' (also referred to as constrained ethyl or cEt) and 4'-CH(CH.sub.2OCH.sub.3)--O-2' (and analogs thereof see U.S. Pat. No. 7,399,845, issued on Jul. 15, 2008); 4'-C(CH.sub.3)(CH.sub.3)--O-2' (and analogs thereof see published International Application WO/2009/006478, published Jan. 8, 2009); 4-CH.sub.2--N(OCH.sub.3)-2' (and analogs thereof see published International Application WO/2008/150729, published Dec. 11, 2008); 4-CH.sub.2--O--N(CH.sub.3)-2' (see published U.S. Patent Application US2004-0171570, published Sep. 2, 2004); 4-CH.sub.2--N(R)--O-2', wherein R is H, C.sub.1-C.sub.12 alkyl, or a protecting group (see U.S. Pat. No. 7,427,672, issued on Sep. 23, 2008); 4-CH.sub.2--C--(H)(CH.sub.3)-2' (see Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4-CH.sub.2--C(.dbd.CH.sub.2)-2' (and analogs thereof see published International Application WO 2008/154401, published on Dec. 8, 2008).

Further reports related to bicyclic nucleosides can also be found in published literature (see for example: Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A, 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129(26) 8362-8379; Elayadi et al., Curr. Opinion Invest. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; and Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 7,034,133; 7,053,207; 7,399,845; 7,547,684; and 7,696,345; U.S. Patent Publication No. US2008-0039618; US2009-0012281; U.S. Patent Ser. Nos. 60/989,574; 61/026,995; 61/026,998; 61/056,564; 61/086,231; 61/097,787; and 61/099,844; Published PCT International applications WO 1994/014226; WO 2004/106356; WO 2005/021570; WO 2007/134181; WO 2008/150729; WO 2008/154401; and WO 2009/006478. Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example .alpha.-L-ribofuranose and .beta.-D-ribofuranose (see PCT international application PCT/DK98/00393, published on Mar. 25, 1999 as WO 99/14226).

In certain embodiments, bicyclic sugar moieties of BNA nucleosides include, but are not limited to, compounds having at least one bridge between the 4' and the 2' position of the pentofuranosyl sugar moiety wherein such bridges independently comprises 1 or from 2 to 4 linked groups independently selected from --[C(R.sub.a)(R.sub.b)].sub.n--, --C(R.sub.a).dbd.C(R.sub.b)--, --C(R.sub.a).dbd.N--, --C(.dbd.O)--, --C(.dbd.NR.sub.a)--, --C(.dbd.S)--, --O--, --Si(R.sub.a).sub.2--, --S(.dbd.O).sub.x--, and --N(R.sub.a)--;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R.sub.a and R.sub.b is, independently, H, a protecting group, hydroxyl, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C.sub.5-C.sub.7 alicyclic radical, substituted C.sub.5-C.sub.7 alicyclic radical, halogen, OJ.sub.1, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, COOJ.sub.1, acyl (C(.dbd.O)--H), substituted acyl, CN, sulfonyl (S(.dbd.O).sub.2-J.sub.1), or sulfoxyl (S(.dbd.O)-J.sub.1); and

each J.sub.1 and J.sub.2 is, independently, H, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, acyl (C(.dbd.O)--H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C.sub.1-C.sub.12 aminoalkyl, substituted C.sub.1-C.sub.12 aminoalkyl or a protecting group.

In certain embodiments, the bridge of a bicyclic sugar moiety is --[C(R.sub.a)(R.sub.b)].sub.n--, --[C(R.sub.a)(R.sub.b)].sub.n--O--, --C(R.sub.aR.sub.b)--N(R)--O-- or --C(R.sub.aR.sub.b)--O--N(R)--. In certain embodiments, the bridge is 4-CH.sub.2-2', 4'-(CH.sub.2).sub.2-2', 4'-(CH.sub.2).sub.3-2', 4-CH.sub.2--O-2', 4'-(CH.sub.2).sub.2--O-2', 4-CH.sub.2--O--N(R)-2' and 4-CH.sub.2--N(R)--O-2'- wherein each R is, independently, H, a protecting group or C.sub.1-C.sub.12 alkyl.

In certain embodiments, bicyclic nucleosides are further defined by isomeric configuration. For example, a nucleoside comprising a 4'-2' methylene-oxy bridge, may be in the .alpha.-L configuration or in the .beta.-D configuration. Previously, .alpha.-L-methyleneoxy (4-CH.sub.2--O-2') BNA's have been incorporated into antisense oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372).

In certain embodiments, bicyclic nucleosides include, but are not limited to, (A) .alpha.-L-methyleneoxy (4'-CH.sub.2--O-2') BNA, (B) .beta.-D-methyleneoxy (4'-CH.sub.2--O-2') BNA, (C) ethyleneoxy (4'-(CH.sub.2).sub.2--O-2') BNA, (D) aminooxy (4'-CH.sub.2--O--N(R)-2') BNA, (E) oxyamino (4'-CH.sub.2--N(R)--O-2') BNA, and (F) methyl(methyleneoxy) (4'-CH(CH.sub.3)--O-2') BNA, (G) methylene-thio (4'-CH.sub.2--S-2') BNA, (H) methylene-amino (4'-CH.sub.2--N(R)-2') BNA, (I) methyl carbocyclic (4'-CH.sub.2--CH(CH.sub.3)-2') BNA, (J) propylene carbocyclic (4'-(CH.sub.2).sub.3-2') BNA and (K) vinyl BNA as depicted below:

##STR00014## ##STR00015##

wherein Bx is the base moiety and R is independently H, a protecting group, C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 alkoxy.

In certain embodiments, bicyclic nucleosides are provided having Formula I:

##STR00016## wherein:

Bx is a heterocyclic base moiety;

-Q.sub.a-Q.sub.b-Q.sub.c- is --CH.sub.2--N(R.sub.c)--CH.sub.2--, --C(.dbd.O)--N(R.sub.c)--CH.sub.2--, --CH.sub.2--O--N(R.sub.c)--, --CH.sub.2--N(R.sub.c)--O-- or --N(R.sub.c)--O--CH.sub.2;

R.sub.c is C.sub.1-C.sub.12 alkyl or an amino protecting group; and

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium.

In certain embodiments, bicyclic nucleosides are provided having Formula II:

##STR00017## wherein:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

Z.sub.a is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thio.

In one embodiment, each of the substituted groups is, independently, mono or poly substituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ.sub.c, NJ.sub.cJ.sub.d, SJ.sub.c, N.sub.3, OC(.dbd.X)J.sub.c, and NJ.sub.cC(.dbd.X)NJ.sub.cJ.sub.d, wherein each J.sub.c, J.sub.d and J.sub.c is, independently, H, C.sub.1-C.sub.6 alkyl, or substituted C.sub.1-C.sub.6 alkyl and X is O or NJ.sub.c.

In certain embodiments, bicyclic nucleosides are provided having Formula III:

##STR00018## wherein:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

Z.sub.b is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl or substituted acyl (C(.dbd.O)--).

In certain embodiments, bicyclic nucleosides are provided having Formula IV:

##STR00019## wherein:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

R.sub.d is C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

each q.sub.a, q.sub.b, q.sub.c and q.sub.d is, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxyl, substituted C.sub.1-C.sub.6 alkoxyl, acyl, substituted acyl, C.sub.1-C.sub.6 aminoalkyl or substituted C.sub.1-C.sub.6 aminoalkyl;

In certain embodiments, bicyclic nucleosides are provided having Formula V:

##STR00020## wherein:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

q.sub.a, q.sub.b, q.sub.e and q.sub.f are each, independently, hydrogen, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxy, substituted C.sub.1-C.sub.12 alkoxy, OJ.sub.j, SJ.sub.j, SOJ.sub.j, SO.sub.2J.sub.j, NJ.sub.jJ.sub.k, N.sub.3, CN, C(.dbd.O)OJ.sub.j, C(.dbd.O)NJ.sub.jJ.sub.k, C(.dbd.O)J.sub.j, O--C(.dbd.O)--NJ.sub.jJ.sub.k, N(H)C(.dbd.NH)NJ.sub.jJ.sub.k, N(H)C(.dbd.O)NJ.sub.jJ.sub.k or N(H)C(.dbd.S)NJ.sub.jJ.sub.k;

or q.sub.e and q.sub.f together are .dbd.C(q.sub.g)(q.sub.h);

q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

The synthesis and preparation of the methyleneoxy (4-CH.sub.2--O-2') BNA monomers adenine, cytosine, guanine, 5-methyl-cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition properties have been described (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). Bicyclic nucleic acids (BNAs) and preparation thereof are also described in WO 98/39352 and WO 99/14226.

Analogs of methyleneoxy (4-CH.sub.2--O-2') BNA and 2'-thio-BNAs, have also been prepared (Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222). Preparation of locked nucleoside analogs comprising oligodeoxyribonucleotide duplexes as substrates for nucleic acid polymerases has also been described (Wengel et al., WO 99/14226). Furthermore, synthesis of 2'-amino-BNA, a novel comformationally restricted high-affinity oligonucleotide analog has been described in the art (Singh et al., J. Org. Chem., 1998, 63, 10035-10039). In addition, 2'-amino- and 2'-methylamino-BNA's have been prepared and the thermal stability of their duplexes with complementary RNA and DNA strands has been previously reported.

In certain embodiments, bicyclic nucleosides are provided having Formula VI:

##STR00021## wherein:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

each q.sub.i, q.sub.j, q.sub.k and q.sub.1 is, independently, H, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxyl, substituted C.sub.1-C.sub.12 alkoxyl, OJ.sub.j, SJ.sub.j, SOJ.sub.j, N.sub.3, CN, C(.dbd.O)OJ.sub.j, C(.dbd.O)NJ.sub.jJ.sub.k, C(.dbd.O)J.sub.j, O--C(.dbd.O)NJ.sub.jJ.sub.k, N(H)C(.dbd.NH)NJ.sub.jJ.sub.k, N(H)C(.dbd.O)NJ.sub.jJ.sub.k or N(H)C(.dbd.S)NJ.sub.jJ.sub.k; and q.sub.i and q.sub.j or q.sub.1 and q.sub.k together are .dbd.C(q.sub.g)(q.sub.h), wherein q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

One carbocyclic bicyclic nucleoside having a 4'-(CH.sub.2).sub.3-2' bridge and the alkenyl analog bridge 4'-CH.dbd.CH--CH.sub.2-2' have been described (Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443 and Albaek et al., J. Org. Chem., 2006, 71, 7731-7740). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (Srivastava et al., J. Am. Chem. Soc., 2007, 129(26), 8362-8379).

As used herein, "4'-2' bicyclic nucleoside" or "4' to 2' bicyclic nucleoside" refers to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2' carbon atom and the 4' carbon atom of the sugar ring.

As used herein, "monocylic nucleosides" refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside may be modified or substituted at any position.

As used herein, "2'-modified sugar" means a furanosyl sugar modified at the 2' position. In certain embodiments, such modifications include substituents selected from: a halide, including, but not limited to substituted and unsubstituted alkoxy, substituted and unsubstituted thioalkyl, substituted and unsubstituted amino alkyl, substituted and unsubstituted alkyl, substituted and unsubstituted allyl, and substituted and unsubstituted alkynyl. In certain embodiments, 2' modifications are selected from substituents including, but not limited to: O[(CH.sub.2).sub.nO].sub.mCH.sub.3, O(CH.sub.2).sub.nNH.sub.2, O(CH.sub.2).sub.nCH.sub.3, O(CH.sub.2).sub.nF, O(CH.sub.2).sub.nONH.sub.2, OCH.sub.2C(.dbd.O)N(H)CH.sub.3, and O(CH.sub.2).sub.nON[(CH.sub.2).sub.nCH.sub.3].sub.2, where n and m are from 1 to about 10. Other 2'- substituent groups can also be selected from: C.sub.1-C.sub.12 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH.sub.3, OCN, Cl, Br, CN, F, CF.sub.3, OCF.sub.3, SOCH.sub.3, SO.sub.2CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving pharmacokinetic properties, or a group for improving the pharmacodynamic properties of an antisense compound, and other substituents having similar properties. In certain embodiments, modifed nucleosides comprise a 2'-MOE side chain (Baker et al., J. Biol. Chem., 1997, 272, 11944-12000). Such 2'-MOE substitution have been described as having improved binding affinity compared to unmodified nucleosides and to other modified nucleosides, such as 2'-O-methyl, O-propyl, and O-aminopropyl. Oligonucleotides having the 2'-MOE substituent also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin, Helv. Chim. Acta, 1995, 78, 486-504; Altmann et al., Chimia, 1996, 50, 168-176; Altmann et al., Biochem. Soc. Trans., 1996, 24, 630-637; and Altmann et al., Nucleosides Nucleotides, 1997, 16, 917-926).

As used herein, a "modified tetrahydropyran nucleoside" or "modified THP nucleoside" means a nucleoside having a six-membered tetrahydropyran "sugar" substituted in for the pentofuranosyl residue in normal nucleosides (a sugar surrogate). Modified THP nucleosides include, but are not limited to, what is referred to in the art as hexitol nucleic acid (HNA), anitol nucleic acid (ANA), manitol nucleic acid (MNA) (see Leumann, Bioorg. Med. Chem., 2002, 10, 841-854) or fluoro HNA (F-HNA) having a tetrahydropyran ring system as illustrated below:

##STR00022##

In certain embodiments, sugar surrogates are selected having Formula VII:

##STR00023## wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula VII:

Bx is a heterocyclic base moiety;

T.sub.a and T.sub.b are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound or one of T.sub.a and T.sub.b is an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound and the other of T.sub.a and T.sub.b is H, a hydroxyl protecting group, a linked conjugate group or a 5' or 3'-terminal group;

q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; and each of R.sub.1 and R.sub.2 is selected from hydrogen, hydroxyl, halogen, subsitituted or unsubstituted alkoxy, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, OC(.dbd.X)J.sub.1, OC(.dbd.X)NJ.sub.1J.sub.2, NJ.sub.3C(.dbd.X)NJ.sub.1J.sub.2 and CN, wherein X is O, S or NJ.sub.1 and each J.sub.1, J.sub.2 and J.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

In certain embodiments, the modified THP nucleosides of Formula VII are provided wherein q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is other than H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is methyl. In certain embodiments, THP nucleosides of Formula VII are provided wherein one of R.sub.1 and R.sub.2 is fluoro. In certain embodiments, R.sub.1 is fluoro and R.sub.2 is H; R.sub.1 is methoxy and R.sub.2 is H, and R.sub.1 is methoxyethoxy and R.sub.2 is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example nucleosides comprising morpholino sugar moieties and their use in oligomeric compounds has been reported (see for example: Braasch et al., Biochemistry, 2002, 41, 4503-4510; and U.S. Pat. Nos. 5,698,685; 5,166,315; 5,185,444; and 5,034,506). As used here, the term "morpholino" means a sugar surrogate having the following formula:

##STR00024##

In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as "modifed morpholinos."

Combinations of modifications are also provided without limitation, such as 2'-F-5'-methyl substituted nucleosides (see PCT International Application WO 2008/101157 published on Aug. 21, 2008 for other disclosed 5',2'-bis substituted nucleosides) and replacement of the ribosyl ring oxygen atom with S and further substitution at the 2'-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5'-substitution of a bicyclic nucleic acid (see PCT International Application WO 2007/134181, published on Nov. 22, 2007 wherein a 4-CH.sub.2--O-2' bicyclic nucleoside is further substituted at the 5' position with a 5'-methyl or a 5'-vinyl group). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (see, e.g., Srivastava et al., J. Am. Chem. Soc. 2007, 129(26), 8362-8379).

In certain embodiments, antisense compounds comprise one or more modified cyclohexenyl nucleosides, which is a nucleoside having a six-membered cyclohexenyl in place of the pentofuranosyl residue in naturally occurring nucleosides. Modified cyclohexenyl nucleosides include, but are not limited to those described in the art (see for example commonly owned, published PCT Application WO 2010/036696, published on Apr. 10, 2010, Robeyns et al., J. Am. Chem. Soc., 2008, 130(6), 1979-1984; Horvath et al., Tetrahedron Letters, 2007, 48, 3621-3623; Nauwelaerts et al., J. Am. Chem. Soc., 2007, 129(30), 9340-9348; Gu et al., Nucleosides, Nucleotides & Nucleic Acids, 2005, 24(5-7), 993-998; Nauwelaerts et al., Nucleic Acids Research, 2005, 33(8), 2452-2463; Robeyns et al., Acta Crystallographica, Section F: Structural Biology and Crystallization Communications, 2005, F61(6), 585-586; Gu et al., Tetrahedron, 2004, 60(9), 2111-2123; Gu et al., Oligonucleotides, 2003, 13(6), 479-489; Wang et al., J. Org. Chem., 2003, 68, 4499-4505; Verbeure et al., Nucleic Acids Research, 2001, 29(24), 4941-4947; Wang et al., J. Org. Chem., 2001, 66, 8478-82; Wang et al., Nucleosides, Nucleotides & Nucleic Acids, 2001, 20(4-7), 785-788; Wang et al., J. Am. Chem., 2000, 122, 8595-8602; Published PCT application, WO 06/047842; and Published PCT Application WO 01/049687; the text of each is incorporated by reference herein, in their entirety). Certain modified cyclohexenyl nucleosides have Formula X.

##STR00025##

wherein independently for each of said at least one cyclohexenyl nucleoside analog of Formula X:

Bx is a heterocyclic base moiety;

T.sub.3 and T.sub.4 are each, independently, an internucleoside linking group linking the cyclohexenyl nucleoside analog to an antisense compound or one of T.sub.3 and T.sub.4 is an internucleoside linking group linking the tetrahydropyran nucleoside analog to an antisense compound and the other of T.sub.3 and T.sub.4 is H, a hydroxyl protecting group, a linked conjugate group, or a 5'- or 3'-terminal group; and

q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6, q.sub.7, q.sub.8 and q.sub.9 are each, independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.2-C.sub.6 alkynyl or other sugar substituent group.

As used herein, "2'-modified" or "2'-substituted" refers to a nucleoside comprising a sugar comprising a substituent at the 2' position other than H or OH. 2'-modified nucleosides, include, but are not limited to, bicyclic nucleosides wherein the bridge connecting two carbon atoms of the sugar ring connects the 2' carbon and another carbon of the sugar ring; and nucleosides with non-bridging 2'substituents, such as allyl, amino, azido, thio, O-allyl, O--C.sub.1-C.sub.10 alkyl, --OCF.sub.3, O--(CH.sub.2).sub.2--O--CH.sub.3, 2'-O(CH.sub.2).sub.2SCH.sub.3, O--(CH.sub.2).sub.2--O--N(R.sub.m)(R.sub.n) or O--CH.sub.2--C(.dbd.O)--N(R.sub.m)(R.sub.n), where each R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl. 2'-modifed nucleosides may further comprise other modifications, for example at other positions of the sugar and/or at the nucleobase.

As used herein, "2'-F" refers to a nucleoside comprising a sugar comprising a fluoro group at the 2' position of the sugar ring.

As used herein, "2'-OMe" or "2'-OCH.sub.3" or "2'-O-methyl" each refers to a nucleoside comprising a sugar comprising an --OCH.sub.3 group at the 2' position of the sugar ring.

As used herein, "oligonucleotide" refers to a compound comprising a plurality of linked nucleosides. In certain embodiments, one or more of the plurality of nucleosides is modified. In certain embodiments, an oligonucleotide comprises one or more ribonucleosides (RNA) and/or deoxyribonucleosides (DNA).

Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds (see for example review article: Leumann, Bioorg. Med. Chem., 2002, 10, 841-854). Such ring systems can undergo various additional substitutions to enhance activity.

Methods for the preparations of modified sugars are well known to those skilled in the art. Some representative U.S. patents that teach the preparation of such modified sugars include without limitation, U.S.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,670,633; 5,700,920; 5,792,847 and 6,600,032 and International Application PCT/US2005/019219, filed Jun. 2, 2005 and published as WO 2005/121371 on Dec. 22, 2005, and each of which is herein incorporated by reference in its entirety.

In nucleotides having modified sugar moieties, the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target.

In certain embodiments, antisense compounds comprise one or more nucleosides having modified sugar moieties. In certain embodiments, the modified sugar moiety is 2'-MOE. In certain embodiments, the 2'-MOE modified nucleosides are arranged in a gapmer motif. In certain embodiments, the modified sugar moiety is a bicyclic nucleoside having a (4'-CH(CH.sub.3)--O-2') bridging group. In certain embodiments, the (4-CH(CH.sub.3)--O-2') modified nucleosides are arranged throughout the wings of a gapmer motif.

Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications can impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds. Modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). Certain nucleobase substitutions, including 5-methylcytosine substitutions, are particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid. For example, 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2.degree. C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278).

Additional modified nucleobases include 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (--C.ident.C--CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

Heterocyclic base moieties can also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Nucleobases that are particularly useful for increasing the binding affinity of antisense compounds include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.

In certain embodiments, antisense compounds targeted to an androgen receptor nucleic acid comprise one or more modified nucleobases. In certain embodiments, shortened or gap-widened antisense oligonucleotides targeted to an androgen receptor nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

Conjugated Antisense Compounds

Antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties. Additional conjugate groups include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes.

Antisense compounds can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense compounds to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the antisense compound having terminal nucleic acid from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5'-terminus (5'-cap), or at the 3'-terminus (3'-cap), or can be present on both termini. Cap structures are well known in the art and include, for example, inverted deoxy abasic caps. Further 3' and 5'-stabilizing groups that can be used to cap one or both ends of an antisense compound to impart nuclease stability include those disclosed in WO 03/004602 published on Jan. 16, 2003.

In certain embodiments, antisense compounds, including, but not limited to those particularly suited for use as ssRNA, are modified by attachment of one or more conjugate groups. In general, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, cellular distribution, cellular uptake, charge and clearance. Conjugate groups are routinely used in the chemical arts and are linked directly or via an optional conjugate linking moiety or conjugate linking group to a parent compound such as an oligonucleotide. Conjugate groups includes without limitation, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins and dyes. Certain conjugate groups have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937).

For additional conjugates including those useful for ssRNA and their placement within antisense compounds, see e.g., PCT Publication No.; WO2013/033230.

Compositions and Methods for Formulating Pharmaceutical Compositions

Antisense oligonucleotides may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

An antisense compound targeted to an androgen receptor nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense compound targeted to an androgen receptor nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the antisense compound is an antisense oligonucleotide provided herein.

Pharmaceutical compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense compound which are cleaved by endogenous nucleases within the body, to form the active antisense compound.

In Vitro Testing of Antisense Oligonucleotides

Described herein are methods for treatment of cells with antisense oligonucleotides, which can be modified appropriately for treatment with other antisense compounds.

Cells may be treated with antisense oligonucleotides when the cells reach approximately 60-80% confluency in culture.

One reagent commonly used to introduce antisense oligonucleotides into cultured cells includes the cationic lipid transfection reagent LIPOFECTIN (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotides may be mixed with LIPOFECTIN in OPTI-MEM 1 (Invitrogen, Carlsbad, Calif.) to achieve the desired final concentration of antisense oligonucleotide and a LIPOFECTIN concentration that may range from 2 to 12 ug/mL per 100 nM antisense oligonucleotide.

Another reagent used to introduce antisense oligonucleotides into cultured cells includes LIPOFECTAMINE (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotide is mixed with LIPOFECTAMINE in OPTI-MEM 1 reduced serum medium (Invitrogen, Carlsbad, Calif.) to achieve the desired concentration of antisense oligonucleotide and a LIPOFECTAMINE concentration that may range from 2 to 12 ug/mL per 100 nM antisense oligonucleotide.

Another technique used to introduce antisense oligonucleotides into cultured cells includes electroporation.

Yet another technique used to introduce antisense oligonucleotides into cultured cells includes free uptake of the oligonucleotides by the cells.

Cells are treated with antisense oligonucleotides by routine methods. Cells may be harvested 16-24 hours after antisense oligonucleotide treatment, at which time RNA or protein levels of target nucleic acids are measured by methods known in the art and described herein. In general, when treatments are performed in multiple replicates, the data are presented as the average of the replicate treatments.

The concentration of antisense oligonucleotide used varies from cell line to cell line. Methods to determine the optimal antisense oligonucleotide concentration for a particular cell line are well known in the art. Antisense oligonucleotides are typically used at concentrations ranging from 1 nM to 300 nM when transfected with LIPOFECTAMINE. Antisense oligonucleotides are used at higher concentrations ranging from 625 to 20,000 nM when transfected using electroporation.

RNA Isolation

RNA analysis can be performed on total cellular RNA or poly(A)+mRNA. Methods of RNA isolation are well known in the art. RNA is prepared using methods well known in the art, for example, using the TRIZOL Reagent (Invitrogen, Carlsbad, Calif.) according to the manufacturer's recommended protocols.

EMBODIMENTS

E1. A compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 12-179.

E2. A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 12-179.

E 3. A compound comprising a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 12-179.

E 4. A compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175.

E 5. A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175.

E6. A compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 35, 39, 43, 124, 150, 155, 169, or 175.

E7. A compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleotides 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, 5521-5536, 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58769, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 102156-102171, 139682-139697, 139762-139777, 139782-139797, 144856-144871, 144938-144953, 148406-148421, 148443-148458, 148520-148535, 181695-181710, 182958-182973, or 183049-183064 of SEQ ID NO: 1, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1.

E8. A compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, 5521-5536, 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58769, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 114874-114889, 115272-115287, 115365-115380, 134971-134986, 102156-102171, 139682-139697, 139762-139777, 139782-139797, 144856-144871, 144938-144953, 148406-148421, 148443-148458, 148520-148535, 181695-181710, 182958-182973, or 183049-183064 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is complementary to SEQ ID NO: 1.

E9. The compound of any one of E1, E7, or E8, wherein the compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within exon 1 nucleotides 2957-2972, 3079-3094, 3099-3114, 3109-3124, 3113-3128, 3120-3135, 3133-3148, 3224-3239, 3226-3241, 3351-3366, 3353-3368, 3361-3376, 3388-3403, 3513-3528, 3517-3532, 3519-3534, 3641-3656, 3735-3750, 3764-3779, 3768-3783, 3798-3813, 3799-3814, 3851-3866, 3870-3885, 3874-3889, 3876-3891, 3878-3893, 3884-3899, 3886-3901, 3888-3903, 3901-3916, 3956-3971, 3962-3977, 3964-3979, 3967-3982, 4019-4034, 4038-4053, 4049-4064, 4056-4071, 4059-4074, 4062-4077, 4066-4081, 4070-4085, 4101-4116, 4103-4118, 4105-4120, 4109-4124, 4305-4320, 4405-4420, 4532-4547, 4534-4549, 4537-4552, 4539-4554, 4555-4570, 4571-4586, 4573-4588, 4578-4593, 4597-4612, 4632-4647, 4655-4670, 4656-4671, 4662-4677, 4699-4714, 4747-4762, 4750-4765, 4752-4767, 4754-4769, 4755-4770, 4769-4784, 4798-4813, 4804-4819, 4807-4822, 4833-4848, 4837-4852, 4839-4854, 4865-4880, 4868-4883, 4872-4887, 4874-4889, 4876-4891, 4887-4902, 4889-4904, 4916-4931, 4918-4933, 4938-4953, 4942-4957, 4944-4959, 4951-4966, 5050-5065, 5052-5067, 5054-5069, 5056-5071, 5060-5075, 5061-5076, 5062-5077, 5133-5148, 5141-5156, 5155-5170, 5265-5280, 5293-5308, 5308-5323, 5392-5407, 5448-5463, 5469-5484, 5481-5496, 5483-5498, 5486-5501, 5488-5503, 5494-5509, or 5521-5536 of SEQ ID NO:1.

E10. The compound of E9, wherein the compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within exon 1 nucleotides 5052-5067 of SEQ ID NO:1.

E11. The compound of any one of E1, E7, or E8, wherein the compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within intron 1 nucleotides 5666-5681, 6222-6237, 6701-6716, 7543-7558, 8471-8486, 8638-8653, 9464-9479, 10217-10232, 10250-10265, 10865-10880, 11197-11212, 11855-11870, 13189-13204, 13321-13336, 13346-13361, 16555-16570, 16793-16808, 16968-16983, 17206-17221, 18865-18880, 29329-29344, 32290-32305, 33315-33330, 39055-39070, 40615-40630, 42017-42032, 56050-56065, 58719-58734, 58720-58739, 58721-58736, 58722-58737, 58723-58738, 58724-58739, 58725-58740, 58750-58769, 58751-58766, 58752-58767, 58753-58768, 58754-58769, 58755-58770, 60902-60917, 67454-67469, 114874-114889, 115272-115287, 115365-115380, or 134971-134986 of SEQ ID NO:1.

E12. The compound of E11, wherein the compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within intron 1 nucleotides 8638-8653, 11197-11212, 40615-40630, 58719-58734, 58720-58735, or 58721-58736 of SEQ ID NO:1.

E13. The compound of any one of E1-12, wherein the modified oligonucleotide comprises at least one modified sugar.

E14. The compound of E13, wherein at least one modified sugar comprises a 2'-O-methoxyethyl group.

E15. The compound of E13, wherein the at least one modified sugar is a bicyclic sugar.

E16. The compound of E15, wherein the bicyclic sugar comprises a 4'-CH(CH.sub.3)--O-2' group.

E17. The compound of E15, wherein the bicyclic sugar comprises a 4'-CH.sub.2--O-2' or 4'-(CH.sub.2).sub.2--O-2'group.

E18. The compound of any one of E1-17, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

E19. The compound of E18, wherein each internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkage.

E20. The compound of any one of E1-19, wherein the modified oligonucleotide comprises at least one modified nucleobase.

E21. The compound of E20, wherein the modified nucleobase is a 5-methylcytosine.

E22. The compound of any one of E1-21, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; and a 3' wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

E23. The compound of E22, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5' wing segment consisting of 3 linked nucleosides; and a 3' wing segment consisting of 3 linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar or a constrained ethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.

E24. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 9 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E25. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 9 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E26. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 8 linked deoxynucleosides; a 5' wing segment consisting of four linked nucleosides; and a 3' wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E27. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 8 linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the five linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E28. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 7 linked deoxynucleosides; a 5' wing segment consisting of four linked nucleosides; and a 3' wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the five linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E29. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 7 linked deoxynucleosides; a 5' wing segment consisting of six linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; the six linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; the three linked nucleosides of the 3' wing segment are each a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E30. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 43, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E31. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 124, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E32. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 150, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E33. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 155, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E34. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 169, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E35. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 175, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises: a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; each nucleoside of each wing segment comprises a constrained ethyl (cEt) sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.

E36. The compound of any one of E1-35, wherein the modified oligonucleotide is at least 90% complementary to a nucleic acid encoding androgen receptor.

E37. The compound of any one of E1-36, wherein the antisense oligonucleotide is 100% complementary to a nucleic acid encoding androgen receptor.

E38. The compound of E37, wherein the nucleic acid encoding androgen receptor comprises the nucleotide sequence of any one of SEQ ID NOs: 1-8.

E39. A composition comprising the compound of any one of E1-38, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

E40. A composition comprising the compound of any one of E1-38 and a diarylhydantoin Androgen Receptor (AR) inhibitor of Formula XVI:

##STR00026##

wherein X is selected from the group consisting of trifluoromethyl and iodo, wherein W is selected from the group consisting of O and NR5, wherein R5 is selected from the group consisting of H, methyl, and

##STR00027## wherein D is S or O and E is N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl, wherein R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group, wherein R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl, wherein R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, and wherein R3 is not methylaminomethyl or dimethylaminomethyl. R5 may be

##STR00028##

E41. The composition of E40, wherein the diarylhydantoin Androgen Receptor (AR) inhibitor is MDV3100.

E42. A composition comprising the compound of any one of E1-38 and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

E43. A method of treating cancer comprising administering to a subject having cancer the compound of any one of E1-38 or composition of any one of E39-42, thereby treating cancer in the subject.

E44. An antisense compound of any one of E1-38 or composition of any one of E39-42 for use in treating cancer

E45. The compound or composition of E44, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer or bladder cancer.

E46. The compound or composition of E45, wherein the cancer is castrate-resistant prostate cancer.

E47. The compound or composition of E46, wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

E48. The method of E43, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer or bladder cancer.

E49. The method of E48, wherein the cancer is castrate-resistant prostate cancer.

E50. The method of E49, wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

E51. The compound of E44-47 or the method of E49 or E50, wherein the antisense compound targets an AR splicing variant.

E52. The compound or method of E51, wherein the AR splicing variant lacks a functional ligand binding domain.

E53. The compound of E44-47 or the method of any one of E49-52, wherein the antisense compound is capable of reducing expression of full-length AR and an AR splicing variant lacking any one of exons 4-8.

E54. The compound or method of E51, wherein the AR splicing variant consists of exons 1-3.

E55. The compound of E44-47 or the method of any one of E49-52, wherein the antisense compound is targeted to AR upstream of the 3' end of exon 3 and is capable of inhibiting growth or proliferation of the prostate cancer cell to a greater extent than an antisense compound targeted to a region of AR downstream of the 3' end of exon 3.

E56. The compound or method of E55, wherein the antisense compound targeted to a region of AR downstream of the 3' end of exon 3 is capable of reducing levels of full-length AR but not an AR splicing variant consisting of exons 1-3.

E57. The compound or method of E56, wherein the region downstream of the 3' end of exon 3 comprises exon 4.

E58. The compound of E44-47 or the method of any one of E49-52, wherein the prostate cancer cell preferentially expresses an AR splicing variant over full-length AR.

E59. The compound or method of E58, wherein the AR splicing variant lacks a functional ligand binding domain.

E60. A method of treating prostate cancer resistant to a anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464 in a subject comprising administering to the subject an antisense compound targeted to human androgen receptor (AR) upstream of the 3' end of exon 3, thereby treating the prostate cancer.

E61. The method of E60, wherein the subject is diagnosed as having prostate cancer resistant to the anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.

E62. The method of E60 or E61, wherein the antisense compound targets an AR splicing variant.

E63. The method of E62, wherein the AR splicing variant lacks a functional ligand binding domain.

E64. The method of any one of E60-63, wherein the antisense compound is capable of reducing expression of full-length AR and an AR splicing variant lacking any one of exons 4-8.

E65. The method of E64, wherein the AR splicing variant consists of exons 1-3.

E66. The method of any one of E60-65, wherein the antisense compound is targeted to AR upstream of the 3' end of exon 3 and is capable of inhibiting growth or proliferation of a prostate cancer cell resistant to the diarylhydantoin Androgen Receptor (AR) inhibitor to a greater extent than an antisense compound targeted to a region of AR downstream of the 3' end exon 3.

E67. The method of E66, wherein the antisense compound targeted to a region of AR downstream of the 3' end of exon 3 is capable of reducing levels of full-length AR but not an AR splicing variant lacking any one of exons 4-8.

E68. The method of E67, wherein the AR splicing variant consists of exons 1-3.

E69. The method of E68, wherein the region downstream of the 3' end of exon 3 comprises exon 4.

E70. The method of any one of E60-69, wherein the prostate cancer is castration-resistant.

E71. The method of any one of E60-70, wherein the prostate cancer comprises cells that preferentially express an AR splicing variant over full-length AR.

E72. The method of E71, wherein the AR splicing variant lacks any one of exons 4-8.

E73. The method of E72, wherein the AR splicing variant consists of exons 1-3.

E74. The method of E72, wherein the AR splicing variant lacks a functional ligand binding domain.

E75. A method of inhibiting prostate cancer cell growth or proliferation comprising contacting the prostate cancer cell with an antisense compound targeted to human androgen receptor (AR) and anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464, wherein the antisense compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell.

E76. The method of E75, wherein the antisense compound is targeted to AR upstream of the 3' end of exon 3.

E77. The method of E75 or E76, wherein the prostate cancer cell is contacted with an amount of the antisense compound and an amount of anti-androgenic agent that are each or both less in combination than the amount of either the antisense compound or anti-androgenic agent alone effective in inhibiting the growth or proliferation of said prostate cancer cell.

E78. The method of any one of E75-77, wherein the antisense compound and anti-androgenic agent provide a greater-than-additive effect compared to the antisense compound alone or anti-androgenic agent alone in inhibiting the growth or proliferation of said prostate cancer cell.

E79. The method of any one of E75-78, wherein the antisense compound targets an AR splicing variant.

E80. The method of E79, wherein the AR splicing variant lacks a functional ligand binding domain.

E81. The method of any one of E75-80, wherein the antisense compound is capable of reducing expression of full-length AR and an AR splicing variant consisting of exons 1-3.

E82. A method of inhibiting growth or proliferation of an androgen receptor (AR)-positive breast cancer cell comprising contacting the breast cancer cell with an antisense compound targeted to human androgen receptor (AR) wherein the growth or proliferation of the breast cancer cell is inhibited.

E83. A method of inhibiting AR expression in a subject having or at risk of having an androgen receptor (AR)-positive breast cancer comprising:

identifying a subject having or at risk of having AR-positive breast cancer, and

administering to the subject an antisense compound targeted to human AR,

wherein the antisense compound inhibits AR expression in the subject.

E84. A method of treating AR-positive breast cancer in a subject comprising administering to the subject an antisense compound targeted to human androgen receptor (AR), thereby treating the breast cancer in the subject.

E85. The method of any one of E82-84, wherein the AR-positive breast cancer or breast cancer cell is dependent on androgen expression for growth.

E86. The method of any one of E82-85, wherein the breast cancer or breast cancer cell is estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, or Her2/neu-negative.

E87. The method of any one of E82-85, wherein the breast cancer or breast cancer cell is ER-positive and AR-positive.

E88. The method of any one of E82-85, wherein the breast cancer or breast cancer cell is ER-negative and AR-positive.

E89. The method of any one of E82-88, wherein the breast cancer or breast cancer cell is an apocrine breast cancer or breast cancer cell.

E90. The method of any one of E60-88, wherein the antisense compound is the compound of any one of E1-38, or pharmaceutically acceptable salt thereof.

E91. The method of any one of E60-88, wherein the antisense compound is the compound of any one of E24-35, or pharmaceutically acceptable salt thereof.

EXAMPLES

Non-Limiting Disclosure and Incorporation by Reference

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

Example 1

Antisense Inhibition of Human AR in HuVEC Cells

Antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 (forward sequence TCCTTCACCAATGTCAACTCC, designated herein as SEQ ID NO: 9; reverse sequence GAGCCATCCAAACTCTTGAGA, designated herein as SEQ ID NO: 10; probe sequence AGTACCGCATGCACAAGTCCCG, designated herein as SEQ ID NO: 11) was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 155 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Tables 1 and 2.

The newly designed chimeric antisense oligonucleotides in Tables 1 and 2 were designed as 3-10-3 (S)-cET gapmers. The gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Tables 1 and 2 is targeted to either the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000) or the human AR mRNA sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NM_000044.3), or both. `n/a.` indicates that the oligonucleotide does not target that particular gene sequence.

TABLE-US-00004 TABLE 1 Target Target Start Start Site Site SEQ for SEQ for SEQ ISIS % ID ID NO: 1 ID NO: 2 No Sequence inhibition NO 3799 937 549332 GCGCTCTGACAGCCTC 84 12 3851 989 549334 CACCTGCGGGAAGCTC 83 13 3888 1026 549338 GGCTGTGATGATGCGG 83 14 4047 1185 549345 TCTGGAACAGATTCTG 82 191 4059 1197 549347 CTTCGCGCACGCTCTG 84 15 4534 1672 549358 ATGGTGCTGGCCTCGC 91 16 4655 1793 549360 GGTCGAAGTGCCCCCT 89 17 4699 1837 549361 GACACCGACACTGCCT 84 18 4755 1893 549362 CCCGAAGCTGTTCCCC 85 19 4865 2003 549366 CTTGCCTGCGCTGTCG 84 20 5060 2198 549371 GTTGTAGTAGTCGCGA 93 21 5062 2200 549372 AAGTTGTAGTAGTCGC 92 22 5155 2293 549374 GCGCTGCCGTAGTCCA 93 23 5265 2403 549377 AGGATGAGGAAGCGGC 90 24 5392 2530 549379 GCTCCCGCCTCGCCGC 86 25 5448 2586 549380 CGCTTTCCTGGCCCGC 94 26 5483 2621 549381 GCCGCCAGGGTACCAC 89 27 n/a 2721 549383 CCAAACGCATGTCCCC 88 28 102155 2800 549386 GCTTCATCTCCACAGA 77 192 102156 2801 549387 AGCTTCATCTCCACAG 84 29 n/a 2871 549388 TCCCTTCAGCGGCTCT 88 30 144856 2801 549390 TTTCTGCTGGCGCACA 89 31

TABLE-US-00005 TABLE 2 Target Target Start Start Site Site SEQ for SEQ for SEQ ISIS % ID ID NO: 1 ID NO: 2 No Sequence inhibition NO 181695 3602 549414 GTTCATTCGAAGTTCA 81 32 182958 4164 549432 GAGGATCATCACAGAT 90 33 183049 4255 549434 CTAAACTTCCCGTGGC 96 34 58721 n/a 549457 TTGATTTAATGGTTGC 98 35 58751 58722 n/a 549458 GTTGATTTAATGGTTG 95 36 58752 58725 n/a 549459 ATGGTTGATTTAATGG 96 37 58755

Example 2

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Gapmers from the study described above exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 18.5 nM, 55.6 nM, 166.7 nM, 500.0 nM and 1500.0 nM concentrations of antisense oligonucleotide, as specified in Tables 3 and 4. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Tables 3 and 4. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in the antisense oligonucleotide treated cells.

TABLE-US-00006 TABLE 3 18.5 55.6 166.7 500.0 1500.0 IC.sub.50 ISIS No nM nM nM nM nM (nM) 549358 0 29 63 85 95 141 549360 2 44 58 79 83 116 549361 0 12 30 52 66 525 549362 0 10 23 57 74 447 549371 0 30 52 83 88 148 549372 0 22 51 85 89 150 549374 15 40 59 83 92 108 549377 0 13 52 72 93 216 549379 9 11 51 68 88 237 549380 14 50 87 94 98 62 549381 4 14 33 71 91 261 549383 2 10 34 75 88 270 549388 0 15 42 36 86 428 549390 12 0 35 55 91 369

TABLE-US-00007 TABLE 4 18.5 55.6 166.7 500.0 1500.0 IC.sub.50 ISIS No nM nM nM nM nM (nM) 549332 24 35 57 79 79 104 549334 9 29 46 63 72 253 549338 30 32 47 67 78 154 549347 5 15 37 62 71 357 549366 8 44 58 72 91 129 549387 2 9 41 68 92 261 549414 0 21 35 53 76 366 549432 10 15 46 80 92 179 549434 27 38 60 86 96 85 549457 50 70 95 99 99 18 549458 22 48 84 97 98 57 549459 51 61 90 94 97 18

Example 3

Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 82 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Table 5.

The newly designed chimeric antisense oligonucleotides in Table 5 were designed as 3-10-3 (S)-cET gapmers or 5-10-5 MOE gapmers. The 3-10-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The 5-10-5 MOE gapmer is 20 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on the 5' direction and the 3' direction comprising five nucleosides each. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has a 2'-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Table 5 is targeted to the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000)

TABLE-US-00008 TABLE 5 Target Target Start Stop ISIS % SEQ ID Site Site No ISIS No Motif inhibition NO 58721 58736 549457 TTGATTTAATGGTTGC 3-10-3 98 35 58751 58766 58722 58737 549458 GTTGATTTAATGGTTG 3-10-3 94 36 58752 58767 58725 58740 549459 ATGGTTGATTTAATGG 3-10-3 92 37 58755 58770 58720 58739 560071 TGGTTGATTTAATGGTTGCA 5-10-5 73 38 58750 58769 58720 58735 560098 TGATTTAATGGTTGCA 3-10-3 99 39 58750 58765 58723 58738 560099 GGTTGATTTAATGGTT 3-10-3 95 40 58753 58768 58724 58739 560100 TGGTTGATTTAATGGT 3-10-3 91 41 58754 58769 58721 58736 560137 TTGATTTAATGGTTGC 3-10-3 95 35 58751 58766

Example 4

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Gapmers from the studies described above exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 31.3 nM, 62.5 nM, 125.0 nM, 250.0 nM, 500.0 nM, and 1000.0 nM concentrations of antisense oligonucleotide, as specified in Table 6. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Table 6. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in the antisense oligonucleotide treated cells.

TABLE-US-00009 TABLE 6 31.25 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM nM (.mu.M) 549457 40 57 78 89 96 96 0.03 549458 15 25 47 70 88 93 0.1 549459 16 23 50 71 85 92 0.1 560071 7 0 19 40 57 76 0.4 560098 20 41 64 83 94 94 0.1 560099 13 29 58 72 89 94 0.1 560100 16 24 53 69 81 93 0.1 560137 27 49 61 82 91 96 0.1

Example 5

Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 250 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 40 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Table 7.

The newly designed chimeric antisense oligonucleotides in Table 7 were designed as 3-10-3 (S)-cET gapmers or deoxy, MOE and (S)-cEt oligonucleotides. The 3-10-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The deoxy, MOE and (S)-cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an (S)-cEt sugar modification, or a deoxy modification. The `Chemistry` column describes the sugar modifications of each oligonucleotide. `k` indicates an (S)-cEt sugar modification; the number indicates the number of deoxynucleosides; and `e` indicates a MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. The SEQ ID NO listed in the table refers to the oligonucleotide sequence. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Table 7 is targeted to the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000).

TABLE-US-00010 TABLE 7 Target Target % Start Stop ISIS inhibi- SEQ ID Site Site Sequence No Chemistry tion NO 58721 58736 TTGATTTAATGGTTGC 549457 kkk-10-kkk 67 35 58751 58766 58722 58737 GTTGATTTAATGGTTG 549458 kkk-10-kkk 71 36 58752 58767 58720 58735 TGATTTAATGGTTGCA 560098 kkk-10-kkk 69 39 58750 58765 58721 58736 TTGATTTAATGGTTGC 560131 kkk-9-kkke 74 35 58751 58766 58721 58736 TTGATTTAATGGTTGC 560137 ekkk-8-kkke 66 35 58751 58766 58720 58735 TGATTTAATGGTTGCA 569213 kkk-9-kkke 69 39 58750 58765 58720 58735 TGATTTAATGGTTGCA 569216 ekkk-8-kkke 68 39 58750 58765 58721 58736 TTGATTTAATGGTTGC 569222 eekkk-8-kkk 74 35 58751 58766 58721 58736 TTGATTTAATGGTTGC 569228 eekkk-7-kkke 67 35 58751 58766 58720 58735 TGATTTAATGGTTGCA 569236 ekkk-7-kkkee 66 39 58750 58765

Example 6

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Gapmers from the studies described above exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 31.3 nM, 62.5 nM, 125.0 nM, 250.0 nM, 500.0 nM, and 1000.0 nM concentrations of antisense oligonucleotide, as specified in Table 8. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Table 8. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in the antisense oligonucleotide treated cells.

TABLE-US-00011 TABLE 8 31.25 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM nM (.mu.M) 549457 34 44 75 82 93 96 0.06 549458 30 36 54 70 85 90 0.10 560098 30 54 65 78 89 97 0.07 560131 16 48 65 82 89 97 0.09 560137 35 39 64 73 89 94 0.08 569213 35 53 65 83 94 96 0.06 569216 38 51 68 83 91 96 0.05 569222 36 48 67 83 91 98 0.06 569228 26 43 62 78 88 92 0.09 569236 17 39 54 79 84 92 0.11

Example 7

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed as deoxy, MOE and (S)-cEt oligonucleotides targeting AR gene sequences and were tested at various doses in HuVEC cells. The oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an (S)-cEt sugar modification, or a deoxy modification. The `Chemistry` column describes the sugar modifications of each oligonucleotide. `k` indicates an (S)-cEt sugar modification; the number indicates the number of deoxynucleosides; otherwise `d` indicates deoxyribose; and `e` indicates a MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. The SEQ ID NO listed in the table refers to the oligonucleotide sequence. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Table 9 is targeted to the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000)

TABLE-US-00012 TABLE 9 Target Target Start Stop ISIS SEQ Site Site Sequence No Chemistry ID NO 58720 58735 TGATTTAATGGTTGCA 569221 eekkk-8-kkk 39 58750 58765 58720 58735 TGATTTAATGGTTGCA 569227 eekkk-7-kkke 39 58750 58765 58720 58735 TGATTTAATGGTTGCA 569236 ekkk-7-kkkee 39 58750 58765 58720 58735 TGATTTAATGGTTGCA 579666 ekkeekk-7-kk 39 58750 58765 58721 58736 TTGATTTAATGGTTGC 579667 ekkeekk-7-kk 35 58751 58766 58720 58735 TGATTTAATGGTTGCA 579670 ekkekk-7-kkk 39 58750 58765 58721 58736 TTGATTTAATGGTTGC 579671 ekkekk-7-kkk 35 58751 58766 58721 58736 TTGATTTAATGGTTGC 569228 eekkk-7-kkke 35 58751 58766 58723 58738 GGTTGATTTAATGGTT 579669 ekkeekk-7-kk 40 58753 58768 58722 58737 GTTGATTTAATGGTTG 579672 ekkekk-7-kkk 36 58752 58767 58722 58737 GTTGATTTAATGGTTG 569217 ekkk-8-kkke 36 58752 58767 58723 58738 GGTTGATTTAATGGTT 569214 kkk-9-kkke 40 58753 58768 58723 58738 GGTTGATTTAATGGTT 560099 kkk-10-kkk 40 58753 58768

Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 62.5 nM, 125.0 nM, 250.0 nM, 500.0 nM, and 1000.0 nM concentrations of antisense oligonucleotide, as specified in Tables 10-12. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Tables 10-12. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in some of the antisense oligonucleotide treated cells.

TABLE-US-00013 TABLE 10 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM (nM) 549458 25 46 55 64 78 203 569227 8 40 33 51 73 388 569228 29 44 63 77 87 158 569236 4 35 54 68 88 252 579666 33 34 47 64 80 229 579667 30 29 44 36 76 411

TABLE-US-00014 TABLE 11 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM (nM) 549458 16 22 44 64 74 324 579669 24 39 45 74 91 207 579670 27 28 55 75 70 236 579671 6 40 54 57 77 288 579672 9 30 50 72 86 258

TABLE-US-00015 TABLE 12 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM (nM) 549458 19 22 45 38 71 470 569214 20 26 61 62 76 265 569217 34 39 49 64 64 247 569221 12 32 59 57 73 294

Example 8

Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 1,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 75 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Table 13.

The newly designed chimeric antisense oligonucleotides in Table 13 were designed as 3-10-3 (S)-cET gapmers, 3-9-4 (S)-cEt gapmers, 4-8-4 (S)-cEt gapmers, 4-9-3 (S)-cEt gapmers, 5-7-4 (S)-cEt gapmers, 5-8-3 (S)-cEt gapmers, 6-7-3 (S)-cEt gapmers, or deoxy, MOE and (S)-cEt oligonucleotides. The 3-10-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. The 3-9-4 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of nine 2'-deoxynucleosides and is flanked by a wing segment on the 5' direction comprising three nucleotides and on the 3' direction comprising four nucleosides. The 4-8-4 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of eight 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising four nucleosides. The 4-9-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of nine 2'-deoxynucleosides and is flanked by a wing segment on the 5' direction comprising four nucleotides and on the 3' direction comprising three nucleosides. The 5-7-4 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of seven 2'-deoxynucleosides and is flanked by a wing segment on the 5' direction comprising five nucleotides and on the 3' direction comprising four nucleotides. The 5-8-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of eight 2'-deoxynucleosides and is flanked by a wing segment on the 5' direction comprising five nucleotides and on the 3' direction comprising three nucleosides. The 6-7-3 (S)-cEt gapmers are 16 nucleosides in length, wherein the central gap segment comprises of seven 2'-deoxynucleosides and is flanked by a wing segment on the 5' direction comprising six nucleotides and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The deoxy, MOE and (S)-cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an (S)-cEt sugar modification, or a deoxy modification. The `Chemistry` column describes the sugar modifications of each oligonucleotide. `k` indicates an (S)-cEt sugar modification; the number indicates the number of deoxynucleosides; otherwise `d` indicates deoxyribose; and `e` indicates a MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

The SEQ ID NO listed in the table refers to the oligonucleotide sequence. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Table 13 is targeted to the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000).

TABLE-US-00016 TABLE 13 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No Chemistry inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 kkk-10-kkk 64 22 5061 5076 AGTTGTAGTAGTCGCG 585233 kkk-8-keeee 69 42 5062 5077 AAGTTGTAGTAGTCGC 585259 ekkk-9-kkk 71 22 5062 5077 AAGTTGTAGTAGTCGC 585262 kkk-9-kkke 77 22 5062 5077 AAGTTGTAGTAGTCGC 585263 kkk-8-kkkee 69 22 5062 5077 AAGTTGTAGTAGTCGC 585264 kkk-7-kkkeee 62 22 5062 5077 AAGTTGTAGTAGTCGC 585265 eekk-8-kkee 69 22 5062 5077 AAGTTGTAGTAGTCGC 585268 keke-8-ekek 72 22 5062 5077 AAGTTGTAGTAGTCGC 585269 ekek-8-ekek 73 22 5062 5077 AAGTTGTAGTAGTCGC 585271 ekk-10-kke 57 22 5062 5077 AAGTTGTAGTAGTCGC 585274 kkk-10-kke 65 22 58719 58734 GATTTAATGGTTGCAA 586124 kkk-10-kkk 82 43 58720 58735 TGATTTAATGGTTGCA 569227 eekkk-7-kkke 51 39 58750 58765 58722 58737 GTTGATTTAATGGTTG 560132 kkk-9-kkke 58 36 58752 58767 58722 58737 GTTGATTTAATGGTTG 569229 eekkk-7-kkke 57 36 58752 58767 58722 58737 GTTGATTTAATGGTTG 569238 ekkk-7-kkkee 51 36 58752 58767 58722 58737 GTTGATTTAATGGTTG 549458 kkk-10-kkk 87 36 58752 58767 58722 58737 GTTGATTTAATGGTTG 569223 eekkk-8-kkk 59 36 58752 58767 58724 58739 TGGTTGATTTAATGGT 569215 kkk-9-kkke 59 41 58754 58769 58725 58740 ATGGTTGATTTAATGG 560133 kkk-9-kkke 53 37 58755 58770 58725 58740 ATGGTTGATTTAATGG 569220 ekkk-8-kkke 58 37 58755 58770 58721 58736 TTGATTTAATGGTTGC 586224 kkkkk-8-kkk 90 35 58751 58766 58722 58737 GTTGATTTAATGGTTG 586225 kkkkk-8-kkk 88 36 58752 58767 58720 58735 TGATTTAATGGTTGCA 586227 kkkkk-8-kkk 87 39 58750 58765

Example 9

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Antisense oligonucleotides from the studies described above exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 31.25 nM, 62.5 nM, 125.0 nM, 250.0 nM, 500.0 nM, and 1000.0 nM concentrations of antisense oligonucleotide, as specified in Table 14. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Table 14. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in the antisense oligonucleotide treated cells.

TABLE-US-00017 TABLE 14 31.25 62.5 125.0 250.0 500.0 1000.0 IC.sub.50 ISIS No nM nM nM nM nM nM nM 549372 2 17 31 51 61 80 271 549458 0 19 40 63 74 90 196 560132 8 19 21 53 65 85 252 560133 17 15 24 35 58 79 336 569215 12 2 26 55 71 90 234 569220 11 29 34 43 59 78 275 569223 21 20 30 59 73 87 191 569227 13 22 45 46 61 74 255 569229 16 14 36 47 74 84 220 569238 4 32 33 54 71 88 202

Example 10

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Gapmers from Example 8 exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 46.9 nM, 187.5 nM, 750.0 nM, and 3000.0 nM concentrations of antisense oligonucleotide, as specified in Table 15. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Table 15. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in antisense oligonucleotide treated cells.

TABLE-US-00018 TABLE 15 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 9 41 66 87 0.29 549458 15 50 85 96 0.19 586124 28 47 84 94 0.13 586224 39 75 93 98 0.05 586225 17 61 89 97 0.13 586227 20 60 88 96 0.13

Example 11

Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 616 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Tables 16-23.

The newly designed chimeric antisense oligonucleotides in Tables 16-23 were designed as 3-10-3 (S)-cET gapmers. The gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

The SEQ ID NO listed in the table refers to the oligonucleotide sequence. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Tables 16-23 is targeted to either the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000) or the human AR mRNA sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NM_000044.3), or both. `n/a.` indicates that the oligonucleotide does not target that particular gene sequence.

TABLE-US-00019 TABLE 16 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 47 22 58722 58737 GTTGATTTAATGGTTG 549458 60 36 58752 58767 2957 2972 ACAGCACTGGAGCGGC 583542 45 44 3079 3094 AACTTCACCGAAGAGG 583556 43 45 3099 3114 AGTCTTTAGCAGCTTT 583559 52 46 3109 3124 GCTTCCTCCGAGTCTT 583564 45 47 3113 3128 CCTTGCTTCCTCCGAG 583566 47 48 3120 3135 GCACTTTCCTTGCTTC 583567 52 49 3133 3148 TCAGTCCTACCAGGCA 583571 43 50 3224 3239 GACTGAGGCAGCTGCG 583583 45 51 3226 3241 CCGACTGAGGCAGCTG 583584 44 52

TABLE-US-00020 TABLE 17 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 40 22 58722 58737 GTTGATTTAATGGTTG 549458 46 36 58752 58767 3351 3366 GCTAGCTCGCCCGCTC 583608 51 53 3353 3368 CAGCTAGCTCGCCCGC 583609 51 54 3361 3376 GCAATGTGCAGCTAGC 583613 51 55 3388 3403 GTCGCCTGGCTCCTAA 583620 41 56 3513 3528 CTGGCTCCGCACTCGG 583635 50 57 3517 3532 ATCTCTGGCTCCGCAC 583637 43 58 3519 3534 TGATCTCTGGCTCCGC 583638 51 59 3641 3656 AGTGTCCACTGAAGTA 583642 42 60 3735 3750 AGGCTCACAGTCTGTC 583649 46 61 3764 3779 GACACACGGTGGACAA 583660 44 62 3768 3783 AGAAGACACACGGTGG 583662 51 63 3798 3813 CGCTCTGACAGCCTCA 583667 42 64

TABLE-US-00021 TABLE 18 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 26 22 58722 58737 GTTGATTTAATGGTTG 549458 48 36 58752 58767 3870 3885 GTCGCTGCAGCTAGCT 583685 47 65 3874 3889 GGTAGTCGCTGCAGCT 583687 41 66 3876 3891 GCGGTAGTCGCTGCAG 583688 38 67 3878 3893 ATGCGGTAGTCGCTGC 583689 39 68 3884 3899 GTGATGATGCGGTAGT 583692 41 69 3886 3901 CTGTGATGATGCGGTA 583693 36 70 3901 3916 GAAGAGTTCAACAGGC 583700 36 71 3956 3971 GCTTGGCTGAATCTTC 583709 39 72 3962 3977 CCTTGAGCTTGGCTGA 583712 37 73 3964 3979 ATCCTTGAGCTTGGCT 583713 36 74 3967 3982 TCCATCCTTGAGCTTG 583714 36 75 4019 4034 GTAGGTCTTGGACGGC 583719 36 76 4038 4053 GATTCTGGAAAGCTCC 583727 40 77 4049 4064 GCTCTGGAACAGATTC 583728 45 78 4056 4071 CGCGCACGCTCTGGAA 583731 34 79 4062 4077 TCACTTCGCGCACGCT 583734 46 80 4066 4081 TGGATCACTTCGCGCA 583736 47 81 4070 4085 GTTCTGGATCACTTCG 583738 36 82 4101 4116 CGCTCGCGGCCTCTGG 583745 40 83 4103 4118 TGCGCTCGCGGCCTCT 583746 32 84 4105 4120 GCTGCGCTCGCGGCCT 583747 35 85

TABLE-US-00022 TABLE 19 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 39 22 58722 58737 GTTGATTTAATGGTTG 549458 50 36 58752 58767 4109 4124 AGGTGCTGCGCTCGCG 583749 36 86 4305 4320 GCTGTTCCTCATCCAG 583759 38 87 4405 4420 TGCTGCGGCAGCCCCT 583771 40 88 4532 4547 GGTGCTGGCCTCGCTC 583787 37 89 4537 4552 TGCATGGTGCTGGCCT 583789 39 90 4539 4554 GTTGCATGGTGCTGGC 583790 39 91 4555 4570 TGCTGTTGCTGAAGGA 583795 63 92 4571 4586 GGATACTGCTTCCTGC 583796 65 93 4573 4588 TCGGATACTGCTTCCT 583797 35 94 4578 4593 TGCCTTCGGATACTGC 583799 65 95 4597 4612 CTCGCTCTCCCGCTGC 583802 37 96 4632 4647 TGTCCTTGGAGGAAGT 583809 45 97 4656 4671 TGGTCGAAGTGCCCCC 583818 42 98 4662 4677 CAGAAATGGTCGAAGT 583821 42 99

TABLE-US-00023 TABLE 20 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 23 22 58722 58737 GTTGATTTAATGGTTG 549458 54 36 58752 58767 4747 4762 TGTTCCCCTGGACTCA 583833 37 100 4750 4765 AGCTGTTCCCCTGGAC 583834 52 101 4752 4767 GAAGCTGTTCCCCTGG 583835 44 102 4754 4769 CCGAAGCTGTTCCCCT 583836 37 103 4769 4784 GTACATGCAATCCCCC 583843 35 104 4798 4813 ACAGCGGGTGGAACTC 583847 34 105 4804 4819 GGACGCACAGCGGGTG 583850 38 106 4807 4822 GTGGGACGCACAGCGG 583851 33 107 4833 4848 TGCATTCGGCCAATGG 583853 33 108 4837 4852 CCTTTGCATTCGGCCA 583855 44 109 4839 4854 AACCTTTGCATTCGGC 583856 45 110 4868 4883 GCTCTTGCCTGCGCTG 583862 32 111 4872 4887 CAGTGCTCTTGCCTGC 583864 46 112 4874 4889 TTCAGTGCTCTTGCCT 583865 45 113 4876 4891 TCTTCAGTGCTCTTGC 583866 32 114 4887 4902 ACTCAGCAGTATCTTC 583868 34 115 4889 4904 ATACTCAGCAGTATCT 583871 47 116 4916 4931 TTTGGTGTAACCTCCC 583880 39 117 4918 4933 CCTTTGGTGTAACCTC 583881 47 118 4938 4953 CTAGGCTCTCGCCTTC 583890 32 119 4942 4957 CAGCCTAGGCTCTCGC 583892 35 120 4944 4959 AGCAGCCTAGGCTCTC 583893 34 121 4951 4966 CTGCCAGAGCAGCCTA 583896 37 122

TABLE-US-00024 TABLE 21 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 37 22 58722 58737 GTTGATTTAATGGTTG 549458 47 36 58752 58767 5050 5065 TCGCGACTCTGGTACG 583917 37 123 5052 5067 AGTCGCGACTCTGGTA 583918 47 124 5054 5069 GTAGTCGCGACTCTGG 583919 55 125 5056 5071 TAGTAGTCGCGACTCT 583920 42 126 5061 5076 AGTTGTAGTAGTCGCG 583922 37 42 5133 5148 TCTCCAGCTTGATGCG 583932 39 127 5141 5156 CAGCGGGTTCTCCAGC 583933 38 128 5293 5308 CCTTCTTCGGCTGTGA 583969 44 129 5308 5323 GGTCCATACAACTGGC 583975 42 130

TABLE-US-00025 TABLE 22 Target Target Start Start Site on Site on SEQ ID SEQ ID ISIS % SEQ ID NO: 1 NO: 2 Sequence No inhibition NO 5062 2200 AAGTTGTAGTAGTCGC 549372 46 22 58722 n/a GTTGATTTAATGGTTG 549458 39 36 58752 n/a 5469 2607 ACACATCAGGTGCGGT 583990 30 131 5481 2619 CGCCAGGGTACCACAC 583996 33 132 5486 2624 CATGCCGCCAGGGTAC 583998 45 133 5488 2626 ACCATGCCGCCAGGGT 583999 29 134 5494 2632 CTGCTCACCATGCCGC 584002 30 135 5521 2659 ACACAAGTGGGACTGG 584006 33 136 n/a 2870 CCCTTCAGCGGCTCTT 584044 29 137

TABLE-US-00026 TABLE 23 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 25 22 58722 58737 GTTGATTTAATGGTTG 549458 51 36 58752 58767 144938 144953 CAGAGTCATCCCTGCT 584069 36 138 148406 148421 CACCCTCAAGATTCTT 584100 36 139 148443 148458 AAGGTAGTCTTTAAGG 584106 30 140 148520 148535 GTTTTCAAATGCAGCC 584111 33 141 139682 139697 GCCATGAGACAGCTTT 584125 35 142 139762 139777 ATTCTTGACTGTCTGA 584128 38 143 139782 139797 GCATGCCAGCTGGCTC 584130 29 144 5666 5681 CGCGCAGGTAGGAGCC 584138 35 145 6222 6237 TCTAAACATGACGGTT 584139 37 146 6701 6716 ATGCAATTGCCTGCCA 584141 39 147

Example 12

Antisense Inhibition of Human AR in HuVEC Cells

Additional antisense oligonucleotides were designed targeting an AR nucleic acid and were tested for their effects on AR mRNA in vitro. Cultured HuVEC cells at a density of 20,000 cells per well were transfected using electroporation with 1,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells. A total of 385 oligonucleotides were tested. Only those oligonucleotides which were selected for further study are shown in Tables 24-28.

The newly designed chimeric antisense oligonucleotides in Tables 24-28 were designed as 3-10-3 (S)-cET gapmers. The gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on both the 5' direction and on the 3' direction comprising three nucleosides. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has an (S)-cEt modification. The internucleoside linkages throughout each gapmer are phosphorothioate linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

The SEQ ID NO listed in the table refers to the oligonucleotide sequence. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human gene sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in Tables 24-28 is targeted to the human AR genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NT_011669.17 truncated from nucleotides 5079000 to 5270000)

TABLE-US-00027 TABLE 24 Target Target Start Stop ISIS % SEQ ID Site Site Sequence No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 63 22 58722 58737 GTTGATTTAATGGTTG 549458 88 36 58752 58767 7543 7558 ATGGGAGTAACTTTTG 584145 76 148 8471 8486 CATATTATTGTGCTGC 584148 85 149 8638 8653 GTCAATATCAAAGCAC 584149 85 150 9464 9479 GAGTTGTGATTTCAGG 584152 88 151 10217 10232 TTGATGGAATGCTGAT 584157 69 152 10250 10265 GGTTAACTTTCTCTGA 584158 69 153 10865 10880 TGGATTGTAAATTACG 584162 82 154 11197 11212 GAACATTATTAGGCTA 584163 81 155 11855 11870 TCAATCTAGATACCAT 584165 70 156 13189 13204 CACATCAGAAGGAGTA 584166 89 157 13321 13336 GAGTGTTAATGAAGAC 584167 78 158 13346 13361 CTGATTAGCTATGACC 584168 70 159 16555 16570 ATGAGTCCTCAGAATC 584179 74 160 16793 16808 GTAGATTCTAGCTTTG 584180 81 161 16968 16983 ACAGGCTCTGACTAGG 584183 76 162 17206 17221 TGTGTGACCCTTGGAC 584184 78 163 18865 18880 AAGTATGAGCATGGTT 584192 73 164

TABLE-US-00028 TABLE 25 Target Target Start Stop ISIS % SEQ ID Site Site Sequence No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 59 22 58722 58737 GTTGATTTAATGGTTG 549458 76 36 58752 58767 29329 29344 GGATTCTCTACACACA 584233 62 165 32290 32305 CCATTTGTGCCAAACC 584242 62 166 33315 33330 AGGTTAGGGAGTAGGC 584245 70 167 39055 39070 TAGGGTTTGGTCAGAA 584263 56 168 40615 40630 CCTTATGGATGCTGCT 584269 57 169 42017 42032 GTTATCTTACTCTCCC 584274 70 170

TABLE-US-00029 TABLE 26 Target Target Start Stop ISIS % SEQ ID Site Site Sequence No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 58 22 58722 58737 GTTGATTTAATGGTTG 549458 79 36 58752 58767 56050 56065 GATTGTGTATAGCTGC 584312 65 171 60902 60917 GGTTATGGTTCTGTCT 584329 58 172 67454 67469 CTTCATTGCAGGTCTG 584361 61 173

TABLE-US-00030 TABLE 27 Target Target Start Stop % SEQ ID Site Site Sequence ISIS No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 70 22 58722 58737 GTTGATTTAATGGTTG 549458 76 36 58752 58767 114874 114889 TAGCCAACTTTCTTTA 584465 58 174 115272 115287 CATTGTACTATGCCAG 584468 64 175 115365 115380 TTTGGTAACATTAGGC 584469 74 176 134971 134986 ATGGTTGTCCTGTACA 584495 58 177

TABLE-US-00031 TABLE 28 Target Target Start Stop ISIS % SEQ ID Site Site Sequence No inhibition NO 5062 5077 AAGTTGTAGTAGTCGC 549372 54 22 58722 58737 GTTGATTTAATGGTTG 549458 65 36 58752 58767 114874 114889 TAGCCAACTTTCTTTA 584465 54 174 115365 115380 TTTGGTAACATTAGGC 584469 63 176 134971 134986 ATGGTTGTCCTGTACA 584495 53 177

Example 13

Dose-Dependent Antisense Inhibition of Human AR in HuVEC Cells

Gapmers from the studies described above exhibiting significant in vitro inhibition of AR mRNA were selected and tested at various doses in HuVEC cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 46.9 nM, 187.5 nM, 750.0 nM, and 3000.0 nM concentrations of antisense oligonucleotide, as specified in Tables 29-37. After a treatment period of approximately 16 hours, RNA was isolated from the cells and AR mRNA levels were measured by quantitative real-time PCR. Human AR primer probe set RTS3559 was used to measure mRNA levels. AR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of AR, relative to untreated control cells.

The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in Tables 29-37. As illustrated, AR mRNA levels were reduced in a dose-dependent manner in some of the antisense oligonucleotide treated cells.

TABLE-US-00032 TABLE 29 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 7 41 70 91 0.32 549458 21 72 91 97 0.11 583542 9 28 47 66 0.90 583556 19 47 68 66 0.34 583559 30 49 63 80 0.22 583564 16 33 55 74 0.52 583566 0 28 50 74 0.73 583567 17 34 60 79 0.43 583571 18 36 53 59 0.80 583583 21 31 49 64 0.79 583584 24 44 52 73 0.41 583608 12 46 67 76 0.35 583609 16 48 63 73 0.36 583613 24 60 70 75 0.19 583635 35 56 69 78 0.13 583638 33 64 79 85 0.11 583649 28 50 68 84 0.20 583660 21 39 61 72 0.42 583662 27 59 75 75 0.15

TABLE-US-00033 TABLE 30 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 13 29 69 90 0.37 549458 22 62 92 97 0.13 583620 0 17 44 54 1.85 583637 22 32 59 75 0.45 583642 18 35 67 74 0.46 583667 35 55 73 82 0.14 583685 32 53 73 81 0.16 583687 34 67 83 81 0.08 583688 3 26 50 60 1.05 583689 20 34 62 74 0.44 583692 8 47 61 71 0.44 583709 8 50 70 84 0.29 583712 15 47 72 78 0.29 583727 18 49 70 76 0.29 583728 9 48 67 70 0.40 583734 29 60 74 75 0.12 583736 21 38 60 63 0.51 583738 16 40 56 71 0.51 583745 19 51 68 77 0.27

TABLE-US-00034 TABLE 31 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 5 36 69 88 0.36 549458 24 59 92 98 0.13 583693 12 39 64 80 0.38 583700 14 34 57 71 0.55 583713 29 51 67 74 0.22 583714 22 34 59 79 0.40 583719 22 46 65 72 0.32 583731 18 24 47 58 1.31 583746 24 44 65 67 0.35 583747 13 38 50 69 0.64 583771 17 27 47 69 0.77 583789 30 49 71 85 0.19 583790 17 42 65 81 0.32 583795 37 61 83 90 0.09 583796 38 69 83 90 0.07 583799 29 60 76 85 0.14 583809 13 37 68 81 0.36 583818 9 46 71 84 0.31 583821 11 35 61 77 0.46

TABLE-US-00035 TABLE 32 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 15 39 70 86 0.30 549458 19 58 89 96 0.15 583749 34 40 75 87 0.17 583759 5 28 61 67 0.63 583787 15 31 66 74 0.43 583797 21 50 74 82 0.22 583802 17 25 47 60 1.07 583834 34 54 73 84 0.13 583835 20 55 74 88 0.19 583836 11 27 67 86 0.39 583850 9 21 54 78 0.60 583855 22 50 81 91 0.18 583856 31 55 74 89 0.14 583864 30 49 72 85 0.17 583864 0 47 62 85 0.37 583865 33 42 68 85 0.19 583871 28 30 68 87 0.28 583880 13 52 78 92 0.22 583881 28 50 85 91 0.15

TABLE-US-00036 TABLE 33 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 14 33 64 90 0.34 549458 21 61 90 96 0.13 583833 26 43 70 74 0.26 583843 22 40 67 85 0.30 583847 8 30 60 84 0.46 583851 8 24 54 76 0.61 583853 24 51 70 80 0.21 583862 15 37 64 79 0.41 583866 17 48 71 91 0.24 583868 19 31 59 81 0.41 583890 0 0 17 33 >30 583892 22 38 68 83 0.27 583893 15 35 62 79 0.42 583896 13 17 49 69 0.86 583918 16 47 68 86 0.30 583919 27 60 85 91 0.14 583920 11 16 50 72 0.76 583969 12 26 66 86 0.44 583975 19 49 55 88 0.36

TABLE-US-00037 TABLE 34 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 14 36 64 88 0.32 549458 14 53 84 95 0.18 583917 6 30 50 70 0.64 583922 16 43 76 92 0.23 583932 9 35 64 81 0.38 583933 22 25 56 81 0.41 583990 0 9 33 56 1.92 583996 26 12 50 70 0.71 583998 4 25 38 70 0.89 583999 13 12 30 64 1.53 584002 12 46 70 92 0.25 584006 21 26 59 88 0.35 584044 23 30 51 78 0.44 584069 18 40 63 82 0.30 584100 6 5 20 44 7.79 584125 12 12 47 76 0.72 584128 20 22 41 72 0.74 584139 13 33 56 85 0.4 584141 22 37 61 85 0.29

TABLE-US-00038 TABLE 35 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 0 28 64 88 0.42 549458 13 49 84 91 0.19 584106 3 13 12 32 >30 584111 22 30 59 84 0.33 584130 0 10 11 37 >30 584138 2 40 62 89 0.37 584145 6 32 63 88 0.36 584148 16 48 79 95 0.20 584149 11 37 68 89 0.31 584152 28 59 87 95 0.11 584162 24 45 80 92 0.18 584163 19 37 74 90 0.25 584166 34 52 84 92 0.10 584167 13 45 76 93 0.21 584179 1 25 62 87 0.44 584180 26 56 84 96 0.12 584183 3 41 64 87 0.31 584184 9 42 76 93 0.23 584192 1 34 73 95 0.30

TABLE-US-00039 TABLE 36 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 2 26 61 85 0.42 549458 1 51 83 96 0.23 584157 6 6 52 82 0.59 584158 14 37 70 89 0.26 584165 12 34 66 89 0.30 584168 5 32 70 91 0.32 584233 0 30 66 86 0.39 584242 12 38 66 93 0.27 584245 4 33 69 90 0.32 584263 9 24 67 90 0.34 584269 6 26 69 92 0.34 584274 17 36 74 93 0.23 584312 17 37 65 93 0.26 584329 0 17 67 86 0.46 584361 0 18 71 87 0.41 584465 0 0 32 51 2.5 584468 9 26 60 90 0.37 584469 13 46 73 89 0.22 584495 0 14 55 74 0.65

TABLE-US-00040 TABLE 37 46.9 187.5 750.0 3000.0 IC.sub.50 ISIS No nM nM nM nM (.mu.M) 549372 9 41 66 87 0.29 549458 15 50 85 96 0.19 586124 28 47 84 94 0.13 586195 41 62 90 95 0.07 586197 27 47 77 94 0.14 586198 39 62 89 96 0.07 586199 25 56 89 97 0.13 586200 23 44 85 95 0.15 586205 34 67 89 95 0.07 586207 0 39 79 93 0.3 586208 32 70 88 93 0.08 586212 20 60 86 94 0.13 586221 39 72 94 98 0.04 586224 39 75 93 98 0.05 586225 17 61 89 97 0.13 586227 20 60 88 96 0.13 586232 24 45 82 91 0.17 586240 14 49 83 93 0.18 586570 16 44 81 91 0.21

Example 14

Selection of Antisense Oligonucleotides Targeting Human Androgen Receptor (AR) mRNA for Assays with Prostate Cancer Cell Lines

Antisense oligonucleotides from those presented in the studies above, targeting different regions of the human AR genomic sequence, were selected for further studies in prostate cancer cell lines. AR-V7 and AR-V567es are major AR splice variants detected in cancer patients as described in Hornberg, E. et al., PLoS One 2011. Vol. 6.

The following ISIS oligonucleotides were selected for further studies: ISIS 549372, which targets the human AR genomic sequence at exon 1; ISIS 549434, which targets the human AR genomic sequence at the 3'-end of exon 8 beyond the stop codon of AR; ISIS 560131, which targets the human AR genomic sequence at intron 1; and ISIS 569236, which targets the human AR genomic sequence at intron 1. Another antisense oligonucleotide, ISIS 554221 (ACCAAGTTTCTTCAGC, designated herein as SEQ ID NO: 178), was designed as a 3-10-3 LNA gapmer with phosphorothioate backbone targeted to exon 4, (i.e. the ligand binding domain) of AR identical to an antisense oligonucleotide designated as SEQ ID NO: 58 of U.S. Pat. No. 7,737,125 for use as a benchmark.

Example 15

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA on Androgen Receptor Protein Levels in MDV3100-Resistant C4-2B Cells

C4-2B cells are androgen-independent human prostate adenocarcinoma cells commonly used in the field of oncology and have been established as clinically relevant cultured cells (Thalmann, G. N. et al., Cancer Res. 1994. 54: 2577). MDV3100 or Enzalutamide is an experimental androgen receptor antagonist drug developed by Medivation for the treatment of castration-resistant prostate cancer. ISIS 549372, ISIS 554221, and ISIS 549434 were tested in MDV3100-resistant (MR) C4-2B cells.

The cells were cultured in the presence of 5 .mu.M concentration of MDV3100 over the course of 2 months to induce MDV3100 resistance. ISIS 549372, ISIS 549434, and ISIS 554221 at 1 .mu.M concentration of antisense oligonucleotide were each added to the culture media at 1 .mu.M concentration for free uptake by the cells. After a treatment period of 2 days, cells were harvested in RIPA buffer containing protease inhibitors. The presence of bands for full-length AR, as well as the variant form, AR-V7, was detected by western blot using AR antibody (N-20, Santa Cruz). Treatment of the cells with ISIS 549372 reduced full-length AR and AR-V7 more extensively than treatment with either ISIS 554221 or ISIS 549434.

Example 16

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA on AR-Target Genes in MDV3100-Resistant C4-2B Cells

The effect of antisense inhibition of AR on AR target genes was analyzed. ISIS 549372, ISIS 549458, ISIS 554221, and ISIS 549434 were tested in C4-2B MR cells.

Cells were plated at a density of 40,000 cells per well in 96-well plates and cultured in RPMI1640 medium with 10% fetal bovine serum. The cells were cultured in the presence of 5 .mu.M concentration of MDV3100 over the course of 2 months to induce MDV3100 resistance. ISIS 549372, ISIS 549458, ISIS 549434, and ISIS 554221 were each added at 0.04 .mu.M, 0.20 .mu.M, 1.00 .mu.M, and 5.00 .mu.M concentrations of antisense oligonucleotide to culture media for free uptake by the cells. A control oligonucleotide, ISIS 347526 (sequence TCTTATGTTTCCGAACCGTT (SEQ ID NO: 179) 5-10-5 MOE gapmer) with no known target region in human gene sequences, was included as a negative control. After a treatment period of 24 hrs, total AR mRNA levels were measured by quantitative real-time PCR using primer probe set RTS3559. Human AR primer probe set hAR_LTS00943 (forward sequence GCCCCTGGATGGATAGCTACT, designated herein as SEQ ID NO: 180; reverse sequence CCACAGATCAGGCAGGTCTTC, designated herein as SEQ ID NO: 181; probe sequence ACTGCCAGGGACCATGTTTTGCCC, designated herein as SEQ ID NO: 182) was used to measure AR-V7 mRNA levels. AR mRNA levels were adjusted to human actin mRNA levels. Results are presented in Table 38 as percent inhibition of total AR, relative to untreated control cells. Treatment of the cells with ISIS 549372, ISIS 549458, and ISIS 549434 reduced total AR transcript levels in a dose dependent manner more extensively than treatment with ISIS 554221.

Western analysis of full-length AR, as well as the AR-V7 variant, was also conducted in a manner similar to the assay described above. The assay demonstrated that treatment with ISIS 549372 and ISSI 549458 reduced levels of full-length AR and AR-V7. Treatment with ISIS 549434 reduced levels of full-length AR but not that of AR-V7. Treatment with ISIS 554221 reduced levels of full-length AR less extensively compared to ISIS 549372, and did not reduce levels of AR-V7. The control oligonucleotide ISIS 347526 did not reduce protein levels, as expected.

The mRNA level of the AR target gene, KLK2 was measured using the primer probe set hKLK2_LTS00963 (forward sequence CTTGCGCCCCAGGAGTCT, designated herein as SEQ ID NO: 183; reverse sequence CTCAGAGTAAGCTCTAGCACACATGTC, designated herein as SEQ ID NO: 184; probe sequence AGTGTGTGAGCCTCCATCTCCTGTCCAA, designated herein as SEQ ID NO: 185). The mRNA level of the AR target gene, KLK3 was measured using the primer probe set RTS1072 (forward sequence GCCAAGGAGGGAGGGTCTT, designated herein as SEQ ID NO: 186; reverse sequence CCCCCCATAGTGAATCAGCTT, designated herein as SEQ ID NO: 187; probe sequence ATGAAGTAAGGAGAGGGACTGGACCCCC, designated herein as SEQ ID NO: 188). As presented in Tables 39 and 40, treatment with I ISIS 549372, ISIS 549458, and ISIS 549434 reduced target gene levels in a dose dependent manner more extensively than treatment with ISIS 554221.

TABLE-US-00041 TABLE 38 Percent inhibition of full-length AR mRNA in C4-2B MR cells ISIS No 0.04 .mu.M 0.20 .mu.M 1.00 .mu.M 5.00 .mu.M 549372 35 47 88 91 549434 9 36 66 88 549458 41 78 94 97 554221 0 0 0 23 347526 28 35 31 17

TABLE-US-00042 TABLE 39 Percent inhibition of KLK3 mRNA in C4-2B MR cells ISIS No 0.04 .mu.M 0.20 .mu.M 1.00 .mu.M 5.00 .mu.M 549372 17 35 68 80 549434 10 47 42 64 549458 0 42 81 92 554221 0 0 47 56 347526 5 38 42 16

TABLE-US-00043 TABLE 40 Percent inhibition of KLK2 mRNA in C4-2B MR cells ISIS No 0.04 .mu.M 0.20 .mu.M 1.00 .mu.M 5.00 .mu.M 549372 14 16 57 87 549434 5 27 49 68 549458 35 47 87 93 554221 24 25 56 66 347526 28 29 23 22

Example 17

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA on the Proliferative Ability of MDV3100-Resistant C4-2B Cells

The effect of antisense inhibition of AR on the proliferative ability of cancer cells was analyzed. ISIS 549372, ISIS 549458, ISIS 554221, and ISIS 549434 were tested in C4-2B MR cells.

ISIS 549372, ISIS 549434, ISIS 549458, and ISIS 554221 were each added to the culture media at 0.04 .mu.M, 0.20 .mu.M, 1.00 .mu.M, and 5.00 .mu.M concentration of antisense oligonucleotide. ISIS 347526 was included as a negative control. After a treatment period of 6 days, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Table 41 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 549372, ISIS 549434, and ISIS 549458 reduced proliferation of the cells in a dose dependent manner more extensively than treatment with ISIS 554221.

TABLE-US-00044 TABLE 41 Percent inhibition of C4-2B MR cell proliferation ISIS No 0.04 .mu.M 0.20 .mu.M 1.00 .mu.M 5.00 .mu.M 549372 0 4 25 43 549434 0 0 21 22 549458 8 16 41 56 554221 11 12 0 24 347526 11 22 7 16

Example 18

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA on MDV3100-Resistant LMR20 Cells

An MDV3100-resistant cell line, designated as LMR20, was created. The effect of antisense inhibition of AR on the proliferative ability and AR mRNA levels of LMR20 cells was analyzed. ISIS 560131, ISIS 549458, and ISIS 569236 were tested along with the LNA gapmer, ISIS 554221.

LnCaP cells were incubated with increasing concentrations of MDV3100 for approximately 6 months. A single clone was selected after extensive culturing in the presence of 20 .mu.M MDV3100. The clone, LMR20, maintained the ability to allow free uptake of antisense oligonucleotides without lipid-mediated transfection, while demonstrating an approximately ten-fold increase in IC.sub.50 when treated with MDV3100, compared to parental LnCaP cells.

Study 1

LMR20 cells were plated at 1,500 cells per well in phenol red-free medium with charcoal-stripped fetal bovine serum (CSS), to remove any androgens from the medium (Life Technologies). ISIS 560131, ISIS 549458, ISIS 569236, and ISIS 554221 were individually added to the culture media at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M concentration. ISIS 549148, which has no known human target sequence, was included as a control. The synthetic androgen agonist, R1881, (Takeda, A. N. et al., Mol. Pharmacol. 2007. 71: 473-82) was added on day 1 at 1 nM dose to a set of cells also treated with each of the antisense oligonucleotides. DHT was added on day 1 at a dose of 10 nM to another set of cells also treated with each of the antisense oligonucleotides. MDV3100 was added on day 1 at a dose of 10 nM to another set of cells untreated with antisense oligonucleotide, which served as a control. After a treatment period of 5 days, the proliferative ability of the cancer cells was measured by the standard MTT assay. Results are presented in Table 42 as percent inhibition of proliferation, relative to non-treated cells.

As presented in Table 42, in the presence of androgen agonists R1881 or DHT, ISIS 560131, ISIS 549458, and ISIS 569236 significantly inhibited MDV3100-resistant prostate cancer cell proliferation in a dose dependent manner more extensively than ISIS 554221 Inhibition of proliferation by the antisense oligonucleotides was also either comparable or more potent than with treatment with MDV3100.

TABLE-US-00045 TABLE 42 Percent inhibition of LMR20 cell proliferation ASO ISIS ISIS ISIS ISIS Treatment (.mu.M) 560131 569236 549458 554221 MDV3100 CSS 0.04 0 0 0 0 0 0.20 0 10 0 1 5 1.0 9 0 0 2 0 5.0 16 12 5 16 11 CSS + 0.04 0 0 0 1 0 R1881 0.20 13 2 22 10 5 1.0 55 34 59 19 31 5.0 70 61 74 54 67 CSS + 0.04 0 0 0 0 0 DHT 0.20 13 10 25 0 1 1.0 57 32 60 10 13 5.0 71 57 70 36 41

Study 2

LMR20 cells were plated at 1,500 cells per well in phenol red-free medium with CSS. ISIS 560131, ISIS 549458, ISIS 569236, and the LNA gapmer ISIS 554221 were individually added to the culture media at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M concentration. ISIS 549148, which has no known human target sequence, was included as a control. MDV3100 was added on day 1 at a dose of 10 nM to a set of cells, and served as a control. DHT was added on day 1 at a dose of 10 nM for 72 hrs to one set of cells also treated with each of the antisense oligonucleotides or MDV3100. R1881 was added on day 1 at a dose of 10 nM for 72 hrs to another set of cells also treated with each of the antisense oligonucleotides or MDV3100. mRNA levels of AR, prostate-specific antigen (PSA) and TMPRSS2, an androgen-regulated gene (Lin, B., et al., Cancer Res. 1999. 59: 4180), were measured. Results are presented in Tables 43-45 as mRNA levels expressed as a percentage of the baseline values. mRNA levels may be lowered or increased after treatment.

As presented in Tables 43-45, ISIS 560131, ISIS 549458, and ISIS 569236 reduced AR mRNA levels in LMR20 cells, treated with or without either AR agonist, in a dose dependent manner relative to the baseline. Treatment with the LNA gapmer ISIS 554221 did not alter AR mRNA levels. ISIS 560131, ISIS 549458, and ISIS 569236 reduced PSA levels and TMPRSS2 more extensively than the LNA gapmer ISIS 554221 or MDV3100. Treatment with MDV3100 increased the levels of AR mRNA in cells treated with AR agonist, and did not reduce either PSA or TMPRSS2 mRNA levels.

TABLE-US-00046 TABLE 43 mRNA levels (% baseline value) of cells without AR agonist treatment ASO Gene (.mu.M) 560131 569236 549458 554221 MDV3100 AR 0.04 107 104 101 124 106 0.20 74 87 75 140 101 1.0 29 42 30 132 99 5.0 17 27 25 98 92 PSA 0.04 113 122 135 106 98 0.20 83 90 85 118 93 1.0 75 78 50 58 90 5.0 71 73 72 87 113 TMPRSS2 0.04 92 96 110 95 101 0.20 67 81 85 117 119 1.0 52 59 54 77 119 5.0 45 48 62 73 141

TABLE-US-00047 TABLE 44 mRNA levels (% baseline value) after treatment with DHT ASO Gene (.mu.M) 560131 569236 549458 554221 MDV3100 AR 0.04 89 94 91 137 105 0.20 55 77 66 135 124 1.0 25 44 34 136 110 5.0 20 34 31 100 143 PSA 0.04 74 108 93 97 124 0.20 61 79 71 86 108 1.0 35 46 47 64 95 5.0 35 46 47 64 95 TMPRSS2 0.04 112 113 127 121 134 0.20 108 123 119 118 144 1.0 93 111 106 122 132 5.0 71 110 91 114 124

TABLE-US-00048 TABLE 45 mRNA levels (% baseline value) after treatment with R1881 ASO Gene (.mu.M) 560131 569236 549458 554221 MDV3100 AR 0.04 87 89 88 131 94 0.20 65 80 56 133 107 1.0 30 44 25 124 115 5.0 26 37 32 99 136 PSA 0.04 92 90 93 100 84 0.20 77 90 67 93 101 1.0 44 57 50 80 92 5.0 35 41 44 57 87 TMPRSS2 0.04 132 126 137 136 114 0.20 117 131 119 134 125 1.0 88 98 96 125 133 5.0 76 95 96 122 139

Example 19

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA in Combination with MDV3100 on the Proliferative Ability of C4-2B Cells

The effect of antisense inhibition of AR in combination with different doses of MDV3100 on the proliferative ability of cancer cells was analyzed. ISIS 549372, ISIS 549434, ISIS 549458, and ISIS 554221 were tested in C4-2B cells.

C4-2B cells were plated at 1,500 cells per well. ISIS 549372, ISIS 549434, ISIS 549458, or ISIS 554221 were individually added to the culture media at 0.1 .mu.M concentration. ISIS 347526 was included as a negative control. MDV3100 was also added on day 1 at doses of 0.25 .mu.M or 1.00 .mu.M. After a treatment period of 6 days, the proliferative capacity of the cancer cells was measured with CellTiter 96.RTM. AQueous One Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Table 46 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 549372 or ISIS 549458 reduced proliferation of the cells more extensively than treatment with ISIS 554221. For instance, as presented in Table 46, treatment with ISIS 549372 alone reduced cell proliferation by 59% and treatment with ISIS 549458 reduced cell proliferation by 74% compared to ISIS 554221 alone, which reduced cell proliferation by 23%.

As presented in Tables 46 and 47, ISIS 549372 or ISIS 549458 in combination with MDV3100 inhibited prostate cancer cell proliferation to a greater extent than an equal molar concentration of ISIS 554221 in combination of MDV3100.

To find out whether treatment of the cells with ISIS 549372 or ISIS 549458 was synergistic with MDV3100, the assay was repeated at 0.1 .mu.M ASO. As presented in Table 46, treatment with ISIS 549372 or ISIS 549458 was synergistic with MDV3100. For instance, MDV3100 alone at 0.25 .mu.M inhibited proliferation by 4%; ISIS 549372 alone at 0.1 .mu.M inhibited cell proliferation by 23%; in combination, cell proliferation was inhibited by 66%. Similarly, ISIS 549458 alone at 0.1 .mu.M inhibited cell proliferation by 39%; in combination, cell proliferation was inhibited by 75%. Hence, the combination of ISIS 549372 or ISIS 549458 and MDV3100 was synergistic (i.e. greater than additive) in terms of inhibition of prostate cancer cell proliferation.

TABLE-US-00049 TABLE 46 Percent inhibition of C4-2B cell proliferation with 0.1 .mu.M ASO MDV3100 0 .mu.M 0.25 .mu.M 1 .mu.M PBS 0 9 38 ISIS 549372 23 44 66 ISIS 549458 39 59 75 ISIS 554221 9 29 59 ISIS 141923 0 4 38

TABLE-US-00050 TABLE 47 Percent inhibition of C4-2B cell proliferation with 0.2 .mu.M ASO MDV3100 0 .mu.M 0.25 .mu.M 1 .mu.M PBS 0 20 46 ISIS 549372 59 69 77 ISIS 549458 74 75 79 ISIS 554221 23 45 67 ISIS 141923 0 5 50

Example 20

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA in Combination with MDV3100 on the Proliferative Ability of LNCaP Cells

The effect of antisense inhibition of AR in combination with different doses of MDV3100 on the proliferative ability of cancer cells was analyzed. ISIS 560131 and ISIS 569236 were tested in LNCaP cells.

LNCaP cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was individually added to the culture media at 0.08 .mu.M, 0.04 .mu.M, 0.2 .mu.M, or 1.0 .mu.M concentration. ISIS 549148 was included as a negative control. MDV3100 was added to the ISIS oligonucleotide-treated cells on day 2 at doses of 0.016 .mu.M, 0.08 .mu.M, 0.4 .mu.M, or 2.0 .mu.M. After a treatment period of 5 days, the proliferative capacity of the cancer cells was measured with CellTiter 96.RTM. AQueous One or CellTiter-Glo.RTM. Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 48-52 as percent inhibition of proliferation, relative to non-treated cells.

As presented in the Tables, treatment with ISIS 560131 or ISIS 569236 was synergistic with MDV3100. For instance, MDV3100 with control oligonucleotide, ISIS 549148, at 0.08 .mu.M inhibited proliferation by an average of 7%; ISIS 560131 alone at 0.04 .mu.M inhibited cell proliferation by 24%; in combination, cell proliferation was inhibited by 41%. Similarly, ISIS 569236 alone at 0.04 .mu.M inhibited cell proliferation by 9%; in combination, cell proliferation was inhibited by 26%. Hence, the combination of ISIS 560131 or ISIS 569236 and MDV3100 was synergistic (i.e. greater than additive) in terms of inhibition of prostate cancer cell proliferation.

TABLE-US-00051 TABLE 48 Proliferation (% untreated control) in LNCaP without MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 106 76 50 26 ISIS 569236 106 91 60 35 ISIS 549148 104 101 91 82

TABLE-US-00052 TABLE 49 Proliferation (% untreated control) in LNCaP with 0.016 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 103 71 49 25 ISIS 569236 104 92 58 29 ISIS 549148 106 86 83 59

TABLE-US-00053 TABLE 50 Proliferation (% untreated control) in LNCaP with 0.08 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 99 59 48 27 ISIS 569236 98 74 51 31 ISIS 549148 93 101 89 90

TABLE-US-00054 TABLE 51 Proliferation (% untreated control) in LNCaP with 0.4 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 68 50 40 26 ISIS 569236 61 48 41 27 ISIS 549148 65 57 50 48

TABLE-US-00055 TABLE 52 Proliferation (% untreated control) in LNCaP with 2.0 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 45 42 38 23 ISIS 569236 44 41 35 23 ISIS 549148 39 42 41 32

Example 21

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA in Combination with MDV3100 on the Proliferative Ability of C4-2B Cells

The effect of antisense inhibition of AR in combination with different doses of MDV3100 on the proliferative ability of cancer cells was analyzed. ISIS 560131 and ISIS 569236 were tested in C4-2B cells.

C4-2B cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was individually added to the culture media at 0.08 .mu.M, 0.04 .mu.M, 0.2 .mu.M, or 1.0 .mu.M concentration. ISIS 549148 was included as a negative control. MDV3100 was added to the ISIS oligonucleotide-treated cells on day 2 at doses of 0.016 .mu.M, 0.08 .mu.M, 0.4 .mu.M, or 2.0 .mu.M. After a treatment period of 5 days, the proliferative capacity of the cancer cells was measured with CellTiter 96.RTM. AQueous One Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 53-57 as percent inhibition of proliferation, relative to non-treated cells.

As presented in the Tables, treatment with ISIS 560131 or ISIS 569236 was synergistic with MDV3100. For instance, MDV3100 with control oligonucleotide, ISIS 549148, at 0.4 .mu.M inhibited proliferation by an average of 6%; ISIS 560131 alone at 0.08 .mu.M inhibited cell proliferation by 16%; in combination, cell proliferation was inhibited by 31%. Similarly, MDV3100 with control oligonucleotide, ISIS 549148, at 0.08 .mu.M did not inhibit proliferation (0%); ISIS 569236 alone at 0.2 .mu.M inhibited cell proliferation by 37%; in combination, cell proliferation was inhibited by 52%. Hence, the combination of ISIS 560131 or ISIS 569236 and MDV3100 was synergistic (i.e. greater than additive) in terms of inhibition of prostate cancer cell proliferation.

TABLE-US-00056 TABLE 53 Proliferation (% untreated control) in C4-2B without MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 84 59 47 41 ISIS 569236 100 72 63 51 ISIS 549148 111 117 118 126

TABLE-US-00057 TABLE 54 Proliferation (% untreated control) in C4-2B with 0.016 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 104 71 53 39 ISIS 569236 107 74 65 55 ISIS 549148 110 107 124 103

TABLE-US-00058 TABLE 55 Proliferation (% untreated control) in C4-2B with 0.08 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 66 73 56 42 ISIS 569236 89 79 51 43 ISIS 549148 84 125 123 114

TABLE-US-00059 TABLE 56 Proliferation (% untreated control) in C4-2B with 0.4 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 69 69 48 48 ISIS 569236 90 63 48 39 ISIS 549148 89 110 88 88

TABLE-US-00060 TABLE 57 Proliferation (% untreated control) in C4-2B with 2.0 .mu.M MDV-3100 ASO Dose 0.08 .mu.M 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M ISIS 560131 37 42 49 43 ISIS 569236 44 45 48 46 ISIS 549148 47 40 52 59

Example 22

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA in Combination with MDV3100 on the Proliferative Ability of 22RV1 Cells

The effect of antisense inhibition of AR in combination with different doses of MDV3100 on the proliferative ability of cancer cells was analyzed. ISIS 560131 and ISIS 569236 were tested in 22RV1 cells.

22RV1 cells were plated at 2,000 cells per well in 5% CSS medium for 48 hours. Cells were transfected using RNAiMAX reagent with ISIS 560131 or ISIS 569236 at 0.4 nM, 1.34 nM, 4 nM, or 13.4 nM concentrations. ISIS 549148 was included as a negative control. DHT at 1 nM and/or MDV3100 at doses of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M were added after 4 hours. After a treatment period of 3 days, the proliferative capacity of the cancer cells was measured with CellTiter 96.RTM. AQueous One Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 58-62 as percent inhibition of proliferation, relative to non-treated cells.

As presented in the Tables, treatment with ISIS 560131 or ISIS 569236 was synergistic with MDV3100. For instance, MDV3100 with control oligonucleotide, ISIS 549148, at 1.0 .mu.M inhibited proliferation by an average of 5%; ISIS 560131 alone at 1.34 nM inhibited cell proliferation by 3%; in combination, cell proliferation was inhibited by 23%. Similarly, MDV3100 with control oligonucleotide, ISIS 549148, at 1.0 .mu.M inhibited proliferation by 5%; ISIS 569236 alone at 1.0 .mu.M inhibited cell proliferation by 17%; in combination, cell proliferation was inhibited by 30%. Hence, the combination of ISIS 560131 or ISIS 569236 and MDV3100 was synergistic (i.e. greater than additive) in terms of inhibition of prostate cancer cell proliferation.

TABLE-US-00061 TABLE 58 Proliferation (% untreated control) in 22RV1 without MDV-3100 ASO Dose 0.4 nM 1.34 nM 4.0 nM 13.4 nM ISIS 560131 103 97 77 57 ISIS 569236 97 83 69 37 ISIS 549148 109 109 109 99

TABLE-US-00062 TABLE 59 Proliferation (% untreated control) in 22RV1 cells with 0.04 .mu.M MDV-3100 ASO Dose 0.4 nM 1.34 nM 4.0 nM 13.4 nM ISIS 560131 96 80 65 39 ISIS 569236 83 70 61 24 ISIS 549148 106 106 100 85

TABLE-US-00063 TABLE 60 Proliferation (% untreated control) in 22RV1 cells with 0.2 .mu.M MDV-3100 ASO Dose 0.4 nM 1.34 nM 4.0 nM 13.4 nM ISIS 560131 95 90 76 51 ISIS 569236 93 77 60 20 ISIS 549148 101 115 110 96

TABLE-US-00064 TABLE 61 Proliferation (% untreated control) in 22RV1 cells with 1.0 .mu.M MDV-3100 ASO Dose 0.4 nM 1.34 nM 4.0 nM 13.4 nM ISIS 560131 96 77 63 40 ISIS 569236 79 70 52 18 ISIS 549148 106 95 98 82

TABLE-US-00065 TABLE 62 Proliferation (% untreated control) in 22RV1 cells with 5.0 .mu.M MDV-3100 ASO Dose 0.4 nM 1.34 nM 4.0 nM 13.4 nM ISIS 560131 91 76 63 41 ISIS 569236 82 72 52 24 ISIS 549148 96 102 98 85

Example 23

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA on CWR22-RV1 Cells

The effect of antisense inhibition of AR on the proliferative ability of cancer cells was analyzed. ISIS 549372, ISIS 549434, ISIS 549458, and ISIS 554221 were tested in CWR22-RV1 cells.

CWR22-RV1 cells were plated and transfected using RNAiMax reagent (Life Technologies) with ISIS oligonucleotides at 1.7 nM, 5.0 nM, 16.7 nM, or 50 nM concentrations. ISIS 347526 was included as a negative control. After a treatment period of 6 days, the target reduction and proliferative capacity of the cancer cells was measured.

Antisense inhibition of AR full-length mRNA was measured with the RTS3559 primer probe set. The results are presented in Table 63 as percent inhibition relative to non-treated cells. The reduction in V7 splice variant of the AR mRNA was also measured by RT-PCR using SYBR Green staining (Hu, R. et al., Cancer Res. 2009. 69: 16-22). The results are presented in Table 64, as percent reduction, relative to non-treated cells. Cell proliferation was measured with CellTiter 96.RTM. AQueous One Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Table 65 as percent inhibition of proliferation, relative to non-treated cells.

TABLE-US-00066 TABLE 63 Percent inhibition of AR full-length mRNA Dose ISIS ISIS ISIS ISIS ISIS (nM) 549372 549434 549458 554221 347526 1.7 24 27 28 24 0 5.0 53 46 41 41 3 16.7 64 69 61 67 4 50.0 78 86 78 72 0

TABLE-US-00067 TABLE 64 Percent inhibition of AR splice variant, V7 Dose ISIS ISIS ISIS ISIS ISIS (nM) 549372 549434 549458 554221 347526 1.7 23 0 18 25 17 5.0 35 20 34 1 0 16.7 56 4 58 7 0 50.0 82 23 82 35 10

TABLE-US-00068 TABLE 65 Percent inhibition of cell proliferation Dose ISIS ISIS ISIS ISIS ISIS (nM) 549372 549434 549458 554221 347526 1.7 0 8 0 17 0 5.0 0 15 0 11 0 16.7 25 13 17 27 0 50.0 53 38 40 47 0

Example 24

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA by Free Uptake of Antisense Oligonucleotide by C4-2B Cells

The effect of free uptake of antisense oligonucleotides on AR mRNA levels was investigated. ISIS 549372, ISIS 549434, ISIS 549458, and ISIS 554221 were tested.

Cells were plated at a concentration of 1,000 cells/well in 96-well plates to measure cell proliferation, and at 4,000 cells/well to measure target reduction. ISIS 549458, ISIS 549372, ISIS 549434, and ISIS 554221 were added individually at 0.04 .mu.M, 0.20 .mu.M, 1.00 .mu.M, or 5.00 .mu.M. After an incubation period of 24 hrs, mRNA levels were measured using hAR_LTS00943. The data is presented in Table 66. The results indicate that ISIS 549458, ISIS 549372, and ISIS 549434 inhibited AR mRNA expression more potently than ISIS 554221.

On day 6, cells plated for measuring proliferation were incubated with MTT reagent until the development of color. Color intensity was measured using a spectrophotometer at 490 nm. The data is presented in Table 67.

TABLE-US-00069 TABLE 66 Percent inhibition of AR full-length mRNA Dose (.mu.M) ISIS 549372 ISIS 549434 ISIS 549458 ISIS 554221 0.04 10 10 16 0 0.20 36 35 48 0 1.00 73 52 80 0 5.00 80 55 86 0

TABLE-US-00070 TABLE 67 Percent inhibition of cell proliferation Dose (.mu.M) ISIS 549372 ISIS 549434 ISIS 549458 ISIS 554221 0.04 8 0 7 0 0.20 34 14 31 10 1.00 44 35 45 21 5.00 45 37 41 30

Example 25

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA by Free Uptake of Antisense Oligonucleotide by LnCaP Cells

The effect of free uptake of antisense oligonucleotides on AR mRNA levels was investigated.

Cells were plated at a concentration of 4,000 cells/well in 96-well plates. ISIS oligonucleotides, specified in Table 68, were added individually at 0.02 .mu.M, 0.10 .mu.M, 0.50 .mu.M, 2.50 .mu.M, or 10.00 .mu.M. After an incubation period of 24 hrs, mRNA levels were measured using primer probe set hAR_LTS00943. The data is presented in Table 68. The results indicate that most of the ISIS oligonucleotides inhibited AR mRNA expression more potently than ISIS 554221 at each concentration.

TABLE-US-00071 TABLE 68 Percent inhibition of AR mRNA ISIS No 0.02 .mu.M 0.1 .mu.M 0.5 .mu.M 2.5 .mu.M 10 .mu.M 554221 0 0 0 0 17 549372 0 0 21 63 78 549458 4 14 67 86 89 560131 0 0 13 31 57 569213 3 0 31 59 78 569216 15 17 49 66 82 569221 18 31 49 78 91 569227 0 0 4 33 55 569236 3 2 21 43 70 579666 0 8 30 49 68 579667 0 0 8 12 40 579671 15 0 19 54 71 583918 8 0 0 0 13 584149 0 0 0 14 39 584163 0 0 19 41 70 584269 0 0 0 12 23 584468 0 0 10 44 73 586124 0 0 19 64 82 586227 0 0 14 44 59

Example 26

Effect of Antisense Inhibition of Human Androgen Receptor (AR) mRNA in the Presence of DHT on the Proliferative Ability of 22RV1 Cells

Dihydrotestosterone (DHT) is an androgen hormone and AR activator. The effect of antisense inhibition of AR on the proliferative ability of cancer cells treated with DHT was analyzed. ISIS 560131 and ISIS 569236 were tested in the human prostate carcinoma cell line, 22RV1.

22RV1cells were plated at 1,500 cells per well. ISIS 560131 and ISIS 569236 were individually transfected into the cells using RNAiMAX.TM. reagent (Life Technologies) at 1.34 nM, 4.00 nM, 13.4 nM, or 40.0 nM concentration. ISIS 549148, which has no known human target sequence, was included as a control. Separate sets of cells, also treated with each of the antisense oligonucleotides, were treated with DHT added on day 1 at a final concentration of 1 nM. After a treatment period of 5 days, the proliferative ability of the cancer cells was measured using the standard MTT assay. Results are presented in Table 69 as percent inhibition of proliferation, relative to non-treated cells.

As presented in Table 69, both ISIS 560131 and ISIS 569236 significantly inhibited prostate cancer cell proliferation even in the presence of AR activator, DHT, compared to the control. The control oligonucleotide did not show any effect on proliferation, as expected.

TABLE-US-00072 TABLE 69 Percent inhibition of 22RV1 cell proliferation ASO (nM) ISIS 560131 ISIS 569236 ISIS 549148 -DHT 1.34 0 0 0 4.0 2 18 0 13.4 29 47 4 40.0 54 64 0 +DHT 1.34 0 0 0 4.0 1 6 0 13.4 13 32 3 40.0 34 56 0

Example 27

Time-Course Study of Treatment C4-2B Cells with ISIS Oligonucleotides Targeting AR

The effect of antisense inhibition of on C4-2B cancer cells on gene expression was analyzed. ISIS 560131 and ISIS 569236 were tested.

AR mRNA Analysis

C4-2B cells were plated at 1,000 cells per well in complete medium. ISIS 560131 or ISIS 569236 was individually added to the culture media to the final concentrations of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M concentrations without using transfection reagent. ISIS 549148 was included as a negative control. MDV3100 was added at dose of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After a treatment period of 8 hours, 24 hours, and 48 hours, AR expression was measured with primer probe set hAR-LTS00943. Results are presented in Tables 70-72 as percent expression of AR, relative to non-treated cells. Treatment of the cells with ISIS 560131 or ISIS 569236 reduced AR expression in the cells relative to the control set. Treatment with MDV-3100 increased AR expression at the 48 hour time-point.

TABLE-US-00073 TABLE 70 Percent expression of AR compared to the control group in 8 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 110 85 68 45 ISIS 569236 100 87 84 58 ISIS 549148 116 105 111 110 MDV-3100 99 100 92 103

TABLE-US-00074 TABLE 71 Percent expression of AR compared to the control group in 24 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 47 18 5 4 ISIS 569236 103 35 15 5 ISIS 549148 87 85 87 107 MDV-3100 88 99 96 84

TABLE-US-00075 TABLE 72 Percent expression of AR compared to the control group in 48 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 33 5 6 4 ISIS 569236 80 19 7 2 ISIS 549148 98 90 87 99 MDV-3100 94 94 113 126

AR Protein Analysis

Protein levels in the cells were also analyzed. The cells were harvested in RIPA buffer containing protease inhibitors. The presence of bands for full-length AR was detected by western blot using AR antibody (N-20, SC-816, Santa Cruz Biotechnology). Full-length AR was significantly reduced in cells treated with ISIS 560131 or ISIS 569236 for 24 hours and 48 hours, normalized to the levels of the house-keeping gene, GAPDH.

mRNA Expression Analysis of Downstream Genes

Expression analysis of prostate-specific antigen (PSA) and TMPRSS2 were also analyzed. Results are presented in Tables 73-75 as percent inhibition of PSA expression and Tables 76-78 as percent inhibition of TMPRSS2 expression, relative to non-treated cells. Treatment of the cells with ISIS 560131 or ISIS 569236 reduced PSA and TMPRSS2 expression in the cells relative to the control set at the 24 hr and 48 hr time points. Treatment with MDV-3100 also reduced downstream gene expressions but not as potently as that with the ISIS oligonucleotides.

TABLE-US-00076 TABLE 73 Percent inhibition of PSA expression compared to the control group in 8 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 12 0 3 1 ISIS 569236 18 3 0 0 ISIS 549148 1 8 8 0 MDV-3100 0 3 23 33

TABLE-US-00077 TABLE 74 Percent inhibition of PSA expression compared to the control group in 24 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 27 46 56 60 ISIS 569236 10 34 44 54 ISIS 549148 22 13 16 6 MDV-3100 24 24 53 65

TABLE-US-00078 TABLE 75 Percent inhibition of PSA expression compared to the control group in 48 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 20 61 71 80 ISIS 569236 4 45 68 76 ISIS 549148 2 0 18 10 MDV-3100 5 5 32 63

TABLE-US-00079 TABLE 76 Percent inhibition of TMPRSS2 expression compared to the control group in 8 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 0 0 6 0 ISIS 569236 0 0 0 0 ISIS 549148 5 0 0 0 MDV-3100 0 6 45 52

TABLE-US-00080 TABLE 77 Percent inhibition of TMPRSS2 expression compared to the control group in 24 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 35 57 66 67 ISIS 569236 10 32 57 66 ISIS 549148 29 10 29 10 MDV-3100 23 31 63 72

TABLE-US-00081 TABLE 78 Percent inhibition of TMPRSS2 expression compared to the control group in 48 hours 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 46 71 77 76 ISIS 569236 22 57 70 75 ISIS 549148 0 4 0 0 MDV-3100 5 16 46 59

Example 28

Antisense Inhibition of AR mRNA in LNCaP Cells Cultured in Complete Media and CSS Media

The effect of antisense inhibition of AR in LNCaP cells cultured in complete medium, as well as CSS medium with DHT, was investigated.

Gene Expression in Complete Medium

Cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. ISIS 549148 was included as a negative control. MDV3100 was added a dose of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. .mu.M in a separate set of cells. After an incubation period of 48 hours, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Tables 79-81.

Protein analysis of full-length AR also demonstrated a dose-dependent decrease of expression, normalized to levels of the house-keeping gene, GAPDH.

TABLE-US-00082 TABLE 79 Percent expression of AR in LNCaP cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 101 53 17 7 ISIS 569236 98 90 47 20 ISIS 549148 102 111 109 109 MDV-3100 111 133 121 139

TABLE-US-00083 TABLE 80 Percent inhibition of PSA expression in LNCaP cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 0 60 87 90 ISIS 569236 0 19 63 81 ISIS 549148 0 0 0 0 MDV-3100 0 35 84 87

TABLE-US-00084 TABLE 81 Percent inhibition of TMPRSS2 expression in LNCaP cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 0 25 50 51 ISIS 569236 0 5 40 48 ISIS 549148 0 0 0 0 MDV-3100 0 0 34 39

Gene Expression in CSS Medium and CSS+DHT Media

Cells were plated at 2,000 cells per well and cultured in phenol red-free RPMI supplemented with 5% charcoal stripped serum (Gibco) media for 16 hours. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M to each cell set. ISIS 549148 was included as a negative control. MDV3100 was added at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After an incubation period of 4 hrs, DHT was added to the medium to a final concentration of 1 nM as indicated. RNAs were collected 48 hrs later and levels of AR, PSA and TMPRSS2 were measured. The data is presented in Table 82-85. In the absence of DHT, AR expression in LNCaP cells was 95%, PSA expression was 7% and TMPRSS2 expression was 24% compared to the untreated control.

TABLE-US-00085 TABLE 82 Percent expression of AR in LNCaP cells cultured in CSS medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 81 46 16 5 ISIS 569236 94 66 35 13 ISIS 549148 106 97 96 104 MDV-3100 91 67 64 77

TABLE-US-00086 TABLE 83 Percent expression of AR in LNCaP cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 101 71 27 10 ISIS 569236 104 86 55 21 ISIS 549148 98 102 96 111 MDV-3100 107 121 110 113

TABLE-US-00087 TABLE 84 Percent inhibition of PSA expression in LNCaP cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 10 21 21 72 ISIS 569236 4 11 45 59 ISIS 549148 0 8 0 9 MDV-3100 15 38 81 82

TABLE-US-00088 TABLE 85 Percent inhibition of TMPRSS2 expression in LNCaP cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 6 11 26 64 ISIS 569236 6 8 40 50 ISIS 549148 0 0 1 10 MDV-3100 8 24 60 69

Effect on Proliferation in CSS Medium and CSS+DHT Media

After a treatment period of 5 days in complete medium or CSS+1 nM DHT medium, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One Solution or CellTiter-Glo.RTM. solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 86 and 87 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 reduced proliferation of the cells in a dose dependent compared to the control. Treatment with ISIS oligonucleotides in CSS+DHT medium reduced the proliferative capacity to a greater extent than treatment with MVD-3100. The proliferative capacity of cells cultured in CSS medium without DHT is 17% of untreated control levels.

TABLE-US-00089 TABLE 86 Proliferation (% untreated control) in LNCaP cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 96 70 48 45 ISIS 569236 100 85 68 54 ISIS 549148 101 95 94 110 MDV-3100 107 88 65 45

TABLE-US-00090 TABLE 87 Proliferation (% untreated control) in LNCaP cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 97 81 46 8 ISIS 569236 95 99 54 17 ISIS 549148 112 96 95 89 MDV-3100 112 95 74 33

Example 29

Antisense Inhibition of AR mRNA in C4-2 Cells Cultured in Complete Media and CSS Media

The effect of antisense inhibition of AR mRNA levels in C4-2 cells cultured in complete medium, as well as CSS medium with DHT, was investigated.

Gene Expression in Complete Medium

Cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. ISIS 549148 was included as a negative control. MDV3100 was added at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After an incubation period of 48 hrs, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Tables 88-90. Treatment with ISIS oligonucleotide inhibited AR expression, whereas treatment with MDV-3100 increased AR expression in the cells.

Protein analysis of full-length AR and PSA also demonstrated a dose-dependent decrease of expression, normalized to levels of the house-keeping gene, GAPDH.

TABLE-US-00091 TABLE 88 Percent expression of AR in C4-2 cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 48 13 8 8 ISIS 569236 72 27 11 9 ISIS 549148 89 90 84 86 MDV-3100 95 99 132 137

TABLE-US-00092 TABLE 89 Percent inhibition of PSA expression in C4-2 cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 48 78 88 89 ISIS 569236 35 62 83 88 ISIS 549148 15 24 24 23 MDV-3100 28 40 72 89

TABLE-US-00093 TABLE 90 Percent inhibition of TMPRSS2 expression in C4-2 cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 29 62 76 71 ISIS 569236 17 54 67 67 ISIS 549148 2 7 10 0 MDV-3100 10 20 44 67

Gene Expression in CSS+DHT Media

Cells were plated at 2,000 cells per well and cultured in CSS media with 1 nM DHT. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M to each cell set. ISIS 549148 was included as a negative control. MDV3100 was added at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After an incubation period of 48 hrs, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Table 91-93. In the absence of DHT, AR expression in C4-2 cells was 153%, PSA expression was 42% and TMPRSS2 expression was 23% compared to the untreated control. Treatment with ISIS oligonucleotide inhibited AR expression, whereas treatment with MDV-3100 increased AR expression in the cells.

TABLE-US-00094 TABLE 91 Percent expression of AR in C4-2 cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 88 57 20 15 ISIS 569236 89 82 52 23 ISIS 549148 101 101 118 111 MDV-3100 101 109 156 148

TABLE-US-00095 TABLE 92 Percent inhibition of PSA expression in C4-2 cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 10 24 49 74 ISIS 569236 0 4 57 64 ISIS 549148 0 8 21 22 MDV-3100 9 8 51 73

TABLE-US-00096 TABLE 93 Percent inhibition of TMPRSS2 expression in C4-2 cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 10 17 51 78 ISIS 569236 0 11 61 67 ISIS 549148 3 0 22 28 MDV-3100 9 0 44 78

Effect on Proliferation in CSS Medium and CSS+DHT Media

After a treatment period of 5 days in complete medium or CSS+1 nM DHT medium, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One Solution or CellTiter-Glo.RTM. Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 94 and 95 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 reduced proliferation of the cells in a dose dependent manner compared to the control. The proliferative capacity of cells cultured in CSS medium without DHT is 17% of untreated control levels.

TABLE-US-00097 TABLE 94 Proliferation (% untreated control) in C4-2 cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 104 82 70 51 ISIS 569236 103 81 57 58 ISIS 549148 106 112 91 94 MDV-3100 105 108 71 67

TABLE-US-00098 TABLE 95 Proliferation (% untreated control) in C4-2 cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 106 94 47 31 ISIS 569236 99 99 88 51 ISIS 549148 102 82 82 91 MDV-3100 122 124 87 22

Example 30

Antisense Inhibition of AR mRNA in C4-2B Cells Cultured in Complete Media and CSS Media

The effect of antisense inhibition of AR mRNA levels in C4-2B cells cultured in complete medium, as well as CSS medium with DHT, was investigated.

Gene Expression in Complete Medium

Cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. ISIS 549148 was included as a negative control. MDV3100 was added at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After an incubation period of 48 hrs, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Tables 96-98. Treatment with ISIS oligonucleotide inhibited AR expression, whereas treatment with MDV-3100 increased AR expression in the cells.

Protein analysis of full-length AR also demonstrated a dose-dependent decrease of expression, normalized to levels of the house-keeping gene, GAPDH.

TABLE-US-00099 TABLE 96 Percent expression of AR in C4-2B cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 34 15 14 14 ISIS 569236 61 23 20 16 ISIS 549148 101 91 88 87 MDV-3100 108 121 157 182

TABLE-US-00100 TABLE 97 Percent inhibition of PSA expression in C4-2B cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 56 84 89 92 ISIS 569236 30 72 81 89 ISIS 549148 3 11 18 14 MDV-3100 8 27 73 88

TABLE-US-00101 TABLE 98 Percent inhibition of TMPRSS2 expression in C4-2B cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 46 71 72 75 ISIS 569236 33 59 69 73 ISIS 549148 0 2 4 0 MDV-3100 3 24 55 71

Gene Expression in CSS+DHT Media

Cells were plated at 2,000 cells per well and cultured in CSS media with 1 nM DHT. ISIS 560131 or ISIS 569236 was added individually at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M to each cell set. ISIS 549148 was included as a negative control. MDV3100 was added at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M in a separate set of cells. After an incubation period of 48 hrs, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Tables 99-101. In the absence of DHT, AR expression in C4-2 cells was 188%, PSA expression was 43% and TMPRSS2 expression was 27% compared to the untreated control. Treatment with ISIS oligonucleotide inhibited AR expression, whereas treatment with MDV-3100 increased AR expression in the cells.

TABLE-US-00102 TABLE 99 Percent expression of AR in C4-2B cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 55 31 15 13 ISIS 569236 67 49 24 19 ISIS 549148 91 104 101 95 MDV-3100 112 144 165 173

TABLE-US-00103 TABLE 100 Percent inhibition of PSA expression in C4-2B cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 0 17 50 61 ISIS 569236 0 5 33 46 ISIS 549148 0 0 0 0 MDV-3100 0 0 37 45

TABLE-US-00104 TABLE 101 Percent inhibition of TMPRSS2 expression in C4-2B cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 0 34 60 76 ISIS 569236 0 6 43 59 ISIS 549148 0 0 0 3 MDV-3100 0 11 48 66

Effect on Proliferation in CSS Medium and CSS+DHT Media

After a treatment period of 5 days in complete medium or CSS+1 nM DHT medium, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One or CellTiter-Glo.RTM. Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 102 and 103 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 reduced proliferation of the cells in a dose dependent compared to the control. Treatment with ISIS oligonucleotides in CSS+DHT medium reduced the proliferative capacity to a greater extent than treatment with MVD-3100. The proliferative capacity of cells cultured in CSS medium without DHT is 12% of untreated control levels.

TABLE-US-00105 TABLE 102 Proliferation (% untreated control) in C4-2B cells cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 93 50 50 41 ISIS 569236 98 64 55 48 ISIS 549148 119 97 103 98 MDV-3100 131 105 72 60

TABLE-US-00106 TABLE 103 Proliferation (% untreated control) in C4-2B cells cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1 .mu.M 5.0 .mu.M ISIS 560131 111 75 49 40 ISIS 569236 109 109 67 39 ISIS 549148 109 131 119 114 MDV-3100 125 100 83 17

Example 31

Antisense Inhibition of AR mRNA in VCaP Cells Cultured in Complete Media and CSS Media

The effect of antisense inhibition of AR in VCaP prostate cancer cells (Korenchuk, S. et al., In Vivo. 2001. 15: 163-168) cultured in complete medium, as well as CSS medium with DHT, was investigated. VCaP cells express both full length AR, as well as the V7 variant.

Gene Expression in Complete Medium

Cells were plated at 10,000 cells per well. ISIS 560131 or ISIS 569236 was added individually at 1.34 nM, 4 nM, 13.4 nM, or 40 nM using RNAiMax transfection reagent. ISIS 549148 was included as a negative control. After an incubation period of 48 hrs, RNA levels of full length AR, the V7 variant, PSA and TMPRSS2 were measured. The data is presented in Tables 104-107.

Protein analysis of full-length AR and the V7 variant also demonstrated a dose-dependent decrease of expression of both compared to levels of the house-keeping gene, GAPDH.

TABLE-US-00107 TABLE 104 Percent inhibition of full-length AR in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 0 59 77 84 ISIS 569236 0 41 49 74 ISIS 549148 0 8 5 17

TABLE-US-00108 TABLE 105 Percent inhibition of AR V7 variant in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 0 57 78 84 ISIS 569236 0 40 53 80 ISIS 549148 0 8 0 14

TABLE-US-00109 TABLE 106 Percent inhibition of PSA expression in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 2 24 35 46 ISIS 569236 7 19 40 52 ISIS 549148 2 0 0 20

TABLE-US-00110 TABLE 107 Percent inhibition of TMPRSS2 expression in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 0 0 0 4 ISIS 569236 0 0 0 36 ISIS 549148 0 0 0 0

A separate set of cells was treated with MDV-3100 at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. After an incubation period of 48 hrs, RNA levels of full length AR, the V7 variant, PSA and TMPRSS2 were measured. The data is presented in Tables 108 expressed as percent expression of gene levels compared to the untreated control.

TABLE-US-00111 TABLE 108 Percent of gene expression in VCaP cells treated with MDV-3100 and cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M 5.0 .mu.M Full length AR 136 135 160 178 AR V7 variant 172 179 244 237 PSA 105 76 75 61 TMPRSS2 131 121 135 141

Gene Expression in CSS+DHT Media

Cells were plated at 15,000 cells per well and cultured in CSS media for 16 hours. Cells were then transfected using RNAiMax reagent with ISIS 560131 or ISIS 569236 at 1.34 nM, 4 nM, 13.4 nM, or 40 nM to each cell set. ISIS 549148 was included as a negative control. After 4 hrs, 1 nM DHT was added. MDV3100 was added in a separate set of cells at doses of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. After an incubation period of 48 hrs, RNA levels of AR, PSA and TMPRSS2 were measured. The data is presented in Tables 109-113. In the absence of DHT, AR expression in VCaP cells was 555%, V7 variant expression was 656%, PSA expression was 11%, and TMPRSS2 expression was 22% compared to the untreated control.

TABLE-US-00112 TABLE 109 Percent inhibition of full-length AR in VCaP cells cultured in CSS medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 12 16 37 38 ISIS 569236 23 21 38 35 ISIS 549148 0 0 0 0

TABLE-US-00113 TABLE 110 Percent inhibition of AR V7 variant in VCaP cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 27 31 39 41 ISIS 569236 37 33 48 39 ISIS 549148 12 0 0 5

TABLE-US-00114 TABLE 111 Percent inhibition of PSA expression in VCaP cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 0 35 69 73 ISIS 569236 8 25 62 74 ISIS 549148 0 3 9 0

TABLE-US-00115 TABLE 112 Percent inhibition of TMPRSS2 expression in VCaP cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 0 21 49 57 ISIS 569236 6 19 40 54 ISIS 549148 0 0 0 0

TABLE-US-00116 TABLE 113 Percent of gene expression in VCaP cells treated with MDV-3100 and cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M 5.0 .mu.M Full length AR 114 94 142 233 AR V7 variant 82 65 101 181 PSA 90 72 57 30 TMPRSS2 115 96 70 42

Effect on Proliferation

After a treatment period of 5 days in complete medium or CSS+1 nM DHT medium, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One or CellTiter-Glo.RTM. Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 114-116 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 reduced proliferation of the cells in a dose dependent compared to the control. Treatment with ISIS oligonucleotides in CSS+DHT medium reduced the proliferative capacity to a greater extent than treatment with MVD-3100. The proliferative capacity of cells cultured in CSS medium without DHT is 12% of untreated control levels.

TABLE-US-00117 TABLE 114 Proliferation (% untreated control) in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 98 66 53 48 ISIS 569236 98 76 68 59 ISIS 549148 98 98 113 106

TABLE-US-00118 TABLE 115 Proliferation (% untreated control) in VCaP cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 95 65 42 37 ISIS 569236 83 68 61 45 ISIS 549148 114 123 104 92

TABLE-US-00119 TABLE 116 Proliferation (% untreated control) in VCaP cells treated with MDV-3100 Complete CSS + DHT medium medium 0.04 .mu.M 49 117 0.2 .mu.M 44 119 1.0 .mu.M 27 71 5.0 .mu.M 17 65

Effect on Apoptosis

After a treatment period of 72 hours in complete medium, apoptosis of the cancer cells was measured with Caspase-Glo 3/7 assay (Promega). Results are presented in Tables 117 and 118 as percent apoptosis of the cells, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 increased apoptosis of the cells in a dose dependent compared to the control.

Apoptosis was also measured by protein western blot analysis of cleaved PARP levels, which were shown to be increased in a dose-dependent manner in cells treated with ISIS 560131, ISIS 569236, and MDV-3100.

TABLE-US-00120 TABLE 117 Apoptosis (% untreated control) in VCaP cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 189 253 356 262 ISIS 569236 176 293 402 581 ISIS 549148 131 108 103 146

TABLE-US-00121 TABLE 118 Apoptosis (% untreated control) in VCaP cells treated with MDV-3100 % 0.04 .mu.M 186 0.2 .mu.M 210 1.0 .mu.M 612 5.0 nM 528

Example 32

Antisense Inhibition of AR mRNA in 22RV1 Cells Cultured in Complete Media and CSS Media

The effect of antisense inhibition of AR in 22RV1 cells cultured in complete medium, as well as CSS medium with DHT, was investigated.

Gene Expression in Complete Medium

Cells were plated at 1,000 cells per well. ISIS 560131 or ISIS 569236 was added individually at 1.34 nM, 4 nM, 13.4 nM, or 40 nM using RNAiMax transfection reagent. ISIS 549148 was included as a negative control. After an incubation period of 48 hrs, RNA levels of full length AR, the V7 variant, PSA and TMPRSS2 were measured. The data is presented in Tables 119-122.

Protein analysis of full-length AR and the V7 variant also demonstrated a dose-dependent decrease of expression compared to levels of the house-keeping gene, GAPDH.

TABLE-US-00122 TABLE 119 Percent inhibition of full-length AR in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 7 19 49 76 ISIS 569236 17 15 37 71 ISIS 549148 6 0 11 17

TABLE-US-00123 TABLE 120 Percent inhibition of AR V7 variant in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 12 29 57 81 ISIS 569236 30 2 46 81 ISIS 549148 0 0 22 26

TABLE-US-00124 TABLE 121 Percent inhibition of PSA expression in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 10 20 27 36 ISIS 569236 0 17 25 7 ISIS 549148 9 11 17 27

TABLE-US-00125 TABLE 122 Percent inhibition of TMPRSS2 expression in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 7 3 19 32 ISIS 569236 0 13 21 36 ISIS 549148 15 9 14 4

A separate set of cells was treated with MDV-3100 at 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. After an incubation period of 48 hrs, RNA levels of full length AR, the V7 variant, PSA and TMPRSS2 were measured. The data is presented in Tables 123 expressed as percent expression of gene levels compared to the untreated control.

TABLE-US-00126 TABLE 123 Percent of gene expressionin 22RV1 cells treated with MDV-3100 and cultured in complete medium 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M 5.0 .mu.M Full length AR 103 93 81 83 AR V7 variant 106 98 87 77 PSA 83 70 71 86 TMPRSS2 101 80 82 93

Gene Expression in CSS+DHT Media

Cells were plated at 2,000 cells per well and cultured in CSS media for 16 hours. Cells were then transfected using RNAiMax reagent with ISIS 560131 or ISIS 569236 at 1.34 nM, 4 nM, or 13.4 nM to each cell set. ISIS 549148 was included as a negative control. After 4 hrs, 1 nM DHT was added. MDV3100 was added in a separate set of cells at doses of 0.04 .mu.M, 0.2 .mu.M, 1.0 .mu.M, or 5.0 .mu.M. After an incubation period of 48 hrs, RNA levels of AR, AR V7 variant, PSA and TMPRSS2 were measured. The data is presented in Tables 124-128. In the absence of DHT, AR expression in VCaP cells was 555%, V7 variant expression was 656%, PSA expression was 11%, and TMPRSS2 expression was 22% compared to the untreated control.

Treatment with ISIS oligonucleotides resulted in significant inhibition of full length AR and the V7 variant, as well as downstream gene expression. Treatment with ISIS oligonucleotides resulted in inhibition of gene expression to a greater extent than treatment with MVD-3100.

TABLE-US-00127 TABLE 124 Percent inhibition of full-length AR in 22RV1 cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM ISIS 560131 65 85 93 ISIS 569236 59 89 97 ISIS 549148 2 13 22

TABLE-US-00128 TABLE 125 Percent inhibition of AR V7 variant in 22RV1 cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM ISIS 560131 63 83 93 ISIS 569236 54 88 97 ISIS 549148 19 19 32

TABLE-US-00129 TABLE 126 Percent inhibition of PSA expression in 22RV1 cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM ISIS 560131 3 50 66 ISIS 569236 28 49 70 ISIS 549148 8 23 29

TABLE-US-00130 TABLE 127 Percent inhibition of TMPRSS2 expression in 22RV1 cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM ISIS 560131 39 50 59 ISIS 569236 27 50 75 ISIS 549148 0 3 1

TABLE-US-00131 TABLE 128 Percent of gene expression in 22RV1 cells treated with MDV-3100 and cultured in CSS + DHT medium 0.04 .mu.M 0.2 .mu.M 1.0 .mu.M 5.0 .mu.M Full length AR 5 11 6 18 AR V7 variant 16 17 19 12 PSA 15 19 18 16 TMPRSS2 17 9 26 18

Effect on Proliferation

After a treatment period of 5 days in complete medium, the proliferative capacity of the cancer cells was measured with using CellTiter 96.RTM. AQueous One or CellTiter-Glo.RTM. Solution Cell Proliferation kit (Promega), following the manufacturer's instructions. Results are presented in Tables 129 and 130 as percent inhibition of proliferation, relative to non-treated cells. Treatment of the cells with ISIS 560131, ISIS 569236, and MDV-3100 reduced proliferation of the cells in a dose dependent compared to the control. Treatment with ISIS oligonucleotides in CSS+DHT medium reduced the proliferative capacity to a greater extent than treatment with MVD-3100. The proliferative capacity of cells cultured in CSS medium without DHT is 12% of untreated control levels.

TABLE-US-00132 TABLE 129 Proliferation (% untreated control) in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 94 72 50 17 ISIS 569236 92 53 20 7 ISIS 549148 97 97 101 83

TABLE-US-00133 TABLE 130 Proliferation (% untreated control) in 22RV1 cells treated with MDV-3100 % 0.04 .mu.M 87 0.2 .mu.M 83 1.0 .mu.M 81 5.0 .mu.M 74

Effect on Apoptosis

After a treatment period of 72 hours in complete medium or CSS+DHT medium, apoptosis of the cancer cells was measured with Caspase-glo 3/7 assay kit (Promega). Results are presented in Tables 131 and 132 as percent apoptosis of the cells, relative to non-treated cells. Treatment of the cells with ISIS 560131 and ISIS 569236 increased apoptosis of the cells in a dose dependent compared to the control.

TABLE-US-00134 TABLE 131 Apoptosis (% untreated control) in 22RV1 cells cultured in complete medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 99 127 131 566 ISIS 569236 91 141 333 1452 ISIS 549148 81 76 72 123

TABLE-US-00135 TABLE 132 Apoptosis (% untreated control) in 22RV1 cells cultured in CSS + DHT medium 1.34 nM 4.0 nM 13.4 nM 40 nM ISIS 560131 121 113 172 518 ISIS 569236 127 106 257 1136 ISIS 549148 113 94 102 108

Example 33

Effect of ISIS Antisense Oligonucleotides Targeting Human Androgen Receptor in Cynomolgus Monkeys

Cynomolgus monkeys were treated with ISIS antisense oligonucleotides selected from studies described above. Antisense oligonucleotide efficacy and tolerability were evaluated. The human antisense oligonucleotides tested are cross-reactive with the rhesus genomic sequence (GENBANK Accession No. NW_001218131.1 truncated from nucleotides 134001 to 308000 and designated herein as SEQ ID NO: 189). The target start site and target region of each oligonucleotide to SEQ ID NO: 189, as well as the details of their chemistry and sequence, is presented in Table 133.

TABLE-US-00136 TABLE 133 Antisense oligonucleotides complementary to SEQ ID NO: 189 SEQ Target Start Target ID ISIS No Site Region Sequence Chemistry NO 560131 59450 Intron TTGATTTAATGGTTGC Deoxy, MOE, and (S)-cEt 35 569213 59449 Intron TGATTTAATGGTTGCA Deoxy, MOE, and (S)-cEt 39 59479 TGATTTAATGGTTGCA 39 569216 59449 Intron TGATTTAATGGTTGCA Deoxy, MOE, and (S)-cEt 39 59479 TGATTTAATGGTTGCA 39 569221 59449 Intron TGATTTAATGGTTGCA Deoxy, MOE, and (S)-cEt 39 59479 TGATTTAATGGTTGCA 39 569236 59449 Intron TGATTTAATGGTTGCA Deoxy, MOE, and (S)-cEt 39 59479 TGATTTAATGGTTGCA 39 579671 59450 Intron TTGATTTAATGGTTGC Deoxy, MOE, and (S)-cEt 35 586124 59448 Intron GATTTAATGGTTGCAA 3-10-3 (S)-cEt 43 583918 3754 Exon AGTCGCGACTCTGGTA 3-10-3 (S)-cEt 124 584149 7260 Intron GTCAATATCAAAGCAC 3-10-3 (S)-cEt 150 584163 9811 Intron GAACATTATTAGGCTA 3-10-3 (S)-cEt 155 584269 41322 Intron CCTTATGGATGCTGCT 3-10-3 (S)-cEt 169 584468 109552 Intron CATTGTACTATGCCAG 3-10-3 (S)-cEt 175

Treatment

Prior to the study, the monkeys were kept in quarantine for a 30-day period, during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed between 2 and 4 kg. Thirteen groups of four randomly assigned male cynomolgus monkeys each were injected subcutaneously with ISIS oligonucleotide or PBS. PBS solution or ISIS oligonucleotides, at a dose of 40 mg/kg, were administered with a loading regimen consisting of four doses on the first week of the study (days 1, 3, 5, and 7), followed by a maintenance regimen consisting of once weekly administration starting on Day 14 (weeks 2 to 6). Subcutaneous injections were performed in clock-wise rotations at 4 sites on the back; one site per dose. The injection sites were delineated by tattoo, while sedated using ketamine, and were separated by a minimum of 3 cm.

During the study period, the monkeys were observed a minimum of once daily for signs of illness or distress. The protocols described in the Example were approved by the Institutional Animal Care and Use Committee (IACUC).

Target Reduction

RNA Analysis

RNA was extracted from liver, heart, skeletal muscle, kidney, and prostate tissues for real-time PCR analysis of AR using primer probe set RTS3559. The results were normalized to RIBOGREEN.RTM.. Results are presented as percent inhibition of AR mRNA, relative to PBS control. As shown in Table 134, treatment with ISIS antisense oligonucleotides resulted in significant reduction of AR mRNA, relative to the PBS control. `n/a` indicates that mRNA levels were not measured in that organ.

TABLE-US-00137 TABLE 134 Percent Inhibition of AR mRNA in the cynomolgus monkey relative to the PBS control Skeletal ISIS No Heart Muscle Kidney Liver Prostate 560131 32 30 19 65 27 569221 52 35 31 60 n/a 569236 42 47 42 33 32 579671 24 31 53 33 n/a 583918 76 74 73 88 58 584149 33 63 77 93 45 584163 53 73 90 98 58 584269 72 76 92 96 41 584468 33 53 88 97 50

Protein Analysis

Serum testosterone protein levels were measured in the plasma with an ELISA kit (Enzo Life Sciences), following the manufacturer's instructions. The results are presented in Table 135, expressed in ng/mL. The results indicate that some of the ISIS oligonucleotides reduced testosterone protein levels.

TABLE-US-00138 TABLE 135 Testosterone protein levels in the cynomolgus monkey ng/mL PBS 12.6 ISIS 560131 14.7 ISIS 569221 8.8 ISIS 569236 12.7 ISIS 579671 7.3 ISIS 584269 14.1 ISIS 584468 13.6

Tolerability Studies Body and Organ Weight Measurements

To evaluate the effect of ISIS oligonucleotides on the overall health of the animals, body and organ weights were measured. Body weights were measured on day 42 and are presented in Table 136. Organ weights were measured at the time of euthanasia and the data is also presented in Table 136. Specifically, treatment with ISIS 560131 was well tolerated in terms of the body and organ weights of the monkeys.

TABLE-US-00139 TABLE 136 Final body and organ weights in cynomolgus monkeys Mesenteric Body Spleen Heart Kidney lymph Liver Treatment Wt (kg) (g) (g) (g) nodes (g) (g) PBS 2.5 2.6 8.5 13 1.4 58 ISIS 560131 2.4 2.5 9.8 12 2.0 58 ISIS 569213 2.4 5.3 8.3 16 2.4 69 ISIS 569216 2.6 4.9 9.3 15 2.7 71 ISIS 569221 2.5 3.3 8.5 14 3.5 68 ISIS 569236 2.4 3.2 8.4 12 2.4 56 ISIS 579671 2.4 3.2 8.8 14 2.5 62 ISIS 586124 2.5 3.3 9.4 14 2.8 58 ISIS 583918 2.5 4.6 8.9 12 3.5 60 ISIS 584149 2.5 2.2 9.3 13 2.1 60 ISIS 584163 2.5 3.2 8.4 15 3.3 54 ISIS 584269 2.5 4.7 8.7 13 3.6 60 ISIS 584468 2.5 4.1 8.3 13 3.8 60

Liver Function

To evaluate the effect of ISIS oligonucleotides on hepatic function, the monkeys were fasted overnight. Approximately, 1.5 mL of blood samples were collected on day 44 from all the study groups. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min. Levels of various liver function markers were measured using a Toshiba 120FR NEO chemistry analyzer (Toshiba Co., Japan). The results are presented in Table 137. Specifically, treatment with ISIS 560131 was well tolerated in terms of the liver function markers.

TABLE-US-00140 TABLE 137 Liver function markers in cynomolgus monkey plasma Albumin AST ALT Treatment (g/dL) (IU/L) (IU/L) PBS 4.2 37 39 ISIS 560131 4.0 87 68 ISIS 569213 3.7 80 47 ISIS 569216 3.7 93 75 ISIS 569221 4.0 73 48 ISIS 569236 4.1 45 35 ISIS 579671 4.0 53 56 ISIS 586124 3.9 94 56 ISIS 583918 4.1 73 75 ISIS 584149 4.5 58 57 ISIS 584163 4.2 68 50 ISIS 584269 4.0 81 75 ISIS 584468 4.0 52 46

Hematology

To evaluate any effect of ISIS oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 0.5 mL of blood was collected day 44 from each of the available study animals in tubes containing K.sub.2-EDTA. Samples were analyzed for red blood cell (RBC) count, white blood cells (WBC) count, platelet count, hemoglobin content and hematocrit, using an ADVIA2120i hematology analyzer (SIEMENS, USA). The data is presented in Table 138.

The data indicate treatment with most of the oligonucleotides did not cause any changes in hematologic parameters outside the expected range for antisense oligonucleotides at this dose. Specifically, treatment with ISIS 560131 was well tolerated in terms of the hematology of the monkeys.

TABLE-US-00141 TABLE 138 Hematological parameters in cynomolgus monkeys RBC Platelets WBC Hemo- (.times.10.sup.6 (.times.10.sup.3 (.times.10.sup.3 globin HCT Treatment .mu.L) .mu.L) .mu.L) (g/dL) (%) PBS 5.3 426 13.6 13.2 43 ISIS 560131 5.8 392 11.3 13.1 44 ISIS 569213 5.6 426 12.9 12.5 42 ISIS 569216 5.6 504 12.2 12.8 43 ISIS 569221 5.6 406 11.1 12.9 45 ISIS 569236 5.7 358 14.4 13.1 44 ISIS 579671 5.4 438 10.0 12.5 42 ISIS 586124 5.8 391 10.4 13.6 45 ISIS 583918 5.8 435 12.7 13.3 46 ISIS 584149 5.7 478 11.3 13.7 45 ISIS 584163 5.5 461 9.1 12.8 44 ISIS 584269 5.2 522 9.8 12.4 41 ISIS 584468 5.9 408 11.1 13.5 45

Kidney Function

To evaluate the effect of ISIS oligonucleotides on kidney function, the monkeys were fasted overnight. Approximately, 1.5 mL of blood samples were collected from all the study groups on day 44. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min. Levels of BUN and creatinine were measured using a Toshiba 120FR NEO chemistry analyzer (Toshiba Co., Japan). Results are presented in Table 139, expressed in mg/dL. The plasma chemistry data indicate that most of the ISIS oligonucleotides did not have any effect on the kidney function outside the expected range for antisense oligonucleotides. Specifically, treatment with ISIS 560131 was well tolerated in terms of the kidney function of the monkeys.

Kidney function was also assessed by urinalysis. Fresh urine from all animals was collected on day 44 using a clean cage pan on wet ice. Food was removed overnight the day before fresh urine collection was done but water was supplied. The total protein and creatinine levels were measured using a Toshiba 120FR NEO automated chemistry analyzer (Toshiba Co., Japan) and the protein to creatinine ratio was calculated. The results are presented in Table 140.

TABLE-US-00142 TABLE 139 Plasma BUN and creatinine levels (mg/dL) in cynomolgus monkeys Treatment BUN Creatinine PBS 30.5 0.78 ISIS 560131 23.7 0.84 ISIS 569213 29.4 0.91 ISIS 569216 28.4 0.81 ISIS 569221 20.2 0.86 ISIS 569236 24.9 0.87 ISIS 579671 22.7 0.74 ISIS 586124 23.8 0.87 ISIS 583918 24.5 0.87 ISIS 584149 26.4 0.85 ISIS 584163 22.4 0.82 ISIS 584269 21.8 0.89 ISIS 584468 22.2 0.78

TABLE-US-00143 TABLE 140 Urine protein/creatinine ratio in cynomolgus monkeys Treatment Ratio PBS 0.00 ISIS 560131 0.02 ISIS 569213 0.02 ISIS 569216 0.08 ISIS 569221 0.00 ISIS 569236 0.02 ISIS 579671 0.00 ISIS 586124 0.01 ISIS 583918 0.01 ISIS 584149 0.01 ISIS 584163 0.01 ISIS 584269 0.00 ISIS 584468 0.00

C-Reactive Protein Level Analysis

To evaluate any inflammatory effect of ISIS oligonucleotides in cynomolgus monkeys, the monkeys were fasted overnight. Approximately, 1.5 mL of blood samples were collected from all the study groups on day 44. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min. C-reactive protein (CRP), which is synthesized in the liver and which serves as a marker of inflammation, was measured on day 43 using a Toshiba 120FR NEO chemistry analyzer (Toshiba Co., Japan). Complement C3 was also measured similarly, and the data is presented as a percentage of baseline values. The results are presented in Table 141 and indicate that treatment with most of the ISIS oligonucleotides did not cause any inflammation in monkeys.

TABLE-US-00144 TABLE 141 C-reactive protein and C3 levels in cynomolgus monkey plasma CRP C3 (% of Treatment (mg/dL) baseline) PBS 2.5 118 ISIS 560131 1.7 100 ISIS 569213 2.8 60 ISIS 569216 3.6 94 ISIS 569221 4.9 91 ISIS 569236 2.6 103 ISIS 579671 4.5 101 ISIS 586124 4.0 93 ISIS 583918 3.5 89 ISIS 584149 1.7 110 ISIS 584163 1.0 102 ISIS 584269 4.9 102 ISIS 584468 1.3 111

Pharmacokinetics Studies

The concentrations of the full-length oligonucleotide in the kidney and the liver of select treatment groups were measured. The method used is a modification of previously published methods (Leeds et al., 1996; Geary et al., 1999) which consist of a phenol-chloroform (liquid-liquid) extraction followed by a solid phase extraction. An internal standard (ISIS 355868, a 27-mer 2'-O-methoxyethyl modified phosphorothioate oligonucleotide, GCGTTTGCTCTTCTTCTTGCGTTTTTT, designated herein as SEQ ID NO: 190) was added prior to extraction. Tissue sample concentrations were calculated using calibration curves, with a lower limit of quantitation (LLOQ) of approximately 1.14 .mu.g/g.

The results are presented in Table 142, expressed as .mu.g/g tissue. The kidney to liver ratio was also calculated and is presented in Table 142.

TABLE-US-00145 TABLE 142 Oligonucleotide concentration of in cynomolgous monkeys Treatment Liver Kidney K/L ratio ISIS 560131 793 2029 2.6 ISIS 569221 966 1372 1.4 ISIS 569236 898 1282 1.4 ISIS 579671 871 2576 3.0 ISIS 584269 698 2823 4.0 ISIS 584468 474 2441 5.2

Example 34

Effect of Antisense Inhibition of Androgen Receptor (AR) on an Androgen Receptor-Dependent Breast Cancer Orthotopic Model

MDA-MB-453 cells express AR in the absence of estrogen receptors and progesterone receptor (Hall, R. E. et al., Eur. J. Cancer 1994. 30: 484-490). The effect of inhibition of AR mRNA expression with antisense oligonucleotides was examined in MDA-MB-453 tumor-bearing mice.

Study 1

ISIS 569216 (TGATTTAATGGTTGCA; SEQ ID NO: 39), which is the antisense oligonucleotide tested in the assay, was designed as a deoxy, MOE and (S)cEt oligonucleotide, and is 16 nucleosides in length. The chemistry of the oligonucleotide is 5'-Te Gk Ak Tk Td Td Ad Ad Td Gd Gd Td Tk Gk Ck A, where `e` denotes a 2'-O-methoxyethyl ribose; `k` denotes an (S)-cEt; `d` denotes a 2'-deoxyribose. The internucleoside linkages throughout the oligonucleotide are phosphorothioate (P.dbd.S) linkages. All cytosine residues throughout the oligonucleotide are 5-methylcytosines. ISIS 569216 has two target start sites, 58720 and 58750, on the human AR genomic sequence (GENBANK Accession No. NT_011669.17 truncated from nucleosides 5079000 to 5270000, SEQ ID NO: 1).

Treatment

MDA-MB-453 breast carcinoma cells (5.times.10.sup.6), mixed with 50% Matrigel, were injected into the mammary fat pad of 10 female NSG mice. Dihydrotestosterone (DHT) pellets, the active form of the major circulating androgen, testosterone, were implanted subcutaneously at the same time. Once the tumor reached a size of 100 mm.sup.3, the mice were randomly divided into two treatment groups. The first treatment group was injected with ISIS 569216 administered by subcutaneous injection at a dose of 50 mg/kg five times a week for 4 weeks. The second treatment group was injected with vehicle only, administered by subcutaneous injection five times a week for 4 weeks, and served as the control group. Tumor growth was monitored once a week and mice were sacrificed on day 32 after treatment. Tumor tissue and TB-interface samples were collected and processed for further analysis.

RNA Analysis

Tumors were excised and the tissue was processed for RNA extraction and qPCR analyses. AR mRNA expression was assessed at the TB-interface and normalized to actin mRNA expression. AR mRNA expression in mice treated with ISIS 569216 was inhibited by 48% compared to the control group.

Measurement of Tumor Volume

Tumor volumes were measured on a regular basis throughout the study period, using Vernier calipers. As shown in Table 143, tumor volumes were significantly decreased in mice treated with ISIS 569216 compared to the control group.

TABLE-US-00146 TABLE 143 Tumor volume on different days in the MDA_MB-453 cancer orthotopic model Day 16 Day 23 Day 30 Day 37 Day 44 Day 51 ISIS 569216 134 142 173 125 92 73 Control 111 141 155 195 287 347

Study 2. Treatment

MDA-MB-453 cells obtained from ATCC were maintained in Leibovitz's L-15 media with 10% FBS. Female NSG mice (Jackson Laboratories) were implanted in the mammary fat pad with 5.times.10.sup.6 tumor cells in growth-factor-reduced matrigel (1:1). DHT pellets were also implanted at the same time in the mice between the shoulder blades.

After 20 days, the mice were then randomly divided into treatment groups. Groups of mice were injected with 50 mg/kg of ISIS 569236 or ISIS 560131 administered subcutaneously 5 days per week for 2 weeks. A group of mice were similarly treated with control oligonucleotide, ISIS 549148 (a 3-10-3 (S)-cEt gapmer with sequence GGCTACTACGCCGTCA, designated herein as SEQ ID NO: 193, with no known human sequence). Another control group of mice was similarly treated with PBS.

Measurement of Tumor Growth

Tumor volumes were measured on a regular basis throughout the study period, using Vernier calipers. As shown in Table 144, tumor volumes were decreased in mice treated with antisense oligonucleotides targeting AR compared to the control group.

TABLE-US-00147 TABLE 144 Tumor volumes in the MDA-MB-453 model Day Day Day 0 Day 8 Day 13 20 Day 23 Day 27 29 PBS 136 336 331 358 338 417 481 ISIS 549148 148 303 312 365 413 490 550 ISIS 560131 144 261 243 204 232 233 258 ISIS 569236 134 283 260 230 264 329 323

RNA Analysis

RNA extraction was performed using an RNA extraction kit from Qiagen. AR RNA expression was measured using primer probe set LTS00943 and normalized to human actin mRNA expression.

Human AR RNA expression was assessed in tumor tissue. AR RNA expression in mice treated with ISIS 560131 was inhibited by 35% and AR expression in mice treated with ISIS 569236 was inhibited by 19% compared to the control group.

SEQUENCE LISTINGS

1

2151191001DNAHomo sapiens 1ctgacagaaa gcagatcatt ggttgcctga ggaggaggag tataggagag gtggagggaa 60aatgtacaaa gtggcacaat aaaaactttt ggaatcatag atatattcac tatcttgatt 120gagtgatgat ttcatgagtg cacgcgtgtg tcaaaaatga tcaatttatg caactttaaa 180tatgtgcagt ttattgtata tatcaattat acctcagtac ggctattaaa aagaaaccct 240ctggctgcac aatgcagaac tgattctagg aaagagtgga gggaggatga ccatttacag 300tgctccaggt ggaagagaac ggtgccttct ggaagtgaac taggttggca acaacagaga 360tgaaataaat gggcagatgt gtgagatact taggaaataa aacccgatgg tcaccatttt 420ccaaaggtca gctcatcctg gctttccaga gcaaagagct agggaagact ttattaataa 480atccctcttg aagttgcaga ggaagcttat agcagaaact tactctcaac ctgactaatc 540tgagagaaca cctctggttc catttgatta ctaaaaaact gcaaagaaca ggaggagaaa 600gaagaagaaa gctggtacaa acagtgaact tatataatat taatcaataa ttgtctcttg 660ttcttaaaag caatgggaag aaaatgagat ttgagctgga agatcagagt tcaaaatcca 720aataaagtat atggccctaa tatgcttata gtagttaacc tttcctgata atgatataat 780tgttgacagc accatcttta aaaataaaaa taacatagta atccttcaga tttgtagaat 840gctttcctgt ttacaagttt gttctataca cattatgtct tttaaatgac acactagcct 900tctgagggta acttatattg gcaacagttt tcagatgtgg aaactgtgaa gacaatgttg 960gtgatgtgga agcaacataa actttggagt ctttcagacc caggtttgaa tgtcagactg 1020ctttttattc agagtaactt cagagcatta tttctcacct taattttttt tcaggcctct 1080ttgtgtctat gtgtcctctt cactcctgtc cattgttcat tcagtgattt ttgcaccttc 1140cttcactgtt agtgtgtaga cacatagttc tcctggctct gagacctatg ttaattccat 1200tctaccatcc tgccagccca ctcaattcct attgagcaat gctagttgaa agttgtggtg 1260ggattaaatg ttgcaatgag tattcaaatg aggttgaagt atctacgcat tctacttaca 1320tatggtgagg tatattcaag gaaggctgta gccattaaaa tctcaggaaa taatttttca 1380cctcctcagg tgaaagggtc ttcaggcctt tgtgttctgg aaggttcatt tatagccatt 1440tcccaaatga caatgcgatt gatgagtcta gagtctagct caaatagcaa tggactggaa 1500gactagttta ggttttacta atgtggaaca tagaacaaat tatgtccttg tttcagcctg 1560ttcatctgtg aaatagagcc tatcatatcc agtcttcctt gcctttaggt ttgagttacc 1620ttctttggtc aaggtaagta aatgcctatg atgtttggct gtgcacaaga taaagctaca 1680acaaagctac aacccatctt ttctctgtag aagactgcaa aaagcaaaag agacccaggc 1740aaaaatctcg gaatgacttt tggaacagag agcctcccca gaatcagaag tcaaaggaat 1800ttaaaacata gggaggccca gggtctctac tgacataaag gaaagatgtt ttccttatag 1860gtttacgttt acattttctc tctctttcca ttcccacttg catctccacc tttacacagg 1920gcttatggga cctcctccac aaaagagcag ttgcagtaac ccacatcatc ctctacgcct 1980ggctgtccat caagaggcga aaagcagccc tatataggtt ctatccttgg atagttccag 2040ttgtaaagtt taaaatatgc gaaggcaact tggaaaagca agcggctgca tacaaagcaa 2100acgtttacag agctctggac aaaattgagc gcctatgtgt acatggcaag tgtttttagt 2160gtttgtgtgt ttacctgctt gtctgggtga ttttgccttt gagagtctgg atgagaaatg 2220catggttaaa ggcaattcca gacaggaaga aaggcagaga agagggtaga aatgacctct 2280gattcttggg gctgagggtt cctagagcaa atggcacaat gccacgaggc ccgatctatc 2340cctatgacgg aatctaaggt ttcagcaagt atctgctggc ttggtcatgg cttgctcctc 2400agtttgtagg agactctccc actctcccat ctgcgcgctc ttatcagtcc tgaaaagaac 2460ccctggcagc caggagcagg tattcctatc gtccttttcc tccctccctc gcctccaccc 2520tgttggtttt ttagattggg ctttggaacc aaatttggtg agtgctggcc tccaggaaat 2580ctggagccct ggcgcctaaa ccttggttta ggaaagcagg agctattcag gaagcagggg 2640tcctccaggg ctagagctag cctctcctgc cctcgcccac gctgcgccag cacttgtttc 2700tccaaagcca ctaggcaggc gttagcgcgc ggtgagggga ggggagaaaa ggaaagggga 2760ggggagggaa aaggaggtgg gaaggcaagg aggccggccc ggtgggggcg ggacccgact 2820cgcaaactgt tgcatttgct ctccacctcc cagcgccccc tccgagatcc cggggagcca 2880gcttgctggg agagcgggac ggtccggagc aagcccagag gcagaggagg cgacagaggg 2940aaaaagggcc gagctagccg ctccagtgct gtacaggagc cgaagggacg caccacgcca 3000gccccagccc ggctccagcg acagccaacg cctcttgcag cgcggcggct tcgaagccgc 3060cgcccggagc tgccctttcc tcttcggtga agtttttaaa agctgctaaa gactcggagg 3120aagcaaggaa agtgcctggt aggactgacg gctgcctttg tcctcctcct ctccaccccg 3180cctcccccca ccctgccttc cccccctccc ccgtcttctc tcccgcagct gcctcagtcg 3240gctactctca gccaaccccc ctcaccaccc ttctccccac ccgccccccc gcccccgtcg 3300gcccagcgct gccagcccga gtttgcagag aggtaactcc ctttggctgc gagcgggcga 3360gctagctgca cattgcaaag aaggctctta ggagccaggc gactggggag cggcttcagc 3420actgcagcca cgacccgcct ggttaggctg cacgcggaga gaaccctctg ttttccccca 3480ctctctctcc acctcctcct gccttcccca ccccgagtgc ggagccagag atcaaaagat 3540gaaaaggcag tcaggtcttc agtagccaaa aaacaaaaca aacaaaaaca aaaaagccga 3600aataaaagaa aaagataata actcagttct tatttgcacc tacttcagtg gacactgaat 3660ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt gaatctaccc 3720ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca ccgtgtgtct 3780tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct cccgcaagtt 3840tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg catcatcaca 3900gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt aggtggaaga 3960ttcagccaag ctcaaggatg gaagtgcagt tagggctggg aagggtctac cctcggccgc 4020cgtccaagac ctaccgagga gctttccaga atctgttcca gagcgtgcgc gaagtgatcc 4080agaacccggg ccccaggcac ccagaggccg cgagcgcagc acctcccggc gccagtttgc 4140tgctgctgca gcagcagcag cagcagcagc agcagcagca gcagcagcag cagcagcagc 4200agcagcagca gcagcaagag actagcccca ggcagcagca gcagcagcag ggtgaggatg 4260gttctcccca agcccatcgt agaggcccca caggctacct ggtcctggat gaggaacagc 4320aaccttcaca gccgcagtcg gccctggagt gccaccccga gagaggttgc gtcccagagc 4380ctggagccgc cgtggccgcc agcaaggggc tgccgcagca gctgccagca cctccggacg 4440aggatgactc agctgcccca tccacgttgt ccctgctggg ccccactttc cccggcttaa 4500gcagctgctc cgctgacctt aaagacatcc tgagcgaggc cagcaccatg caactccttc 4560agcaacagca gcaggaagca gtatccgaag gcagcagcag cgggagagcg agggaggcct 4620cgggggctcc cacttcctcc aaggacaatt acttaggggg cacttcgacc atttctgaca 4680acgccaagga gttgtgtaag gcagtgtcgg tgtccatggg cctgggtgtg gaggcgttgg 4740agcatctgag tccaggggaa cagcttcggg gggattgcat gtacgcccca cttttgggag 4800ttccacccgc tgtgcgtccc actccttgtg ccccattggc cgaatgcaaa ggttctctgc 4860tagacgacag cgcaggcaag agcactgaag atactgctga gtattcccct ttcaagggag 4920gttacaccaa agggctagaa ggcgagagcc taggctgctc tggcagcgct gcagcaggga 4980gctccgggac acttgaactg ccgtctaccc tgtctctcta caagtccgga gcactggacg 5040aggcagctgc gtaccagagt cgcgactact acaactttcc actggctctg gccggaccgc 5100cgccccctcc gccgcctccc catccccacg ctcgcatcaa gctggagaac ccgctggact 5160acggcagcgc ctgggcggct gcggcggcgc agtgccgcta tggggacctg gcgagcctgc 5220atggcgcggg tgcagcggga cccggttctg ggtcaccctc agccgccgct tcctcatcct 5280ggcacactct cttcacagcc gaagaaggcc agttgtatgg accgtgtggt ggtggtgggg 5340gtggtggcgg cggcggcggc ggcggcggcg gcggcggcgg cggcggcggc ggcggcgagg 5400cgggagctgt agccccctac ggctacactc ggccccctca ggggctggcg ggccaggaaa 5460gcgacttcac cgcacctgat gtgtggtacc ctggcggcat ggtgagcaga gtgccctatc 5520ccagtcccac ttgtgtcaaa agcgaaatgg gcccctggat ggatagctac tccggacctt 5580acggggacat gcggtaagtt tttccttcca gaaatgtcgc ctttcggccc agggcagagt 5640cactctgtgt tctggggtat ctagcggctc ctacctgcgc gaacactcag attgcccctg 5700ggagagctca gcagggtaaa cctagagctc tcccgtggac tcccggcctg ccagaggttt 5760aacctgagct ctcctaattt ctgctgcgtg ccctgggtgc tgattcctgc cctcccagat 5820tcttcaactc ccccaaccgc cccaaattct cactacctcc tggtactcga ggtcccaaac 5880agaaatccta ttgcacgggc caccttcaga gataaagctc ccaagccctc cactcttcct 5940ttcctcctgt cctcaaagtc tgagaacctc aacaggaatt tgggcaattt ctcctcttca 6000ggtctgttag gatttcactt tcagcctgcg cagattagag tcaaaaagac cggcccaata 6060gcttctcagc gggtatcctc cagagaggta aagtgaaatt ctcggttagg gaaagaaagt 6120ggtctctggg tgctgaggtc tgctgtgtga aagggtgaac ttctttctcc tgaagcaact 6180ggggacttgc tccagggctg gaggtcagta gagataatcc aaaccgtcat gtttagagta 6240ggcagagggg caactttctt ggtaaagact tcacaggatt tgcactcaca gtttctcaac 6300gttggttgac tatgttgaaa gtagttgctt gggtcggttt tctcttgtaa agtgtttatt 6360ttctctgtgg attataacag atccacagcc ccctacttca ggtttgcatc agatctataa 6420agaggagaat attcttttaa tgtacaattt aattaggctt gactctgact tacaaaactg 6480ttggaaaaca tttttttgta aagcatttcc tgctatttca gtgtgctcca aaatctccac 6540tggggagggt ggagtgaggt tttttattat attcctttat ttttaggaca tgtttgcatt 6600ttagaatatg tgcagttagc tctaacaaat tgagtaagaa ctcttaatga cctatgagcc 6660gtaatcttac cccaaagttt taattagcat atgagaaaag tggcaggcaa ttgcatcgtg 6720cttattaaaa attattcctc accgcagttg ttgagcttct tggagaccat gctgaagatt 6780ttctccccca gcaaattaag atattagttt atctgctgag ggaggacaga ctgaattggg 6840gaattaactc ctcaggtagg ccaggtgctg atgtccctgt ggacttttgt cttattcttt 6900gtttctatgg ctgttttctt ttacctgtga cttctccgaa atttctttgt tagccttaac 6960atctttgttt ggggacttaa atccagcaat ttgccttctt tcactgatgc tttccttctt 7020acaaggtaga tagcacagtg ttagtaaaga aagaaagagg agggtaggat ttcatattat 7080ttcgtgggct gttgaagaaa cagcttctta ccaggcttta cattccatta ggtttttaat 7140gtttgactta caagattttc agagggttca tttgatattg tcaaagtctt ttccagttaa 7200tttagactct tcatttttgt aatgggttta tgctatggga caaaaaaagt attcttcatt 7260ttataagaac aaatttactt ggtagggtta attttttttc tagggctgtc actagacggt 7320ggagcccctc ttctactgta aacttttctt gggggaaaat gtctaaggtg cattttgacc 7380tgccatgata ctaaacccag acactggaac cttccatctt ctgcatgcct cccccacaac 7440ttacttactt aacagggaaa aaactgatgg ttccacatat ttgctaaaaa atgtgtgcct 7500tcaaagacaa aaccaaaatt tttagggaat aactatagag agcaaaagtt actcccatca 7560agtagacaac gagcttggtg attttatttc aggtcttaat gaaaaaagct tctttatgag 7620gaaggttatc atatcttggt gcctccttga cagtccgctt aaattaatga cataaactaa 7680tgagaattta gcagttcctg cagaaagtac aagtttattt tttttttctg gtttgtgatt 7740gctgcactga atatgaggag tctagttaaa gggacaactg gtgttcctgt cttgtgagtt 7800gacgaagact ttccatttct aggatataga aaatccttaa gccggtttat tgaaaattaa 7860tcaatttaat cagaatgcaa tcaattccaa tacaaaagtt agtattttct ttctttttat 7920tgaaaattaa tttaatcaga atacaatcaa ttccaatcca aaagttgata ttttcttact 7980ttctcttttt ttccctcatt ttgtagggat acaatttggt gaaaggcaag agatttctta 8040agccaaagca agagtgtctt ccctctctgt gttgcatgca ttatgtgcca tgtttgagct 8100aaaaatctca aaattgggca ggcttccaat gacctgttgg gtccctccct ttaccattca 8160tgtgtgtgtt tatgtacata attttgtgga ggggtttttt taaaccttag taacatctgc 8220actcactctg tgttcttata catttacagt gtttctgctg agaggaggga agatgcaaag 8280gtggtctctt ttacttaatt tagcatgtgg tttgaacaga aggaaaaata aaaagtgatg 8340gggcttgtgt gcaaccctga tgatatttta tggagctgtc tgtcttctct ctgagatcaa 8400acaggactac aactttgtta attgaccact ggctcccttg gcaaaagtag ggcttcttat 8460attccagcaa gcagcacaat aatatgacaa aaatttattc ttgggagttg ggttctaaga 8520gagtgcatgc cagaattaga gtttggggtt tagagaaatt atccagatgc caaaagaaca 8580ttttaatttt tctcttggta atttgttctg gtctccatag taggtagtat tttagtagtg 8640ctttgatatt gacaagtctt gctccctttc tctattagat ttttcaaaat aaggcatttt 8700attaattcct ctttccttct cctctctcct ctcagttatc aagcattttt atgactatct 8760tacaagcaac agtttgtctt gtaaagcaga attttccttt gaaaccaaga cagattattt 8820ctgcccatag gcttcaggaa ccaatatttt ggcaagaagc atcttttctt tgtggtcagc 8880aaataggtgg tgagttctgt ctggatccca acaatcaaca cctgaggacc aaatagccac 8940actgggtggc accccattcg gaagtataca caggaagtag ccctcttgct tgttcacagc 9000tcaagtcagc caaagattaa cactggtgag agatattttc aaagaagttt gcaggcttcc 9060aattgcaggg tcattttggg gtgctttctt gcctgtacta attttatctc atcaagcttc 9120cattctttga gctgtaaact ttgaaataat atactggatt tgctggtacg tttaattttc 9180tttgttaagt gttttcattc ccatagtaat ttttcatcta gtgtacatat atgcatttaa 9240aacaaaaatt ctttggtctc cttatgcgta tatgcactgc ggcttgtaca cgtacaagct 9300acttggtggg attatgtgaa ctggagttag aaatgtggac aattttatta tgattatttt 9360taatggtgat atcaagatca ccagtttcat tcggaacctt gcataagcag ggagcagaat 9420gcggactggg tgtggcaaag caagggctta ttttatagcc aaacctgaaa tcacaactct 9480gaaaaataaa aaaaaaaaaa accaaacaaa aaaatcaagt tttgtgagct tggtcagaga 9540aggaaaagga aatctctccc taccccccac ctccaccatt ttctctttgt ctgcagcttc 9600ctcaagtgct gcctgtcccc gattttcttt tattccactc ctttcatgtt tttgacattg 9660aaatacagac tcttctttcc acttctcagg gtatttttct tattacacct gtggcatgct 9720cctaaagaat ttctttttta aaaaaaatct gtagagtagt agattagatt aaccccagta 9780tctctccctt aagactagat gacatgaggg gattgcaaaa tgaatagctg ggtttttttt 9840tttttttttt tttttacctt gaggttaaag cctggttcaa cagttgctga gagagttaac 9900tagattgctt gaggacttgg caatttcata aagtattttg tcttatgctg tctctgtctc 9960tgtcttgatc tctgtctctc tctgtctact gtaatgttgg ctactttctc tcagagcctg 10020agagacagct ctgagacact tcccaggtct gttcggttca gacctcagta gctggatcac 10080aagcagtacc caatatgcat atgagggtgc gtgctgcaag tgtccggctg ggctaatctg 10140cttaagcttc ataaaaatta atcatttgaa aacaaagaaa gatattaaag aaattattct 10200atctccgact tcccctatca gcattccatc aagttctggg atgttaaatt cagagaaagt 10260taaccttatc ttaaacacaa agttgacttt taaacaaaat tgcttataaa gttctgtaca 10320gttaccagca ttggttgccc tttgtcgtac ggaagagaat tatgaaatct catatttaca 10380tagcattctt ccaaaaaaag agacggtgtt ttccagttta ttcactgcat tcgtgtaagt 10440gtgagtaggc caggaggggt gcttagtgat tacccttttg ctaggtaaca aagtagaaag 10500ttagattttc tatgatattt gtttaccacg taggggaacc tctctagagc aatactccca 10560agctttttct tcttgaaatt tcccacctga cagataatac tttagattgt tgctcttaag 10620gacttctctc agtagctgct acatagagat gattgtccgt gaattattgc ttgcacactc 10680atgggtgatg ctactccctc tctctcatgg caattcttgc tgccaacctg caggccacac 10740caggattgag ggcagctcat ctcgataaat ttatagcatt aaagtgctgg gtcatttgag 10800aatgttgtca atttaggtta cttagtacct aagttttatt ctttaaataa cagctttatt 10860gagacgtaat ttacaatcca tacaattcac tcatctaaag tgtacagttt catgcttttt 10920agaatattca gagttgtgca accattattg caatcaattt tagaacattt taatcacccc 10980caaaggaaac cctatgcacc tttgtgttca tccccctata ttccctcagt ccttagcaac 11040caataatcta cttctatcta tggatgtgct tattctaaca ttttgtatga atgaaatcat 11100gtaatatgtg gtcttttgtg actagcttct ttcacataaa atatgttttc aaggtcatcc 11160atgttgaagc acatatcagt acttcactat tttttatagc ctaataatgt tccactatat 11220ggatatacca cattctatct atccatttat caggtgatga gcattacggt tgtttccacc 11280ttttggctat tatgaataat actgctgtga acattcacgt gcaagtttat tgtggacata 11340ttcagtccac atattttgga cattttcagt tcttttggat acatacatag gattgaaatc 11400tctgagtcat atgatacctc tgtgtttatc cttttgaaga actgtcaaac tgttttctaa 11460agtgtctgca ctgttttaca atcccatcag caacctatgg gggtccattt cttccacatc 11520cttgccaaca cttgttattc tctgtctttt tcattatagc tatattagtg ggtgtgaagt 11580ggtacctcat tgtggctttt atttccattt ccctaataac aaataatgtt cagtatccat 11640gttcttattg gccatttgta tatcttcttt tttgagaaat atctatttgg atcctttgct 11700cagtttttag ttgggttttt tattattgag ttttaagatt tttaaaaaat atattctgga 11760tacatgtcct ttaatagatt gtgatttgta gatatttttt cacattctgt gagttgtctt 11820ttttactttc cttttttttc tttttacgtt cttaatggta tctagattga agcacaaaaa 11880tgtttttaag tttgatgaag tccaattcat ctatttattt tctgttttgg cttatgattt 11940tggcgtcgta tctaagaagt ctttgcctaa tccaagatca caaagattta catatgtttc 12000cttctaagag ttttatagtt ttcgctattt acatttaggt ctttcatcag ttttgatgta 12060atgtttatat atgactgagg taggggtcca acttcattct tttgcatgta gatattcagt 12120tctcacaata ttgttgttga atctttcctc acttaactgt cttggcaccc tttgtgtaaa 12180atcagttgac cgtaaatgtg agggtttaat tgtggactct caactatatt cagttgatct 12240atatgtttat tcctatgccg gtaccacgtt atcttgatta ttgtaggttt ttagtgagtt 12300ttgaaattag gaattttgaa ctcttcaact ttggtcttct ttttcaagat tgctttggct 12360cttgtgggtc ccttgaattt tcaaatgaat tgggataagc ttgtcaattt ctacgaagaa 12420gtcagctagg attctcacag gaactatatt aaatctgtaa accaatttgg ggagcattgt 12480catctcaaca acgttaagtt attttcatcc ataaatatgc gatgtcttcc catttattta 12540ggtcttcctt ttgtcaacaa tttttattgt tttcagatta taagttttgc agttcttttt 12600aaaatttatt cctaagtgat ttattttttg atactataaa ttgaactgtc ttattgattt 12660tattttcaga ttattcgctg ccaatgtatg gaaatataat tgttttgtat attgatcttg 12720tatcctgcaa ccttgctgaa aatacctgag ttttgaatgc ttctgggact tatggggaag 12780agggcttctg ctgctgcact gaaagttaaa gcttacttca tttcatcctg tatgaaggct 12840gcatggggac attcttctca gttttactca gctataaatt cgaactggta atcccatccc 12900ctttcgggat gaataggaga gtgtttttaa atgttcatct ctttagagaa cagcaggaaa 12960gaagcctagt aaggtttggg tagtttataa tccctttttt agaatttgga tttgggaact 13020attagcaagg cagtgagtaa taataataat ttctatatag aaaactaaca tgtagaggtg 13080acaaatgaaa tcactagcta tattaggctt atgtttaggt tatcgtaagc agctaaaatc 13140ataattttat gtttttatat gttgtccttt ggacaaagta aattccagta ctccttctga 13200tgtgcatttc tagatgggga aaggattcat ttactctcat ataatttaag cttcttttta 13260gggatgtact ccatagccat gaagcaaaga taaaattcat ctatacacag actgaacttt 13320gtcttcatta acactctagg ctaagggtca tagctaatca gctacaactg taatgtcctg 13380ataattgtga attaactgca gggcacccag caaaaggttt agttataatc taatagctgt 13440ctgtagagat tagcctaata aagggatttt ttaaaaaaga atctggccgg gcatggtggc 13500tcaatcctgt aatcccagca ctttgggagg ccgaggtggg tggatcacct gagatcggga 13560gtccaagacc agcctggcca acatggtgaa accccatgtc tactaaaaat acaaaaatta 13620tccaggcgtt ttggtgagca cccacaatcc cagctacttg tgaggctgag gcaggaggat 13680cacttaagcc taagaggcag aggttgcagt gagccgagat catgccactg cactccaggc 13740tccgtcaaaa aaaaaaaaaa aaaagaatct atcaatcaac cacttttcat taagcacctg 13800ctatgtgccc agcatgtgct aggaagagat aaggtgaaag gggacacaat tcagacagaa 13860tcttcttgag gtaactgctt acgaggagct tatagccact aaaaacaaaa acaaacaaaa 13920accaaacaac caaaaaccaa acagaaatgc agtatcatca tgccatgatg cctgtatgag 13980atcctggatt gtacggtatg gatttcttaa aatgtagata ttttaaaaaa aaagaggaat 14040gaatcaatag aggctgaagt ggtcagcaat gttacctgtg gctgctttta atccttcgtg 14100gaagtaagta ggagcatgtc taaactcaag caatagatta aagatcttga tgtatatttt 14160aaataacaga agttagtacc actggaaaga atgaactgga ggaatgggtt gaaatctatt 14220tctgcttatt caatagtgca ccccagtcaa gttagttgcc aatttcttct tcagtttctt 14280tggctatatc attgcacttg gtgggtacat gtttatgatg tctttatctg aacaagtcag 14340caataatatg agtaataaat taaaattgaa ggtgattaat ggctctgaat ttgacataag 14400agttgttttc ctgccttcta agtttccatt gatcctgatg aattgcacaa accaaacaat 14460tcggggagta agggggcaca tgatgatctt ataagagctt tgctgtatta gacaacgtaa 14520cattctgaaa tggcctacca cctaacatgg gctctgttct ctgcaggttg agtaggttcc 14580ttgcttgtgg aactgtagtc ccgctatttg gccgctaggg ggactgcaag tgccccgtgg 14640caggatttcc ctgggaatgg tgagcctcca ttgatggttt caacacacag ccaaggccct 14700atcgcaggat aacttgaacc agaactgcct agcaccagac aataaataag ctactatggt 14760acttactgtt tcatttggga tgttgtttct cgaagtggca agcatttttt agtaatattt 14820tgacttttta atacctttct ttgcatatgg agcagaaaac agtgacactg gatatattca 14880agtagcactg tccagtttat agagaagttt catattccat tattgcattt cattcttgtt 14940tctacctttt acaagtaact agagtttgga gtattataat agtattcata ctattacagt 15000actattattc ccattataaa aattgtgcaa agagtggtta

agttacatgt ttacaatcaa 15060acagcttcaa agtgactgat ctggaatttc agtcccattc tttcttctcc agatcatgtg 15120ttccctgctt ttatctcaca gctcttttta ccttatagat gggaaacatg agagtcagag 15180aggcaaaaga accacaagtg gtatcaatac tagaaattta tgaatttctt aaggcttcta 15240ggtttgttac ccatccacca gactgatgga tttggttgtg tgagagttct gggtgccaat 15300aaccttgcca ttctacttta cagactgcat atattcaata aatgcttatt aagcatctac 15360tatatgccaa attctgtact aggcaccaat gatgtagtgg tgaacagaac agacaaaaat 15420ctcttcgtgg agcagacagt ttaatgagag gagacatgta gtgtacatct gagcatgaaa 15480agtgccatgc agaataactt cacagagtgt agggtataga gattgatggt gagagggaat 15540attttatatt tgctggccag ggaaaacctt actggaaaag taaattttga gtagtgacct 15600gaaggaaatt aggaaatgag ctgctatttg gacatctgga gttagaatat tccaggccca 15660gggaaccaca ggcgcaaagg gcctgaggca ggagcacact tgctgtgatg gaggacaaag 15720aggcccatat ggctggttta aataagtgaa ggatggtaga caatgagatc agagttaatg 15780aggttgcatg gtaggtcttc cttaggactt tgaattttac tcctaagcag gttgtattgg 15840acggttttga gcagggtaac atgacctgac ttacatttta acaggctccc tcctcttcat 15900aacatctgtc actctgatat attatacgtt tgtttgttta cttactgtat gtggggggaa 15960gagactgtgg gagcaagggg ggaagcaggg aaacaagtac actgcagtga tctgggtgag 16020aggtgaccgt gtctcagact aaggtggtat tggtggagaa ggtaggaagt ggctgaattc 16080tggatgagtt ttgatggtat agccaacagc atttactgac agattggata ttcactgtga 16140aaaaaataga gatgaggatg attgccaagt ttttggtctg agtaactgga aaaatgagat 16200tgccatttac tgaaatggtg aagactgtat gtagagcagg tgcatgggca gggtagaaat 16260caagagtttg atttttgact tataaagttt gaattatctg atgaacatcc tgatggcttc 16320ttctcagtta gttctcatgc agtgccttca gctttgctgt tcttcaagaa aattaaaaag 16380gaacttagag atcgcctagg ctgtaggtac cctctcccct ctttcctttt actttataga 16440ggtctataga agggtaggga cttatccaag gtgaaacagt gagctggcga cagaactagg 16500gcacaaaccc agttctcttg aattctgaat cagtagattt tcttttttta gtgtgattct 16560gaggactcat ttgggcaaga gtgagttttt tgttattgtt ttttgtttgt ttctttgccc 16620aaacctaaaa ccaggtaatt aaactaaata gtgaataaaa ctgggaaact atacaaattg 16680gttgctctcc ccaatcacac tgaaatatta ttatttttac tgaaccacat accaaaatat 16740ttttcctgta aaaacacagt aagtgaactt ttaaaggcaa ttgagctttt aacaaagcta 16800gaatctacag aggacctgga cagaaatggc cttaaatcct aggaaattag agttcatgga 16860acctgggaga ccatcttgtc cagctagctc attttatggg tgaggtgcct gaggcaccaa 16920gatggaaagg gacctggcta agctcataca gcaagctagt gcctgagcct agtcagagcc 16980tgttttaagg gttagtcgta tgttgttttc ttgaaaaaag ttacattgga aaagtgaaaa 17040ttctttggtc catactgaga acaaagaatt atacataatc atatataata ataatgatag 17100cacttcctga atgtttgctg tgtaaacttt ggcaccttgc atgaattgat tcatttaatt 17160ctcatgtcaa ctttaggaag caggcctaga gaggttaagg aacatgtcca agggtcacac 17220agctaggaag tagcagaact tgtgtgcact cccaggaagt ctggcttcta accacaaggt 17280tctaactact gtgcaatacc aggagcttct cagattaccc ttcaccttta ccaacccaaa 17340tgactggtga cgtaggtgac ttcattatgc tctgccccta ttatagtcca ctgatcctca 17400ccaaataggt gggtggccta gaggttaaag tagaggcaga gtgatggaaa ggggtggtta 17460gaagaagttg atgactcatg atagggattg gaaaacagga ctacaggaat tattgaaaag 17520ggcctagaga tcccaaggag gttgatctcc gactgctaca aacctgggca attcaatgcc 17580tgcttaaata ggagagttaa gataagaaaa ataaaattgc caatttttac agtcagacat 17640tgttttattt attttacatg tattaattca tttaatcctc aaaatactcc atgaggtagc 17700tacaattatc atttctatgt tgtagatgaa gaaacaggca cagagcaatt aaataacatg 17760cacaagatta gagaacaagt aagtggaagt gccaatatta gaatctaggt agttcagctc 17820cacaacttat gttattttcc actatattta tggaatgagg taattttctt ataacagaaa 17880gtttttaaaa tgcaaaaaca ttgtgcctga acttcaaaca ctgaacaact catatcctta 17940atatgcacca gtttctttta agcactctta gaaggaagga tacttaacct aatgtcacat 18000ggtgagtaag tagcagaacc ggaacttgaa tttgagactc cggactgcca gacctctttc 18060cactctatca cttgggctcc cttctaacat tgacttgtct ccctccattc ctcctccgta 18120ttgttctgcc cttcaccttt taattacctg tctccatcaa caagattgga cagagaattg 18180ggagagtgag cagagtccat ttccttccag agactggaca aaaggaacaa aatgttagga 18240aaaaatgtca gcatgtggga tttgtgggat ttacactaaa taagaaggga cacttcccag 18300gactgacaag atgctacctc cgtccctcta ggccccaatg tgttgtgcag gatcccatag 18360gaagtcatga atgtggttgt cagataacct ttttgttact gtggaaatgg aagcaggcta 18420ctgcaaaaat ctgtctctcc aggttttctt ttaaagaagg tagtcttgct aaatgataac 18480tatttcagca tttatttgaa aatgggcagt gcaggagaga aagaattttt ccaagcttgt 18540cacattgggc cacctctctg aagcattgtc caacttctaa ttagatgagg agactgcata 18600aaccaagagt tgagagtaaa gatggaaaca cttgatgttt ggtgtttggg tgcagaaagg 18660attccagaac atgttttggg tctctttact ctgtccatcc ctccttccct ttcatctttg 18720tttaaaaacc acagttagca aatgtgtagt ctgtttgcaa ttgttcatct gaaaaatttg 18780tttgatcagc cttttgaata aaaaagacca aattagactg agatatttca gtcaccaact 18840atctaataat agaccaaaaa ttttaaccat gctcatactt tcatatggta tgtagtttgc 18900tttagacatt ttctgggctt cagtgaggtg ctagattgac tcaaaatatg gcaggtcaga 18960tgtgggattg agcagggtgg actcttctct acccttccca attcagagtt ccccatcaaa 19020gatgatctca tagtgtttga aaaaccaagc tgaaggcttt gggaattagg gtgctgaagg 19080gatatgctgt ttcccaaagc cttctcagtc attccttctc cccccagttc agattcttaa 19140cacctctttc caggattagt gcagtgatcc cacgtccttt ctctctagct ctctctgcta 19200ctctctaatt cctattgtat ttgtgccacc agatctttcc aaagtttagc tccaatcttg 19260tctgtatact gctttaaatg tctattagtc tttaagctcc ttaagggtgg gagtcctgtc 19320ttattttttc cctattcttc gtgcttaatg caaaggaagc cttgctgtat agttgtgtaa 19380tgcatgatta caatttcagc ttctccccat tggcttatgg gttaaagtcc aaattattta 19440aatctggtgt tcaagtcctt ttatgatctg cttatttttc cagcctgaat tcctggagtt 19500cccttacaaa actcttaaaa cccagccaaa aggatctagt cactgtcact ttaaaccatc 19560ctcactctct tgttttttga acatgttatt tttcttataa tccctttgac cttgaaggct 19620atcccaattt caatactatc cattcttcta tgacagcccc ctacaaaatg aatattctca 19680acctcccaac ccaaggagaa gtgatctata tgacacaata tggttgaaag aatgttggct 19740tcacttcttt atctgtaaac caggggctag aaatctctag tttataagat tttgtggaga 19800ggggatcata tgtgattatg gatgttaggc acaagtcaag agtgcataag accttttgga 19860tttatccctt ttttctttct ccatcaatat ggtacttagt cccttaaatc agaagtactt 19920gtgttaatgt ctgataacgt ccttctaaat atacctctaa acatctgtct ctctttaggg 19980caaaggttgg atatatctgc aaagattctc tttggatata agatatccac agcacataac 20040ttaacagtgg tgtacacagt aggtattcca taagtatttc tttatgaaat gattcagagt 20100caatagtagt aagtaactgc caaaaacaac tgatggattg taagttccat taacataaat 20160acagtcagcc ctccatatcc atggattcca tatccacaga tttaagcaac tgcagatgga 20220aaatatattt tagagacaca gtaaaaataa caattcgaca gtaaaaaaat acaaataaaa 20280ttatgtaaaa caactattta cataacattg tattagctat tacaagtaat ctagatataa 20340atgaaatata tgggggatgt atataggtta aatacaaata tgacaccatt ttatatgttt 20400tagttaagga acatgaatat ttttggattt tggtattcat gggagtgggg gaatggaacc 20460atgccccttc aaataccaag ggactattat atgggacaca gaataaagga gttgattgtc 20520ttgctctgtt aaattctggt cagacacatt tgcaatgtat tgttcagccc cagtattcat 20580ggagcatctc cttttgtaaa gcatggagga gctgtgagag agacatggag cagtgaacat 20640aactattgtt tcaacgtacc tgaaggatta tcatggaata aagaagttag atgtttttct 20700gtagtacccc aaagggcaaa agcaatgagg acagattaca gttcagtaaa cgaaagaggt 20760tttttttttt tttttttttt ttttttgaga tgggagtctt cactcttgtc gcccaggctg 20820gagtgcaatg gcgcaatctt ggctcactgc aacctcgcct cccgggttca agtgattctc 20880ctgccttagc ctctggagta gctgggatta caggtgtata ccaccactcc tgggtaattt 20940tatttattat ttatttattt ctttatttat tttagtagag acggagattt catcatgttg 21000gccaagctgg tctcaaactc ctgactgcag gtgatccgcc tgcctcggcc tcccaaattg 21060ttgagattac aggcgtgaat caatgtgccc agcctgaaag atattttctt agaatagctt 21120ctttcaccct tcatcagaag ttgtcaacat ggaccatatg agttttgttt ggtctatatg 21180gtgtatatgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtatgt gtgtgtgttt 21240attgaattac ttgctaacat tttacttcaa aattcagatt tccaccatag ggaatgaaga 21300tctggcaata caggactttc attcctacat ggtaatgacc agctgtaggt gaaaagcagc 21360tgatcctctg gatgggccat gcactttgca gtttgcccag gcagcactga tccgctttat 21420tcatttaagt tacctgcttg actcttctag tcattcgagt atgtcatccc catcagatca 21480gagacctaag caaatcttgg gtcccttgct tactccaagg gctttcactc ctcgtatagg 21540aggagctaaa gaaatgtaca agcagcacca caataggatc agacctggct ttcaattcta 21600gcacggccac ataacatagt tggatgacct caggacagta acataacccc tctgagcctc 21660tagatcttca ttatctgtag agcactcttc ttatagagtt attataagaa tgaaataaaa 21720caactaggat aaagggcatg gcacttagta ggtgctgaaa tattagttcc cttcttctaa 21780ttcaccacac catatctgtc tatctattgg ctgaatcaca taaatagtaa attcacattc 21840actgaagaca ttcaagaaga gtctggaccc tttgggaacc atgtataggg caaaggtttg 21900aactcatagt agatgatttt tacagtcact ttttaacaat ttaaaagcct atagatgact 21960ccaaaatgcc catttggatg atatgaggca tactttgtgt agttaaggat tttaaataca 22020taacagagag gctgaagggc cttcgggaaa gaagctgggg taagagtcaa agtgtagtat 22080gttgaccgat gttcaggaat aggctttggc atctgacaga ttttgtttta aatactggct 22140ctgggtctta ctagcttcca gttctgggct gcttcacctc tcttgagttt cagtttcttc 22200atttctaaaa tgaagatact aatgcttcct ttgttgggtt tttgtgaata taagtgagat 22260aataaatgta aatatctagc ccagggcctg gtgcatagta caagcttcat aaattgtacc 22320tattattatt agtagtagta gtagtccaga caaacagagc ttgggaaaac gctagactct 22380ggctgacata catgggcttt tccccaggcc actgctgcct ggcttcccct tccacaaagc 22440tttgagtctc caaaatgctt tggctggaat gtaagcgtga ggtcattgca gataacaggg 22500gagcatgatt tgcttcggta atgcaagtta ttaagttact tccctcagcc cagctgaaat 22560ctcttattgg ttgatgtgtg cttcaaagtg tgagacagag ctagtctgag gagagaggga 22620gagtgagaag attcctcttc ttggccagag gtcatggtct tccacaagga acagaatgac 22680tcaatgcaaa ttatgggacc tctttgagtt tggggcccct acatttaaac tagtaactcc 22740gttgcacata ttggcaccct tcccccaaca aaattactgg gcaggaattt tcttgaatcc 22800ttccgtggcc tggaatgatc tcccttctca tccttgtgat ccacacagct ggcaaatggc 22860aggcagcaga acaaaaacaa gcctcttagc atatagggag agaaagagtc acagcagtac 22920tgaatttgct tgggaaccta atgttaacaa aggaccttcc tctcaacacc ccaaacagat 22980taaaacattt ttttaacagc aagttgtgtc tcggagcagc tctttgcttg ggtatattta 23040aagatctgct gagtcattta agagcaggct ggcatatcct aagaggcaag gactataccc 23100cagtctatgg gggagtaagt tgagaggtga aatctgtttg gctttctccc atggaaacaa 23160acaaggtgat ccacttccat ctcccacgac tctggagagc atctactaag ccttcttatt 23220ctatcaactt tgaactcctc agtgtataat agagtaaggg tgagagggaa ggagcagtcg 23280taccagtgtc attattggta tgttcaggag ttcaatttct tcctgattca gtcttggcgg 23340gatgtatttg tttgggaatt tatccatttt ttctagattt ttctagtttg tgtgcataga 23400ggtgttcata ataccttctg atagttattt ttatttctgt ggtgtcagtg gtaataaccc 23460ctgctgtctg aaattgtaat ggccctgcta ttggtagctg agagtagcat ggaagtgtca 23520ggttgatggg ttcatttaat tcttttcttt tcagtttcag tcacatgcat tgttaccatg 23580gcatatgaca gttgctagaa agtgaaataa ttttttttct actttattct ccactgcact 23640tctaaattta ttagtggaga aattagcagt taccaactgt tcattatagg tacacattgg 23700ggtttcctta gagccaattt tccccctggt tttcatcttg taaatctgta atcctaaaaa 23760ttagcaaaac ctagagcttc tctttggtcc tggcctgttt gaaccctgtt ccacagaccc 23820caatcttctt tcttgtttga ggcaactatc cttctctttg cccaccgcca ttttccttca 23880tctacttttc ccttctctag cacctcagac tgtcttccca cagtggcaca gcctcccact 23940ccactttcac tgtgccatct ccttgccatc aaaaccatcc tcacagaccc ttctgaaacc 24000acttctagga agggaaatca caatggatcc atgaaggatg ctttctggat gactttaaaa 24060gattggtatt aagatatttt atcagtggta gcaacactga cttattcagg cagccatgcc 24120ccggatctat aagaaatcag gtaagctaaa agttgcttga gctggcagga gacctagttc 24180tcttttttcc tttccctctt gcattttgtt tatcgatggt tttcaaagga cttagaggct 24240ggctttgtta tagttagttg gtaagagaaa tggtggagga ccggaaaatg ggagtggaac 24300gaatgagcat gtttgagact aagttattac aattcctagg atgtataaat tgcttgaaat 24360ctaccaagta ctttcagaca cattatcttt tttactcttc aaaatcaact tggaggtagg 24420cacaacaggg atcaaatcct tagttcacag atgagtaaac tgagactgga ggaaattaaa 24480ggagattcca aggtaactca gacaataagc aacagaacca ggatttggtg aattttttgg 24540ggggtgggag gtacagagtc tcactcaggc tggagtgcag tggcaaggtc tcgtctcact 24600gcaacctctg cctcctgagt tcaagtgatt ctcgtgcctc aacctcctga gtagctggga 24660ttacagacat gtgctacaat gcctggctaa tttttgtatt tttagtagag atgaggtttt 24720gtcatgttgc ccaggccggt cctgaattct tggtctcaag tgatccacct ccattggcct 24780tccaaagtgc agggattata agcatgagcc actgctccca gccccagacc attaattttt 24840gacagtaagt ccaacttttt tcaagttcac agctcagatt tgctattgaa tgaatgagta 24900tatatgtcat ttgggaacat tctttccaac ttttggttga agatttgttt tatcacttgt 24960gaaaattttt tttcattctt agcaatgtca gtttagttaa atgagcattt catttgcgaa 25020ttcactaatt aattatttta ttcatcaata catttcctga gtaccaactt tctatcaaac 25080cctgtgctgg attctgaggc tacaaagaga aataagatac catctcaggc ctctaaaatc 25140tcacagactg gggactgaca tctcagtagt aaacatatga acagcaactt gtgaaacgcc 25200attagcaaaa tctcaagtta tattcttcag tgactatggc catcctaaaa atggggtgtc 25260ttttatttgg ggtaaatgaa gatgaagcct tatgagaaat tgcattttaa tctaatcttg 25320tcttgctaag aacagaagtg gaatgtttca gcctctgtgt gtgtatttgt gtgtgtgaag 25380gttgagtgtg tgatgatgga tggggctgcg agattgttaa gtaggatcta tggggggcct 25440taaatggtcc tggtgagtcc caactttctg gttatgtatt tgagtagagt atgggggtga 25500caaagattgt tgtttaagag ttgattttag attttttcca agtaaatggt cagctgactt 25560ggagcatcat cattccactt gctttgaaaa cctgccactt aaggctcctt ccagtcatag 25620gttaactctt tctggtcaag tattactctt tttgagcatt tacctgtcag tgacaggtac 25680aatgttagat gttgtctctc tgttttcttg tttaatcttt actttgatcc taggtagctc 25740ttattagttc cactttatag gtaagaaact gaatttcaga gacttgaatg acttgttcaa 25800gatcacatag tatagtaact tggtagtttg ggacttgaat tttgattgtt cagttttttg 25860tttgtttgtt tcctggcctc cctgctgttt tcactattcc acaccacttc agctttattt 25920ttcatagagg ccattaaatg taccctccat cagccaaagc ctcttgcctc ccttcaacgt 25980aactcttctc tagcgtcctc ttaataatct tctgaaaagg ttttacagcc tttctgggta 26040ctgggaccca gagtcttaat ccaggctctt aagtgcctta tttaactgta atatggaaaa 26100tcaaagtcac agctaattca ggaaaaatga gtttgggatg tgaatttcct aggcaacttg 26160tcatctcttt tttacttcct tagcttcata aacttaccca caatgttccc tgaggactaa 26220gagtaatgga gggtgatgag gaaaggcttt cctcccttcc tttccgagag tcctttagcc 26280aaatgccaca cctcctcctg tttccctagt ctccgtgcag agatggaagt gggagataga 26340catgggttcc tttcagccct gagttcatgc cagggttttc tttccctcta gctggactga 26400ggtaggagga gaggttgaag tccaccaata agaccatgag tgaagaagac taaagtactt 26460gaaagagcag cagacctacg cttaaaatac tagggtttgt gtccagactt tgtgggttac 26520tatctgtata attttgggca agtcaacagt tctgagtcag agttccctta tcagcagatt 26580ggaagataaa ttctaattat atagatgaaa cattaagtct agaagtaatt tgtaaattca 26640gaaagggctt atagatttaa agtgtagccg ttttgattac cacaaactaa atcctatact 26700tcagggataa aatcttctcc tgttttttct aaaagcctgt gcatgtgtgg tgtaaggggt 26760gggttttccc ttgtaccagc aacttagcaa ttgtagtaac ggggctgagg gcagtggcat 26820gcttcttcat tgagcaagtg tgaaaagagg gttatgcatt caggggtcag cagatggcag 26880gcagagtagc ccctccaaat ctccctccca taccacaaag ccctcttatt tattcaaact 26940taacattaga agctcatttc aagtaggcac gtctgtgtct gggcgtctat tttccttctt 27000tgtatatagc aggcatttgt caacttggtg aaaagcatta ctcttctttc catttctgag 27060gactaattgt gcttcttcgc tagacacgag ttcaaaacag tgggttgaaa gagggcaagt 27120ttatgccaaa gaatcagaaa tagtcataat ttagagagaa ttctagaggt cagttccctt 27180tcgtatggac tgggcaactg aaacccagac agggaaggga attagaccaa gttcacaagc 27240acaaacactt tactggcaca ttcagattgg aaatcgaggg cttctgctcc caggtcagaa 27300ctaaatgccc tttctagcta gggtgttctt tgatctcagt gattttgact ctttctactg 27360cactctgggg acagtgggtt ctgcggtacc aactccaatt aaagtgggaa tatgtaccag 27420cccctcccct tggtttttat ttttcagagg cctggcagtc agagggattc tgatctctat 27480atgcaatatt ttcacactac tgtacttatt gaaatcacat ttgaatcttg gcaattaaca 27540aggcagtaat tggcatcagg agggtatgtt agtttgctta tctgcgccgt ccctcctctt 27600cccaacccac tgtgtattgc agaatgtttt atcagctctg atttgccaag ttgctctctt 27660ctccagtagg tgctgcgagc agagagggat tcctcggagg tcatctgttc catcttcttg 27720cctatgcaaa tgcctgcctg aagctgctgg aggctggctt tgtaccggac tttgtacagg 27780gaaccaggga aacgaatgca gagtgctcct gacattgcct gtcacttttt cccatgatac 27840tctggcttca caggtgggag gttcttcaat tgaaaactta gaactcagtt tctagggtag 27900tgagtgttgt aaggtttgga ctgtgaccta atattacgca gccatgacat tatctattag 27960gcatctagac tagcttgctt gaatatctta gcatgttgac taatttgggg cagaatatag 28020tgtgggtggg ggattttgtg tgtggggggg ggttgggggt tgagcaattc attattatta 28080aaatgcaaaa agcacttaat tcgctatgat aagattgcct ttttcatgca tactggccta 28140cctgcaagac ccctagagac agtaagcagc atacatggtg tcttccagtt ttcagccttt 28200gtgcaaggaa caactgtggg tttctgcaca tgtgttgtgg tttgatgttt gtatgtgatt 28260gtgtaccagg gtatgtgtgt ctgttattgt gagttcattt ctgagcagtt gtgacacaca 28320gagatccaga aacagtgtct taccctgtgt gctttgctag tgggaacgtg tcttttcttt 28380tgtgctcgta tctctgtgta atcgagtgtc ttgctaagtc aatgtgcctc tgtctctttt 28440taccagttct gtctttgtgt ctctgtgcct tcatgtattt tttcccctga gtttgcacgt 28500ctctgtctat gtggatatct ctcactccag gccactgtat cactgtgtct gtattacagc 28560tgtttatttc tgtcggtgtg tggatttcta tgtctgtttt catcttaatt tgtgtgtcta 28620agcaagactg ttttggggtg actatttcag tttatgtcat agccattctt tgtgtgactg 28680cttctaggta tgtctttttc tatgccccta ttgtccccat ctccatgtgt ctctgtgtgt 28740atatgttcta atgtatctgc ctacttatct tagtttgtat ttctctgggt gtatatccct 28800ctcttgcagt tctgggcctt tgcagttttt ggcttatgtt tttgtatata tccactagaa 28860ttggcttctt atcttttttg tgcatgtttt agtttgtatg agtgagcata tccaactctg 28920tctttgagaa gcagaactgt ctgtgtttgc agtcagttgt gttggctgtc cctgtgtttg 28980tccctgtgtg tgcatttcat tgtatgtgta cgcatccatg tatctttctg cttctctgtg 29040accagatatt tctgtgtagc tgtctatgta tattggcttc tgtctgtgtc tgtgttgttg 29100gctctacgtc tgtgcatatg cacccaccgg gttcataaaa agctcacctg ctctccaagg 29160aatctaccag attattttgt gaaataactc acgtttcgtt tttttacttg ccagctgcta 29220tggtacttaa aagtgtgttg gtacgtaggt gtgcataatt tattcatgta ggatgtcaaa 29280agagtcagtt aaaaattatg cacagtgtgt ctttattaac aggacacttg tgtgtagaga 29340atccttgaga aatgagtggt tagatgataa atcttttcat attaatttca tgatgtcagt 29400gaagtaaatt tgcaagatat gggctgcata agaactatgt tctttttaaa actcagcata 29460ttgatggtgg agaaagcatt tatttgtact gcaaagtctt atttctgata agacatcaca 29520aataagaatt attgtgatga gacttatcac aaataagaat tattgtgata attcttattt 29580gtgataagaa ttactgggtt agaaggtgtt acttttctgg ttttgtttgg gtttttgttt 29640tgaagtgtta ctacagatgg tgtcttaggg acaaagagct ctgaggttga cttagaacac 29700atggagtaca gataaaaagg agaatgaaaa gtaacagaga gatgggcata ttccttgttt 29760gaatggagtc atccaggggc tcaggatgga gtgcacagga aatggagagg tgaaggtcat 29820agagagaagt ttagcaggac cagatctttc cttgtcctgg gctgctgtga ccatataagg 29880aaggcagtaa ggggaggggt agggatgagg aagagaccag ctctcctctt tctttctgat 29940ggaaggttac cacctctatt taaaacttct gttcttttgg tttctctttc tttctttgat 30000tatattattt tctggacttg ttctgccaaa gcaagaagga aattccacat gtggctcact 30060catttattat acttgtttct ttgcacgata ttaaagacag

cttgttaagt gtcactgcaa 30120acatcataca cactgatcca ctgatatggg cagggggttc tttatgccag ttctgctctc 30180ttcccagtgt atctgtggtg cttaatgggc gcaaccatga tttttctgat gtcagtctgt 30240gatgtcagtt gtccagtgtg tatgcaggct gcttaagagt acatacagtt ccttcacaat 30300tatggtagtc cctgagaagg aagtggtcat taataaaaga ctaggttcag tagaaacatg 30360taagttgtct aggtgttgga aattaataca gtactgtgct aagggaacat atatctagaa 30420gttaactgaa ttatgctcaa taaaaagagt acaaatgttt cataaatatt ttgacctaat 30480cctcctgtaa gattaggaga gggatatttc cgatattcaa ataatttttt taattggcaa 30540acaccttaga catactattt acataaaatt gacatgacaa aattaagtca ttgtgtctgt 30600tttatgataa aacaggctct tttgatttag ttagaattat tgaatgtaaa ataatgaaaa 30660ttaaaaaaaa aacaaggagg aggaatctat cctattttat aattcagacc gttgaattga 30720gtttttcttt tgttgtattg atttaaatgc agagaagtct atgatgctgg attccagtca 30780gaagataaac atttgtatgt gggctctaca ttgcagccaa ccttgataat ttcaaacctc 30840gattttctca tctgtataat ggtaataata aagcctgtct cagtagctac caaatgattg 30900catatgacaa acttctcact tatttaaggg aaaaaataag aaaaagaagg acaatagggt 30960ggatttttca tatagtaaaa tttattcagt tagggtaata ttctgagatt gtcttctgaa 31020gcaaaccctg caaaccctgg ccattctgtt ttgtttagga aagaattcat cagttctgat 31080tctgcctttt ctggggaggg aggctgagta ttggattgaa gaggagtcac tacttttctg 31140agatgatata tccgtggtaa aaattattaa tgctttgcac atgcaacata gagtgttcaa 31200ttttgttagt caacaaatat ttaagtggca gctgttatga cctcaggggt gtagtgactt 31260ccttattgtc ctttaattat taaaaaagaa atctatatca gaatatcagg taaactctta 31320ttacatcaaa tattataata aagatacttt ttatattctc taaacaaagt agagatctca 31380gatgttggtt catttatcaa tataatatta gatttgaaaa ttccagtata caaaaggaaa 31440aggacagctt cttaaagttt atagtgattt tctatgaact atcaattccg tttttttctg 31500ttttactggt atgatggaaa ctaaatttcg agttgtaagt agtagataat tagactgcag 31560ggtaagcctt gagattactt cttttcaggt aggaaactct actgtgtatt tggctagttc 31620aacctatcat gggtagtcaa aaatagttac atatacaagt cagcattttt taaattgttc 31680agttgtgctt aagattggtc ctttccagga acaatccagc tttatcaaaa aattattgcg 31740tacatgtaaa gtgttctgac attttaatgc tcacaatagc cgaatgacgt gggtaagaat 31800cttcgtcttc attttataga tgaagaaatg aagacacaga gacataaatt aactgggcca 31860gggtcctacc actagaatgt gatagatgat aatttgagct cagcacatag ttatttccct 31920ataatatttg ttttatgatt gtatagatgt ctgctgacca accttaatct ctgctcccta 31980agattaacca ttctacaaag cagaaactgg aggtcattca aatgaaagct ctacactttt 32040agagggccat taacaatgct caagttaaag aaaagcaatc aaagacaact aaaatactgg 32100taccttcaaa cagtacttat gaattattta accttagata atttggcttt gagttagaaa 32160gatagagtaa gatggaggaa ccaattcttc cctgggttga tatttattta tcttgctctt 32220ttgaagtcta ggccaatcat cctatttatt ctgaatggcc cgttaacgtt tatccattta 32280gggacagcag gtttggcaca aatggattgg ttttctgagg tcttatgtag agggctgcac 32340tgactgactt ctgaaagtcc cccctaaccc ttcaaatctc agggtcatct ggtctcaagc 32400cttcaattat gaatacattt ctattgcctt tttgagtaac agcacaacac tgcaagctga 32460cccactgggt ggatggaatg gggctcttgc cctaccaccc tttggcaaac aatttgaggg 32520tggcattgtc actacctcat tgtatatagg gtctcttgag gcccagaatg gcaaaataat 32580tttcccagtg tcacacagcg agttattgtc agagtaaata tcaattttga atttgtagac 32640cacgtggttt tacctcatca tttctgtttg ttatgaaagt tttacaaata attagaagta 32700gaaataatga ttaaaataaa gcataactac taaaaaatag tttattgcag caccacctaa 32760attcatctca ccactctacc agtagcatac atttcacaat tgggttaaca ttgctctgga 32820tcttatagct gttgaagaag acaaaattct ttccattctc cagcttatat tttccccatt 32880tgtaaaacat aatggaagtg tacggaaaat aggagttgat aatttttaag gcccttgcca 32940gcacattagt acataggatt cttgcaagtg gtggtttact tcacttcaac tatagaaggc 33000ctatgcgaca ccacccatag agggtagttt gaaagaaaat gctagtgact acgtgtgttt 33060ccttcctgac atattttata gaaggtgatg agttccagca ttttttcaga cttggatctg 33120gctttcattc cccttctcct cccaccctct aaaacaacag aggcagcaac catttacaca 33180ctttccagaa gtaagtaagt aagactgtat tccagaaaca ccctatatca aaatggaaat 33240atactcaagt gccccaatga cccattgggc tagtttgaac gtgtgcagtc tctgtgctcc 33300ccgttttagc ttaagcctac tccctaacct gtcatatgtc acccagccat ggagcctagg 33360gcaatgactg ccatcatatc tgactttatg gcctctcagc tttcaatgac tagctttgta 33420gcagaagttt agcctctcat ccccataact ttggaagtag tgttgagata aagaaacgtt 33480gaattgaagg ttgtgttttc tagatttctt tcaattgctc cttaggcttt agaagataaa 33540ttctcctaaa agagaggtgc tacaattaat ccaagcaaag ggaaagatgt cagtaaaact 33600gccccttttc atagaggtgt ggcaactgct gggaaggaag aaattagcct gaggccatgt 33660gattactaat aaactcaaag cggcattttt ttacttctca atatgaggtt gaaactataa 33720gcttaaattg ctgactttct ggcagcacca aacagtaagg aaaccacaaa gataaaccca 33780aataatagag ccaattttct ttttttccgg gggggatgac ttctaactag tgatatgagg 33840aaggataaga aaatgtttct ttgtaggaca tatgatcttt gctaagtgca ctgaatgtat 33900gtagaggaga caagtctgct gagggtatga gaattgggcc aagatttaac acattttcaa 33960agctccatga agaagcctac tgagcagtgg gagtggagca ggttggggat agtgaagtat 34020ttgtaattca tttttaaaaa ggagagggag agagaaaagg aaaaactggg ccacccatcc 34080tttgaaaaga aaccttgaaa gaggtccaaa tatccttaga aatccttgac ttcttaaaag 34140tgatgtttgt tttttccccc tgacaattat agaggtcaga gagtttttct tttctattac 34200aaaacattga gagtgtgtag aaataattgt aggtagctta gccttggctg tagtcagaac 34260ttttgtactg tgactttagg atctgtatgg aatcgtatga tatgcggata caccaaaaac 34320tctatgggtt atcaaaatgg gatagcatta aaagaaatag tgcttttgtt tagaagaaga 34380aatgaaatgc ttgtgtccag atgcttaaag gaaggcagtg cagactttca gaaactagac 34440tttaagagct gtactcagat actgagaagg gctgatggct gaaggaggaa caatttaaaa 34500gaataaccgt ctctcctctc cctgtatatt ggacataaaa gaatatccca ttcttttcag 34560aaatgtaata caacagttta gcttgctagt aacttcacat gctatttcct ttacctctta 34620tatttgaggt gtctatttgg agtgggctgt gtttctagct attctgttta tctggtttgt 34680ttttgttggt gtaggaaact ggtataaatt ttatttgggt aaatatcacc tcaattttca 34740actaaagctt tatttaagtt tcacatgaaa aagacaaatg aggcaaagga agagaaaaat 34800gcattgtcag aatcagaatt atgagaaaaa aagtcaaaca aacatatttg aaatgtccag 34860aaaacctgtg agtttttatg tatactatac aggaaagata ttctgtcatc tggttgccaa 34920actatggagg gtgggagact tcgaattttt gtcaaaaagt attctttcat tagaaagata 34980catgggtgtg cttccatgtc agcaacatga ctgcagacca ggaagtcctc acggagagct 35040ggaatatggg tattttggac tctctggtta gatgcagctt ttacttcaca tcctcagtgg 35100tactactgta aattttcatt ttcctgtgga ataccctatt tggttccatt gtatatagtt 35160gacaactaga attcgttcgc tgttgcttga gcccaactat aacttcttgg cactatacct 35220atcttctgat gtgcctgtgg aagagctacc ataatgaatg tgtacatgga caaaaaaaaa 35280gagagagaga gagagaatta aatcatgagt ttgtgccttg ggagctacag tttaaacatt 35340tgctgttttt ctcacttaat gaaaaattta tttgaaaata acagcacaga aaggaagaaa 35400gacaggctgg caagcatcct cctcctaata cacttatcca cgtttggata ccttggtctc 35460agcctcagag gtcatatttt tagtaaaatg gccaccagaa ataaaggatt ttattttcca 35520gactttggtg tttggagctg gtgtgctgag agctagcaga gaaagcccta ctcaggtaga 35580tgtaccagag caggatggtt gctggtggat atggtggaat accttttatg tggttatctc 35640ctccttgtaa ctcttggctg cataaccctt attttctttt ctatttttat tctctctctt 35700ggaaaaaaaa ttggtggtaa attttcatgt gagccatatt gtctttttaa atagttttat 35760taatataaaa tgtacgtacc ataaagcata cccatttaaa ctgtaaatgt caatgggttt 35820ctctctctct ctctcttttt tttttttttt ttggatgctc agagttgtgc aacaattatc 35880aaaatcaatt ttggaacaat ttcattgccc caaaaggaaa ccctctgccc attagcagtt 35940actccccatt tcccccaccc cctgaccctt caaccctagg caagcacaaa tgtactttct 36000gtctctatag atttagccat tctggacatt tcatgtaaac agaatcatgc aatatgtcac 36060cctttgtatc tggcttcttt cacttagcat gatgtttcca aggttcatct gcattgtagc 36120atctgccaat acttcattcc ttatttatgg ctgaataata ttccattgta ttaatgtatc 36180atatttgttt tttccaatca tcagttgatg gacatttggg ttgttttcat ccttttttta 36240gctattttaa ataatgctgc tatgaacgtt cgtgtacaag tttttgtatg aacatctgtt 36300tttatttctc cttggtatac acctaggagt ggaattgctg ggtaatatgg tagcttaaca 36360tttaatcttt tgaggaactg ccagattttt ccaaagcagc agaatcattt tacattttga 36420ccagaagtat atgagagttt tagtttctcc acatcctcaa caacactcat tattgtcatt 36480gtccttttca gcttttttga taatagtaat ctcaatgggt gtgaattggg accccatcat 36540gcttttgatt tgcatttcct tgaagagtaa ggatattgat catcttttca tgtgcttatt 36600ggccgtttgt atattttttg atcctttgct catttccaaa ttgggttatt tgtctttgca 36660ttattgagtt gtaagatctt acaatatatt ttggatgttt gtcattttag ggatgatact 36720tcacagttat atgatgtttt ctagcaagca tttgcgttgt tctactggtg ttacatatct 36780tagctgcatt agccactttg ctgggtatga atgccagcag aatctaagtg accttggctt 36840cactactgag aatgcaaccc aagaacagaa atttgtcaga aatttagcac tgaagccccc 36900cacttcccaa acttatctgg gacaaggaga atctacattt aaagctctat actttgtgtt 36960gtgttttttt tactttagct tggttggatt taggatcttt tctttttgtt ttgccttatg 37020catacctaag cagaggcaag ggaggaaagg gatatgaacc tggtagaaaa gtaagtaagc 37080tttattcaga ttggcatatc catcttaata tggttcaatt ggctgaagaa gtatctcaac 37140taaaactctg gaatactttg aagtaccagc aatatgtacc aaatgtactt tttatttatg 37200tttggtctct atgtacttgt gtgtgaaaca atgagcacaa ataataccct ccttgttttt 37260aagcaattta tattggtgat ttaaaaataa aataaactca agtgggaaat catgaaaccc 37320catgtaaaaa caataagagc atgttttaaa atcccacaga ctttagtttc aaatagtggt 37380tttgctattt cttagctgtg tgtcactgtg caagttactt tgtttctctg agtctttatt 37440ggtgatatat gtaaaaaccc accttctcaa attattgtga ggacaaaatg aagtaattaa 37500cataaagttc ctggtgtata ataagtgttc atattttgta tttgagcaca gggcaactgg 37560gtttttgaaa ctgcacatta ctgttgcagt caaatctggc atgaaattag tgcatagaca 37620gaatgggctg ggaaaatgaa aggactttga acatttatat tctgctttat ttaggcataa 37680gtgcttaata attattgata gtttcttctg gttatctgac attttgaaga tactattacc 37740tagcagaaat ttcttgtaat aataatctct tacacttata tactgttttg tgcctttaga 37800agtacttaat gctctttatt tcactatctg ttcataaaca ttctctgaag caagcataca 37860gtcagtatga attccatttt tcagatgaga cagctgaggc tgaaagacat agagttactt 37920gtctcaattc acaaagtaaa gtgccagagt ttgaaccaga gcccaggtct tctctctcaa 37980cgtagctctt tttctccttc attatatcag gcatagtagc aacgtattct tttactagct 38040ttttatcttg aatatccttt tagcgacttg cctttggtgt tagtgtgcct ataacattgt 38100cgttgaatat cttaatacat ttagtggtct tggcaagcag ttttgtcttc agaaggacac 38160tgaaatctgt ggaaaggact gcagaagatt gggtgggcag acacctatca ctttcggggc 38220tggtagactt tctattgaag caatttgcaa ggctactttg tattgtctaa aagcactact 38280tcagaaaagg gttgtgatgt caaaataggc actttgagtg aagaaagggc tgtaagcatg 38340ggtggaaaat gtggtagatg attgtcttga gttattttct ttaatgtcaa acaggcagtc 38400cttggaatgc tacttcaaaa agtgttgtat aatgttgaag atacagttac agatttccaa 38460cacgaaactc ataaatatgc aattccctgt cctcctaggc acatgaagga aaatttatga 38520gcttcaggtt tctatgcagc tattaaagca tatttaatct gctttgagct caagctcact 38580ctcgttggct ctcttcgttt cttcctctta catgagcaaa ctgcctttct ttttgtttaa 38640aaatagtaag taggtttgtt ttcctccagg tgtcatgaat gcaaacattg taatttctca 38700tctgttcagc ctttttgcac aacaaaatgg cagcacccag gaggttgaaa gggttaaatt 38760gttccttctc tgagtagtac cataagttgt tagtctgcta ctctttctcc cagttggcac 38820atgaccctaa catccaatcg ctagtggtgt ggccattttt tggtcttatt ttggcctttc 38880ctcagccacc actcatcagt tctcatgcgt atttgtcaga tcctgctccc caactccaca 38940gttcttagtt catcttaagc atatggctgt ctgtcttttc tctaaagatc ctcaagggaa 39000aaaaaaaaaa gcatctccag ggggaattta ctgcctcata gccctgacag agatttctga 39060ccaaacccta acgaaaaaat ttcttccctc catttgtctt ttattgtttt tacaggggag 39120atatgtaaca taataacaat tatattgcac ataataatta cttctacaaa taataatctg 39180ttgtcaaaaa tatacacagc tttggatttc cttattatgg cccttcatta agttgtggtt 39240taagaatagc tatgattatt acttttgtga taattataat ccataatatg gaaacttata 39300aaattacctt taaagtgtta ctattattct ggccacagga tggaaagttg ttcgctagtt 39360actcatttat aacctgaatg tactttttac tgaatctaaa ggtatcatct ttgcttggca 39420attcccatga cttgtctttc tgactcttca gatctcagct taaaagctct cccttcaaag 39480aagccttccc tgaccactct ggttttttct tcttttttta cctctactcc ttttcccatt 39540acttgctgtc atagcattct gtttgtttcc tttgaagtgc ctattccaat ttgtcattat 39600gaatgagttt ttttgttctg ttgcttatta tccattttcc ccactagatt gtcaactctg 39660tgagggcaga gaccatgata ctctgttcac tcctatatac attcccagca ctatcagact 39720ttttggcaca tagaagatac tcagtaaata tttgttgaat gaataagtca taaagaagag 39780tttatatttt aactcttagt tgaataatct aagccaagaa ttatcaacct gggttggacg 39840tgagaatcat taatgaatct ttaaaacaat gacaaggcaa tctatttatt aattatctcc 39900aggtctaaac tttagcacgt atatacattt taaaagccca taagtgattc ttacgtatag 39960ccagtgctat ctgtctcttc tcctgtcctt tcccctcctc tccttactcc tctctcatag 40020ttttaggatt agcatggccc cacaacaaat ctttaattca catggcaatt tctaggattt 40080atcatggaaa atgagccaaa ttgccttcaa gaagttttta cgtacctctt atatagaatg 40140tgatgtttta tatgtacctc ttatagaatg tgagctttta agaggcatat cttattgcaa 40200gaaatttcaa tgttgaaaaa aatattgaat atttataaag tcaaaaatgc aaacttttat 40260atgattttca aacctatgaa gttatatcat gttcaggcct tctttccagc atgtggctct 40320cagccctggt actgtcctta accataaacc tcatctttgc cctctatagg gagaggttta 40380tggttataat tactcatttt aaatagtgta tattagtaat gtacactatt tgtatatttg 40440ttgactgcct cctatatgcc aaccactatg ctagaaattt tgtaatattc ttcacgatat 40500tcaagatatt aacatatccg cattttataa atgaggaaac tgctctcaaa gaggttagtt 40560tacacagcca gtaagccgct aagcctagat tggatggaag gtatgtgaga aaaaagcagc 40620atccataagg ttttcattct cctaccctgt acgacagagg taatagaaat tattagttaa 40680agaaataata gaattttaca agactctagg aagggagaat gtgaaggata cagttctcag 40740ttactggaat gagtgccaga gtaccagtac atggcttgcc ttggggtttg gactacctat 40800cttaactcct ttgctcctcc caatcttgat ctcatttgtt tgaaagatca tctgcccaac 40860ataaaaatgc atttctaatt ctgtaattta agtcagtggc aagatcagat tcagttaaag 40920tttactttcc tgacagcttt ttagtatcat atctattttg caaaactcta gtgataaatg 40980tatgcacatt tacacataca gcatctcttc tgattctgac taagatatta ctgggttgtg 41040tagaagtgat gggctcttta gaagaaaggt ttgatatact actaatctaa ggactgaatt 41100ttctcatctt tgtctttgcc ccttttgact gatgaccaga gcaggagcac ataacattct 41160tttgtgctaa cagtatctct gcatcacatt gatcaggaga attggcatct ccagagccct 41220gggatggtaa cttctctgtt gattttcagg aaagattagg tgatattttc tccatgggaa 41280gaggatgttt gatgtgtgtt ggctttagca aaaggaagct tgtggagtca actgtaagta 41340gacagaattg cctttgactt aatctgtttc agtcgttgtt catactcagg tcctccagag 41400gacctttaag catttttatt gactttgtgg tctattacac gaaactaaag atactgattc 41460tcagtcatga gtctgctcca aaattgccta gggaatcaaa aataattgta ccagttccta 41520ttcctggaca ttatgattca tttggtctgg tatgaaggcc aggaatctgt atttttaaaa 41580ttcactcaag caattttcat atatagctat aattgaaaat ctgtggctga acttctccac 41640tcccgtatcc atcgcaatac ttccccaagg tggcatttaa gatgggccta gagggttata 41700taagatttca atattaaaac atggattaaa agtgaagact tttcacatgg agataatttg 41760gaagaaaaac ttgcaaaaat gtgagagcat tgagaacttt tctttcccaa ggaaagaagt 41820ggcagcttca tttttggtca ttgcaaacag cagtgccata catgaaagga aagtggtggt 41880gctcatcaac tttgaataac tttgtacaga acccttgaga ctcctctctg cttataaaga 41940aaaagtgtca actgtaaagt tgatttattt atgaaccata ggctactatg aaatctctgt 42000tcccagctag aggcctggga gagtaagata actacttgtt tattccacgg agccacttat 42060tagctttttc tatagcacat acctcaaatg aagcatttca ataaaagaac cacattctat 42120tcacatgctt cattttattc tgatttatgt aaaaattccc aaactcctca agcagtgttt 42180ctttgtaagg caataatctt cagttctgtt gcaaaggtca ggagtgatag aatgaaaatg 42240gtactagata caacagctct ttggtatttg catggccatt acattgccat ggggctgcaa 42300gacttgtgag tgcttgatat tttgcttgtt gatgaatgag tctgtgtttg tgctaatgga 42360gtgatttgag aggtagttct ccactgtcag tcaagaggtt ggttttgaaa gctgattgcc 42420aatggtcatt ctgctaacca ctctggttct cctttagata gagacttatt cagattcaag 42480tcttcatgta ctttgtggca taaacattgt acacaccaga tgtattcaac aaccataaaa 42540aaaaacaatt aggactcaag tagtatgtca gagtgtagtc actgatgata tataattctc 42600cactaccaag aagatggaag cacactgttg agtagctaca tcctacatat gttggccaga 42660atttaggaat acacatgtga tctatacatt ttgaggtatt gtctgacccc tagaaaatcc 42720tggtgaagtt tttctggtgt cagtttggtc ttaatgttta ggaaatgccc acagactact 42780cctgctttct gcttattcac atagtaaacg caaagcacag gactagtttg tcatctggat 42840caaggagaaa tgagttagca gatataaaat aaatcagaaa ggaggtagtt ctcaaatatt 42900tactccatga atagttgctg gatgttcatt aactctatag catttgttac tacttattgg 42960ggatcctgga aagaaaatat attgtctata tccactgttc actgaggccc tctccctacc 43020cagaaactcc ctgtctccat cactcactct ccacattcat tgacccaggg gaacagttca 43080tggatgagtg aacttgagct ctatcttaaa ggatggagtt cgatttcaag gcaagaggta 43140taagagaaag ttcagagaca acactggcta tggtctttgt gaagaaaagt gaattgaata 43200ggctcctgtg gagatcttaa gtaagtactt ctggagataa ggttgaggaa aagtaggttt 43260gaatcttcat ccagaggtag cccctaaatg tgttgagttt attgaaagag tacttgactt 43320ggattcagac agatctgcat ttgactcctg ttttgccatt tataagaatt tgagtaatta 43380ttgtttctaa ataagagttt attgagccaa gcactcagta aatgtttgaa tgggaaaatt 43440aactgccctg tttttctatt gtcagatggt cctcttcgtt ggataacttg gtaactgttg 43500ataacctttt ctcaggaatc agaaggtaga aaggttggga aaatataaga aacaaaaagg 43560catattccta tttttatttt catattgtct tccaactctc ccaggcttct ttgtttgcaa 43620ggctgacttt tataatactt tttgggtaga gcaggtcctt ctttggtttg gggttaaacc 43680gtgagtaacc ttattttcta ggtctcagcc aactttgaag ggcatgaact cacagtagcc 43740tcactaggat cacttcagca gtgagaattt atctttcttg tataaaagtg taagagttga 43800tggcggccag gcgcagtggc tcacgactgt aatcccagca ctttaggagg ttgagatggg 43860tggatcacct gaggtcagga gttcaagacc agcctgacca acatggtgaa accccatgtc 43920tactaaaaat acaaaaatta gttgggtgtg gtggcacatg cctgtaatcc cagctactca 43980ggaggctgag acagaagaat tgcttgaacc tggaaagcag aggttggaga ttgcagtgag 44040ccgagattgc accactgcac tccagcctgg gtgacagagt gagactgtca aaaaaaaaaa 44100aaaaaaagag ttgatagcaa aataactatc tgtagcataa acctcagtat tctttatcat 44160tcagtatcaa cattattact gaaaacaata agcaatatgg actgagtttc tgtggggtgg 44220aaatgtgaag tggatcatag catgatataa cttgtcattt ggcttccttt ataaacatta 44280tcaactacct cagctctatc aatcacttgg cagtccgtag tgaacattat aactcaaatg 44340actagtcagg tctgttcatt gcccatgtaa aggcatatac ctgaagtgag aagtctgagg 44400taacttagca ataagcttgc agtacagtgt ttagtgaagc cgaggaattc aaggatttga 44460gtcatgccag attgctccat aaccatagcc tatctttgtc acaagtaaga aggtttaaaa 44520atcaccatac cattattggt cacaacgttt ggagataggg aagagtttgt ggatggatca 44580tggcagtgca tggacagtga ttagcccata acacaaccag tgaacactgt tgtacccaaa 44640gcacataaat caccacatat actattaata tatttatgga tgacaacaga cactataatt 44700ttatgtcagt gctttctgct gtgaaaaaca aagaaagtta agggtacctt ttttatattt 44760gcatcatatc tccagacctt ttcctttatc tccttcttgc aagttcttct ttctttcagc 44820tgactatctg ctgttcctgc tatggctccc agtggctttt caagagggta cttgtttttt 44880aagagaagac ccttgaagga cagagagagc ctgaatcatt caaaataatg aattactcag 44940gatgaaattt caataatttg caagtgtgtg gagatagata ttttgaggaa gcataatttt 45000ctatgtaccc ctcaaatcgt ggctggagat gacagcctct tccacctcca tataagacca 45060tttcatttcc ttctactttt ttctccctcc ttcccccaaa cacacaaaca tacacatatc 45120ctgtgcttca gtcacacaga acttcttact atttcatttc

aattctctat ggctttgcat 45180gttctgctcc ttctgcctag aatgctcctt tccttttttc acctggaaac atcccaattc 45240aaatgtcacc tcccttattt ataccaactt tgtctgtaac tcctttatca cacttcttcc 45300tgtgattagt caattcactt gtctgctgtt acacctctat gagagatgaa aattccttct 45360ccatctctgg aactcatgcc cttcgcatat agtaggcaat ctgtaaatgt ttgaaggttg 45420agtgaattaa tgaatgacct tcaacctttc aggcttccaa ttttctctct gaaaaggaca 45480gccaaatgaa aactcataat tttagaagat gaggttagac ggttggtagg tgcatgcaga 45540gaccagttat tatttaggta ttatggaagt ttatagttct tgtatgttga gttcagtgta 45600agagtggccc caaacatagt taatgaccac tccagaccca gttgttatag agttggcccc 45660agctgtattg cttctattta agactaggat aagaaatgac actttcctac tttttacctt 45720attgaaaggg tagaggctca ctgttatcaa tctcagttca cttgttgatt gcactggctt 45780gccaagtgag aatattagca cctctgcaca tttctatagc tctgccactt atgagatctt 45840tccttcccat tgtcatattt aataatcagg atagccctat aaaatatgca ttctcatttc 45900ccagatgagg atactaaggc tcaagtagga gaacttactt gtttagtaag atcatacagc 45960taggaagtgg gagaggcaag agttgaaccc agatcttcct agctcctagt ccattgttct 46020gtctactggg tcacactgga ccagccagga ggcaggaaaa tcagctgggg aatgtggtgc 46080caacgtgtga tgtttgccta aatgtgtgca tccttgctgg aagccagcca tgattcatgc 46140tgcataagta ttcattaatg ttcatttcat ttatttggct atccatatgc tttccagggc 46200gaaggcaagc taggacaagg gcagacaagc agccttaaag tttgggtgct ttccttcgaa 46260gttgagctgc ctgtttgaaa atcacacttt ttggtgatag aagatggttc cagtacagat 46320tttatttatt actgcatcta catggataga cattttccaa agcatagctg aaaatatgtg 46380taagtcccag aatattttct gatttagaca cagactttga gcatgataac cacatttagc 46440atgttaggaa attctgtcag aatgcttctg gaaaggctac ctttccagaa tgaaatgaaa 46500aaagaaaagg atggactttg aaactggcta gatttgggtt atacttactc atagtgtgac 46560cctggcaaat gatttaactt ctccgaattt cacttttctt attctttgaa gtgaaatttt 46620aaaatgccat cttgcctgat ttttgtgaga atgaaaatga gatcccacac caggaattta 46680gaagctactc agtaaatatt gcttctctcc tttccccttc cccagtcctg tcccccgaga 46740cattcagtag ttattcacag gcatgcattc tgaagtctgc ctactgctcc atgttgaaat 46800gcactgctct tgcaaggact gattatctat ttttctgtct tccaaggccc cctgtgttcc 46860actccaccct cccaattctg ggggcttcca aagtgggcag gtacagaatg ttctgtggag 46920catcggaggc tgttactcaa tatcttggcc agcactctca actgctcttt gcacacactc 46980catatgaagg caaactccag atcttggagc ccatgtgtgt gtcatgcatt gtactgcttc 47040ttgtacccaa atccatctca agggtgagta gaccaggctc agacttgtcc tgggagcaga 47100tttctcaagc tgcccatgtc cccacactgt ttgattaaaa ggaggtgctt caaactcttt 47160ggctttatat agactagaat cagaatgatt ggtggtgcct ctgttctcaa ggtatcccaa 47220agcactttgt aaggaaatat gacaagcgct gaggccatgc aggccagtac aacagccgcc 47280acccagcact tcacaattag tcatgcccag cctgggatca tcaagcctgt ttttattgga 47340agagcaagag agagagggaa tgctagctgg caatttcccc aggtaccctt tatgaaagtg 47400cccttggctc ttccaatttc atctgaataa ccagctcagg caaattttcc tctatcaaaa 47460agcagaatgt gatagtgaca agctgatgcc cggctgatgc cccaggacat tgactaaata 47520gacttggcct cacaattggt ttttattctc tatctccttt cttccctttt gttctttttc 47580tgtgtttctt tccccattgc catctgcaga gtgttctcag tcagaagtca gctgtggggt 47640ggacagtttg tcattttaag atcatcccta ttctgtctac ctttcttatc cctcatatca 47700ttgcttttag agcaaggaca attctggaag tgaaactaca ataacactct gggctccttt 47760ccctctagta gtactcaaca cacttgtaat tacatgttca aatttgtctt tcttatttct 47820acttaggttc atgaaggcaa gggacatgcc tgtgttgctt actttctctt ggcaggcaca 47880tacagcaagt cttcaaaaaa tgcttgttaa ctacaaatta agtgtttaag aagtccactg 47940ttaattagcc gggcgcggtg gcgggcgcct gtagtcccag ctactcggga ggctgaggca 48000ggagaatggc gtgaacccgg gaagcggagc ttgcagtgag ccgagattgc gccactgcag 48060tccgcagtcc ggcctgggcg acagagcgag actccgtctc aaaaaaaaaa aaaaaaaaga 48120agtccactgt tagtatcttt tcccctgcct agtttgtaag caactggcct cttctatttg 48180taagttacct gttttcattt ccatatgccc caaagcaaac tttagctcac ggccttacag 48240agtgtgtatg ttagtatgtt aaaatgaaat caactttcct ctcccaggcc ttctaattga 48300catgaatttg ggagtagact tgcattggcc tttgtcctga cagccaacag agtcctcttc 48360tgttgtattc actgttgcct tccatgagga tcccatggag aaagtttgtc attgatatac 48420attttgaggg cagactcaac ttgagtaaac ctgattgagc tttccccatc tgcctcccag 48480agatcactgc ctgtgctttg ttaaaaagag aattatagga gtcctctcaa ggcagagagg 48540cctaaaatta gacatggcag ccatgccttt ggtgtgcatg gaggttggat acaggcagcc 48600agtttcccct ctgttttctc ccttgcttac acagccaagg agtggagcca agcctcaagg 48660ggaggagctg tatactcgag catgccctgt ggttcctggc cctgactgag ggactatttt 48720atatatccca atagagaagc gtggaagaca tctaggttgc cactgtcatt tgaaattgga 48780atttttaaaa gagaaacctg aagacttgaa gaaagctttc ttttgcctcc ccttacagtt 48840gatttttgag cttcttaaag ctacctagtc caaagtaccc acactcttat tcttttgtct 48900ttcctactgg ttttattttt ttttcatctt cccaggtgtt tgatgatcac taagagcttc 48960aacattgctc accctgacca ggtatgaagc caagagtttg gtttagggca taaaagaatg 49020tcggaactca aggactaggt tgaggtgggg aagggggatg aaggcttctt tttttcttgg 49080gttaagcaga aataacttag atctcagagt gaaagccttg aattatcaca tatatcactg 49140gaaaagacta gttctttgct atgataacaa ttgttcatca tctctcccct gaggatttgg 49200ggtcaaggcc tggctacacc ttttaatgat ttcagtcatg tgacttaacc tctttaaact 49260tggattttct tcatctttac aatggaaatg atgacaataa tcactacctc acagatattg 49320ataataatga tatctcacta ggaagagaat taagtaatat gagggataaa aaggcatttg 49380taaatggtaa aatgagatta tgattttgaa agctattatt attttccttt cactgtctat 49440tatctcaact cttctatttt cttgcctttt gtacagcatg gataatttag atgtgactct 49500ggacagaggg atggatcaga tgacttctta agttatcttc cagtttagga gttcgtaaac 49560tatactttct cctttccaga ctatcctagt aagaaaattc tcttttaaga cagagtagaa 49620ctctggaatt catcagtttt gatgtttctt aaagtgtaat ctaagatagt gctcctgtat 49680taagttctga tgtctgacca ttgttcaaat aaagagtaaa atgcaaatga caggaaattg 49740gctgcgttct gaatcctatt tttatttggg ataacaataa gcctgtatgg tcactgtgac 49800ctttgatttg ctgtttctgc aacctcacac ttgtctcagg attcttcttc cacttctgca 49860ctttatattg ggtttcttcc aggcatcata ttaaacttta agccaggtat gtgtatatgc 49920atgggctgtg ggcctgaaaa aaattagccc gagagagaaa aaaatttaag tagtgggcta 49980gaagtaagca tgctactaga aacagaattt gggaacacag ctctgggcct agaaaagcga 50040cctgtcaact tgttacagtt aacatcaata actataggat gggtttggtg gaaaattatg 50100ctgaccaaca gggtgggaga gaatagggtc agaatatata tcgctgtaag gttgagaaaa 50160aaagaagtga aaaaaaaaga aatgcataga gagaaaaagg agtttagagg taacatgtta 50220aagtgtgaga aataaactgg agagcttgac ttctcttgaa tatattttta aataaagtac 50280tcctttcaac tccaaatgca gcaggcttgg ttcccttctc ctacctccat tgcggatgaa 50340agcttaatct ttaagatggg cttgggtggg tagagtacgc cccttggtga gcactgtgct 50400ctctgcaacc ccaataaggc ccaacagggc tctccaagga ggcaaaattc tgatgataca 50460tttctgttta gtggaaaatg ggtagggaaa attatgtctt agaatcaatt aaccaaacat 50520aaaatcctcc aaggggcttg gtaggatgcc tagggaagag ccacgagata aaaactccag 50580gctggaaggg cattgttgca gcactgtcat tctccagttt ctcttggagt tgtcaccacc 50640ctctcctttg ttctcactgc tgacatcatt tgtaaaataa tttcttccct taaataaaca 50700agacatacaa tcctctaaat gactaaagaa cagttaccta gaagaaacct tagtggaaag 50760tattttcttc atctaacgga tgattgtctt tacagaggtg gagtaaagga tgtgcgaggg 50820agcataatca agctaagaga tgcatgctga cttaaaaggc atgatatatg tgaaactaag 50880ataatgtgtt caagagtgat gctttgttga tgcagaacca ctgaattcct tactattatg 50940tttgcctgac tatcggcctc ttaataaaga acttgtggtt tgagtgttca ttgaaattag 51000ccatattagg tttatgtggg gatgtgagga tctatgtcta ccaattgcag cctctgctgc 51060aaattggagg cagaaatctg ggctgaacaa taggtaagag tgtcaactct acagatctct 51120cacatgctaa gcaagcacaa tatagggcaa tccaggttta cacaaaggat taatttggga 51180acaattatcc tcattttcac ttcctaaaaa gattttgaat aagatgtctt ttaagtaaga 51240agctccctga atgcatttaa aatatgattt gattatgtac atttcagatt tttctacctt 51300tctaggagta tctctgttgt ataaaaacac aaaattctgg aacttttgaa aggaagatgt 51360gcctctcttc atacatttgt cattcttgaa cgattgtaaa atgaagtgac tgcatatcac 51420gtcatgtgcc ctattgattt cttttcttgt tttaggaata ttcccagaaa aaaaaaaaac 51480tttttttttt ttaaaatcta ctaagcatgc taggtaagac tgaagatgaa tctatttaag 51540ttatgtcaat atctatttat aaagattttt gtgatattct tttcactgta gaacttcaag 51600catatcctaa aaggaacggt tagatacctc tacaaactgt ggcaatgact tactgagtaa 51660ttgctggcaa ctgatttttg gtgcttcttg ttttgatagt atagcagtgc gagtaggttt 51720cagaagagca aaactaagac aatccaggga aatgccattt gagaatttct aactttaaaa 51780aaacaagtaa aatagtgcca agaatattat ctaactaacc ccaaagtcta caatgtaact 51840cttttatttt gataatgctg ttctaaccct atctacttca gtcctttccc acccagctgg 51900tttaggaatc aaattcccaa tgtttcatca ctgttaacat tactgtttta ctcttcactt 51960tagttcttaa atggcatagt gtcttaaatt ccctcagcct ctttcacatt tgatttcttt 52020ggaaactttt taccttttca ttgaagccca tatgatcttt tccgaaacag acccttatct 52080ttacctcctt ctttggagtc tttctcctac ttgaatttct gaacttctta aaatggccgc 52140tttgggttgg tgtcagtaat tcagtaataa gttttctttt cttttttttt ttttcttttt 52200ttttgagaca gagtcttgct ctgtcaccag gctgcaggct gtagtgcagt ggagtgatct 52260tggctcactg caacctccac ctcccgggtt caagcgattc ccttgcctca gactcccaag 52320tagcaagtag cagcaccatg cccagctaat gtttgtattt ttagtagagt cggggtttcg 52380ccatgttggc caggatggtc tcgatctctt gacctcatga tctgcccgcc ttgccctccc 52440aaagtgctgg gattacaggc gtgtgccagt atgcccagcc agtaataagt tttcttaagt 52500gctttcttaa tattctgata tttttaaaaa agatctggac tattttgtca tacaggcaac 52560agaatgttaa accatttcat aaaacaatga caaatataca tgaatttttc atcagttata 52620aatgcatttc ctttataaca ttgaacatgt ttttgcaact gaaataagta cggttttcat 52680ttttagaagg cacatgataa agttaaggca gtggttaatt aattttttca gattaatttt 52740tcagaaaagt gactgtttct gtctattgtc ttaaccccag gcatcaaagg attttaatca 52800gaaagaaccg aggaataatt tggttatttt agtgcctttt tttgagacaa agtcttattc 52860tgtctcccag gctggagtac agtagtgcgc tcatggctta ctacagcctc gatctcctgg 52920ttcaagtgat cctccaactt cactttccca gctaactggg accacaagtg ggcaccacac 52980tctctgcaat ttattttaat ttttcataga aatggggtct cactatgttg ccctggctgg 53040tctcagaatc ctaggttcaa gcaatccttc cacctcagcc tcctaaagtg ctgtgatttc 53100aggcataagc cactacactc accctatttt agagctttgt caagctttgg aaagaaaacc 53160atttataata taatagataa attatggata tttgaggcag tttttatcat agtatacatg 53220gtaaaccaca gccccccttt ataatatttg tatttaataa aaatgaaaat attactttta 53280tcttaaacat gttttaacaa agcaagcata tgtagattag cactaattaa aacaaaaacc 53340tttgtaatga tagctgtttt ttatatgatt acaaaaaatt tactatacaa atttttatcc 53400taatcagtgt gaaaaactgc aaatattagc ttatagggct agtcttcaga gtcctcttcc 53460tacctactac tgctaataag ccaatgaaaa actctctgat gtgtgtggtg gctcaggcct 53520gtaatcccag cactttggga ggccaaggtg ggtggatcac ttgcactcag gagtttaaga 53580ccagcctggg caacatggtg aaaccctgtc tctactaaaa atacaaaaaa ttagctaggc 53640gttgtggtac gcacctgtag tcccagctac tcaggaggct gaggtgggag gatcacttga 53700gcccaggagg ttgaggttgc agtgagccaa gatcacagga ctgcactcca gcctgagcta 53760caaagtgaaa ccttgtcaaa aagaaagaaa gaagagagag agagagagac aggctcctcc 53820gctttttcag ttcctaaata attttccaat ctagaatgca aaagattctg aaggaagaca 53880gttaccattt cagatcggca gaagttgtgg ctttaatcta gactcgaata tgttttacat 53940caaagggttg cctcaacagt gctcaaacct gcctctctga aaacatgctg agcacgaagg 54000ttacttgaag tcttagcttg agtacttaag agagtgctat ggagggattg ttgatgagag 54060ctgtgtcaca gctaattttt ctttagtaat taaaggttta taaaaatctt acactgtata 54120ttgacaaatt tagcaacaaa atgagcttga gaaaaaaatc aaggcctgcc atggcatctt 54180tgcttttttt tcttaaaaaa aaaacttttt agaaagatta tgcgactgta ttatctgtaa 54240ctactgcaat ggtgtaaatc ctgatggtat aatttgcttt ttaaagctat ctttacttca 54300gtataactta gattaaattt attttaaatt taaatgatat ttttctcttt gtttattatt 54360ttataatgtt tcccatagaa ttcacaaaat tcattagaaa gatttttttt tacttcctta 54420ggtcattaag attctgattt gtcaatggat ttcacataaa ccctgtcttt ccaaaaatat 54480acaaaaaaaa aaaaaatagc caggcgtgat ggtgcgtgcc tatagtccca gctactcaga 54540aggccgagtt gggaggattg cttgaaccca ggaagttatg gctgcagtga gctatggtca 54600caccactgca ctccagcctg ggcaacaaag tgagacccca tctccaataa ataaataaac 54660aaataagtaa ataattttca ccttgaaaag cttataaatg tatgaaatca caatgagggt 54720cgctgatata gtttggatgt gtgtccctgc ccaaatttgg ttttgaattg taatccccag 54780tgttggagat ggggcctgga gggaggtgat tggatcatga gggcagtttt ttcatgaatg 54840gctcagcacc atccccttgg tgctgttgtg gtgatagtaa gttctcatga gatctggttg 54900tatagcacct ccccccttgc tctcttgttc ctgctttcac catgtgacat gcctgctccc 54960ccttcacctt ctgccataat tttaagttgc ctgaggcctc accagaagcc gaacagatgc 55020cggcaccatg ctttctgcac agcttgcaaa gccatgagcc aattaaacct cttttttttt 55080tttttataaa ttacccagtc tcaagtattc tttatagcaa ggcaagaatg gacttacaca 55140gtctcttttg tatcagggag agggtcttct tggtgactcc acttcttttc tttgtttatg 55200tatccttcca gatgatgtat ttatttcctt tgtttttcaa ttgatattta ctcttaaatt 55260aaactaatta tttaaaaaag cattttaaag tctcatttta gattattttg actatctgat 55320ttttaaaatg gtttaaaaaa tctatcttgg cctccatatg caatcaaata agaaacacat 55380tttaagcata ttatttacct tgtggattct gccttcctca gtgtgttcag tctgtgtata 55440ttcatttctc ccacactgta agaagctagt cagatgtata attggattat catgctacat 55500aatcttagca cactcatttt aagcatacat agactagtga gcaccactca ttacatgtca 55560tttctctaga gaaactagtt gggccatggc tgcaggactc tcacttgaaa agacatgtgt 55620ggtgatgttt tctcaggcag ttaagcaata aagtgtaccc tgatttgcac tgaaaataaa 55680gattccttta aagggagcag ttctagttat ctctctcttt aggtaccata tgctgaacgt 55740ttttctatgc actaaaacag caactaggtt ttatactctg ccttacagcc tacttcacac 55800ccatttcaca gggagaggaa cagagaggta agtgatttgc cccaaattac ataactagga 55860agttatttgc tcagtgtgga aacttgttca gaaggtcatt tcattgaaat gtaggaagag 55920tttctggcac ttctcttgag caggagtcaa aaaccttttt ttgcactagc ccagatagta 55980aacattttag gctttgtggg ccatatgatc tctgtcaaaa ctcctctact tcgttgttgt 56040agtgcaaaag cagctataca caatcctgaa atgaatgggt gtggccgtgt tccagtacaa 56100ccttacagaa aaggcaatag gctggatttg gctctgagac tgtagtttgc tgacctcagc 56160tcttgaactg agctctttaa ctgacctcag ctcttgaact atggtacaag atcccatggt 56220cctgtttggt acctccattt gccctccttt tcactctctg ggagcatagc taagttcaaa 56280attgaattag gtacttgtag taagagcata cttataatcc tgggatcttc atgttgccag 56340atattaacct cttgaagttt ttcaccacaa cctgggcact tttctgattt gctcacttct 56400agccccacct ttgggcccct tcataagcaa acatgcaggt tttccagaga gctgtatgct 56460actgaatgca gaaaatttgg ctcatactgg cctatggact atctgctcac tgccctgata 56520actattttcc aagggagtgg gtgccctacc tttcctacat gaagtttttt gctagtcttg 56580ccctaaaaat tctaggtatc ccttgctttt aggataaata tgtttcactg ggaccagctg 56640gaaaacgaaa aatagaatta tccaactacc actttaaaat tggacaaaga cttttgttgt 56700tgttgttgga gggggtggta aacatcattt tagcagacca aatatacttt tggtgaaagg 56760cagcctgttg caaagacaca acacttggac aagattttga agccctggtt gcctttacta 56820ctgacttaac tacagtattt gcggacttga gcaagttgct tcccttctgt gagcctcagg 56880ttattcatct ttgaaatgag tataatacct gtgattataa ttacttatct ggattctgca 56940gagaattgaa ggagataatg ggtgtaaaag tactttagcg cccagcactg ctccttatga 57000aaatgaggaa ataattgaga tgagtgagcc attgaggcaa cagtacaaaa agtgctgaaa 57060actcactgct taaataagca cctcttactg cttttgtggc actttgtagc aatgtttttt 57120tttttttttt tgagacggag tcttgctgtc ttgcccaggc tggagttcag tggcacgatc 57180tcggctcact gcaacctccg cctcacaggt tcaagcattc tctgacttca gcctcctgaa 57240tagctggatt agaggtgcgt gccaccacgc ccagctaatt tttgtatttt tagtagagac 57300ggggtttcac catgttgatc aggttggtct cgaactcctg acctcatgat ctgcccgcct 57360tggcctccca aaatgctagg attacagatg tgagccaccg caccccacct cagcaatgtg 57420tttttattct gactagaaaa gtaatgtttg gttttgtttg gctctttgct taatataccc 57480ataataaggg tacctatttg cctttggacc attagttcaa atattatttt attaatatgg 57540aattactggg ctccagaagc catagtcttc ttagctgctc cctatcccca ctctcacctc 57600aatttttttt tttcactttt gtttttcttc tcagggaaag gtttgaggca aagaatgtct 57660tcttatgatc caaaaccaag catggtggtg atttattcac caagagattc ctaagtacct 57720gtgtgatgga catggtagaa tctttgtcct gagggagcta tctagatcca ttccttctga 57780tatgcagcca gtagccactt gtggtaatgg agcaatagaa acaacactag ttcaagtgga 57840aacgtgagat gagaagtagg aggtggagag aactaaccag aagagggtac ccaaataaac 57900cagaaatatg tatgtgttag agaaggggcc tattgagcgg gtggcagtgg catgtgtggc 57960attacttgct cctgtattct ctgcttttta cttagttgtg gctttggtgg tatagtctca 58020aatctaagtt acgtaggtaa tattgttatg tatcatgttt tggcaatgta gactaaatac 58080ttgctcataa gagtacagga caatgaggat agtttggttt tgtttactgc atggaaaatg 58140caggatgttt agtaaataga ttcatggcgt agtgagttca ctactaaaat cagactctga 58200gaatgggttt gatttaaatg gctagtttag aagactgaat ttaggccact tgattgagaa 58260aggccatttt gggtaattat aaaccaccaa cattgtgttt tgaatgttaa agcttatatt 58320tgtcttccag ttaccagaat gtaagcttct tgaggaggga gagaggagtt ttcttaatct 58380ctgaacctgc acctttcttc tgtgcctagc ccagtgcctg gcaccaaaca ggtgctcaat 58440caatgttgat tctatgctac caacaaaaat gagtccatga tgtttactat tcaacaaatg 58500aatacaattt tagagtaaat ttttactgct tacactacat gtagattttc tttttagaga 58560tttcgcaatg ctgatttatt tcaaaataag cttgaagcta agcgacaaag ctgaatgatg 58620atttgttttt tatttatttt taaatccaaa cttacaattt tacatgtcat tgccagaaaa 58680atcattaaat aaattatgat atgcgcatat ggaatacttt gcaaccatta aatcaaccat 58740taaatactat gcaaccatta aatcaaccat taaatatgtt ggtatatgca aatgtgcata 58800taccaacata ttatatagtt gagtaagaaa agctagtttc aaatgagtat gttaatatca 58860tctgactctt gcaaaaggaa aaccatacat ttgaatgtac atatatgcat atgtttatat 58920gtgcatagaa aaagctatga ggggatatac ctcaagttgc taaaagtggc tccacctgga 58980gagggacatg gaaaggagtt ggctaaaaac tgaggtttgt tatggtatac acccctgcac 59040agtttgattt tttaaaaaca atgattataa attactttta ttatttataa aaatattatt 59100taaaattttg gtactaaaaa cagagctcca tcaacaggtc aatggataaa gaaaatgtgg 59160tacatatata caaccgagta ctattcgtca taaaaaaatg agaccctgtc atttttgcaa 59220caaaatggat ggaactggaa attattatat taagtgaaat aaggcaggca cagaaaggca 59280aacattgcat gttctcattt aatctgtgga atctaaaaat caaaacaatt gaactaatgg 59340atatagaaag tagaaggatg gtaaccaaag gctagaaagg atagttggtg gggcagggga 59400gggtgaggtg agcatgttta atgggcacaa aaaaatagaa acaatgaata agacctatta 59460tgtgatagca caataaggtg actatagtta ataataattt aattgtacat tttaaaataa 59520ctaaagaggt ataataggat tgattgtaac acaaagaata aatgcttgag ggatgtatac 59580ctcattctct ataatgtgat tagtacacat tgcatgcttc tatcaaaaat tttcatatac 59640cccataaata tatacatcca ttgtgtactc acaaaattaa aaaaaactgt gcattaaaga 59700aaaacaaaaa taaaaaccat agttcaagtt ataaacaaaa taaaggtaat ttggaggaaa 59760actgtcttca gttatattgg atatttgggg gacatttttg tatgttagtt agcaaagatc 59820acttgaaaaa gaagattctt ccttctatga ttcaagggag cctagcaaaa aataaatgaa 59880atgaaataaa ataatacaaa gagaaaagat tattccataa attctgctta cttatttctg 59940gcaaacttgt tgacagcaca tgtgaccttt tggtaaaaag acatttttat atttttagtt 60000aagtttcaaa tataaattgt ttgtgttttt aaaataaatt aaatggatga tttcagccag 60060atcattatga aaacacatga gatattgggt tatgcaatga ctaacagtgt gtaccttttc 60120ttgatattta ttcataaact ggggaataaa agtacatttt ggcccattta ctccttaaat 60180aattttatgt ctcccaagga gagttgtaag ttgcttgata

gtaaatgcta tgtattttgt 60240accttagtgt atatattatg ggatttcagc gttagaagag ctcttaaatg ccgtgttcat 60300agtccaacct gtcttctgat gcttgaaatc cccttgcagt aggaaatgca aagtagagag 60360cagacactca ataatgtagt tagtgaatta tttagaaaga ggcattttga gcccataatg 60420tatgataggt acttctacat ttattatttt attctttgca gacctgcaga aaactgtaag 60480aaaaaagttt atttcagatt catgtgttta tttgattaat ctcttcatag gtttcatttt 60540tcagctcctg tcagaaaata cagattctta taaggttcac cttttaccca taagaataat 60600agtataaagg ggataatgtg aaatacaatc acttcacaga ctgtttcaat taaataagag 60660ctcgtagata attcagtcca ccacacccca ttttacagat gttgaaattg aagcccccac 60720caaaaggaaa agacttgttc aaagtcacac agcaagtcag tggtgaacct aattaggccc 60780cctgccttcc attttagtga gattcctgtg ctgatagtca tacccatatc aaatcctctt 60840tggcagttat agcttgccca cagtaatgtg tcctgaaaaa tatgacaatt aattaagttg 60900gagacagaac cataacctct ttataaaaat tttctggaaa gtttacatga cagtaagtaa 60960tatataatta gaaaggataa ttcttatttc atatttatct ttttgtttca gaataataaa 61020ctaagctatc tctactcagt ccattttaat acaaaaatat ttttacccgg actgagtttt 61080tatgcttttt aggaactttg tatctgcctc acttagttaa aatcctagct gcactaatca 61140cttactgtgg tgggcagaat tctagaatga ccctgaatac cttgtccttg tatgattcct 61200tcctctttaa gtaaggataa aaactgtgaa tatgatatca ctcccttgat taggctttgt 61260tatatggcac agttaacttt aagaaaggac caatcacaca agccatttga aagcagaggg 61320tttgggtatt ttttaactgg tggcagaaag ccacgcagag atttgaacat tgaggggaat 61380ttgaatttga tgtgccagta ctaacttgaa gatagaggag gctgcatgga aagtggcctt 61440taggagtgat ccctggctga cagccagtaa gaaaatgagg gcctcagacc tacagccata 61500aagaattctg tcagtgaact tgaacttgga agtggattct tcctctagaa cttccatata 61560agagtccagc ctgattgaca ccttgatttt ggacttgtga gaccctgagc agagaatcca 61620gttgacttct gacctaaaaa aaaagtcaga taataaatga gtattgtttt aaactgctaa 61680ttttgtgata atttgttatg cagcaataaa aaactaatat atttaccatg caaggcaagg 61740catttatcct ctcatgattc agtttctttt tacctgacat aatggaatta atttatactg 61800ctgtgaagtt gtagttgaga aacatgactt ctaaagtaat agaggacatg tattattaat 61860tttagtagta ttaatagtaa tgatactgat tctcccaggc ctatacaaat cctttgatac 61920acaaatgaat agtaaaggaa cataaattgt ctctaggtag actttcccac aatgcaattt 61980taggatacag aggtcatatg cctgttattc tactgtggca gagaaaatat ggagcctgga 62040aaactgttca tttgcatcac atacatcttg ggagctcact ctgaacctgg taccataata 62100agctctgtag acagtataaa gaggaaagga atcagacatg gtgtctgacc tcaagtgtct 62160cataacgtag tagaagaggt aaaatatggg tcacactaac tctactgcaa agtaggaagt 62220gcttgtcgcc ttgagattga caaaatttgg taagagttca gaggagattg tctgtgaact 62280gggccttgaa gaatagttag gatttgaata ggagaaggtg aagaaggaag gcattccagc 62340tagggagaag agcacaaaca aaagcataga taaccttgaa catcatcata tgggataatt 62400caatagttca gtataatgga agtataagat gcataaaaat aagtgtagta ggaaacaagt 62460ttaaaagtat agattggggt tagtcataca aggccttgaa tttcaggcta aggagtttag 62520acattaacat ttgtttttga acaaaggggt gaactgatca catctgtgat ttagaaagaa 62580aattctagca atagtgtaga taagggttga tggtaaagtt tggaaggtgg tgaggcagag 62640gctggagaca gggagcacat ttaggataga aagatgataa agagatgatt tagaagagtt 62700gttttggaaa aggagaagac agaaaatgtt ttagaggtgt catagagata aaattggcat 62760ggcatggtgc aaggaggtaa agcccaatag ctttgtaagg tgctgagata gattgaaatc 62820acagagttag gaagttttag agtcaggatt agtaccaaga cagcttggct ctagatctca 62880tacttaacac ttacagtata attctgagag ggtgggtaac agcaatagtc agaggaaaga 62940acccttttat acatgatggt acaggaacaa cactggcttc caaccccaca gctgctcttt 63000aacagaaggt cagaagctgg ggagaaatat gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 63060gtgtgtgtgt gtgtgtatgt gccatttctg ggactaagga tgggaagtag attagttgag 63120gccactgcag tggggtctgc aagttgctag cactcacccg ttccaagagg ccttaaaggt 63180gttgatctgt tccctgggca tcaccacatt ccacaaatta atgttcctct gagagaatag 63240ggtgattcaa tttcactgtg cccgaaggtt acttttgggg ttcatgtttg ttctaagtct 63300atgctaatga tctgccaact gtctgtttgt cactttctct aacccttagc atgtataaac 63360tgatctgttg ggaaatgtgt agcatttata ggatggtagg atttgtaaca tgcgatcaca 63420ggactgttta tatagagtcc ctgggaaggg gagagaagag tatttctgtt acaaatgtgg 63480attctttggc ccctcctcaa acttactgag gttcaagaat tgacatttat aataagcaca 63540tatccatttt caataaacat gaaagtttca taccctcttt taatgtttga aatcctcaaa 63600taaattagtc attggtgcca gagtatcaaa taattatggt acagaatgta tttctctgaa 63660tgacaccttc tcccagagat tctgatatat attcctctgc actcaccctg tttgataatt 63720accagtatat ggaccattta cctgaagaat aagagtaggg tttcctactg ttgttgaaaa 63780tttgcttgac tcttaacaac ttgtgtgtga ctgtaacaag atcacacagg gtaaacaata 63840ttagcttatt caaccactgg ctgaagaaat ttaggaaagt gaacacattt ttctttacat 63900ttctctttgt tctgtgagcc ttttatgctg gaatagtttt cactgcaggc tgttattgtc 63960tgcctccaga ggagggagtt gacctagcag tggtaactgg agagtgtttt ttgaaacctc 64020tttccaaggt tagttgccaa tggcatcttt ggaacagtgt ccttcacttt tgtccctcag 64080ggaccagtgt gagaatggga actttatgat ctggagctgg ttaagtgaag tccaaaaata 64140attaagaaag tgtttccttc cctgggaatg agttcagtag gaatctcaat gtattgtaga 64200gcactaagga ctcagcctca ggcatttgca aaggattctt ccagttgcct gtgttacaga 64260ggacacagtt ggcatttcct tttggtgttg aggggagatg tgtacatggt tgtgagatga 64320ctcacccttt ttgcttagat agttccactt tcattgtgga cagactcttt ggagggccag 64380tttggcatgc acgtgtgtgt tcattccatc ctggagcatt ctttatgaga aagccatttg 64440ttgagtggtt tgccattttg ttttacagcc actctgtggg ctatgaaatg gtcatccggc 64500cgctttattt gtccctaaaa aaagcagttt ttccctttct tatcttcatg gctgccaagc 64560agcagaaaga gtaactcagg gaagccatgt gatagccttt tatctgtctg ttcagaaact 64620gatgatgtat tggatttgat aattcatcaa atctgaggtt tactggtttg tatttgcctc 64680aaaatgggca tataatattt tgtcaggtaa cataatagac agatcattgg cattgcttta 64740ttgaagtgaa ttaattcaat aagcctgtaa gtgcctgaca tgtgccaggc actgtgctag 64800gcattctgtt aacagatgag acaaatctct gtcttttagg tgttttcagt cgaacagggg 64860agacaaatat atgagcaaat tgctattttt tttaaatttc atagtgtaca tgagtataag 64920gtgctgaata tgtgattgat tctgagggaa aagagagata agggaaagtt ctcagagaaa 64980gtcaagctga gggaagaaaa gcaccccaga cagagggact agcatagagc tatgctagta 65040cattgagttt aagggaatgg cacatacttc actgttgctt cagcagacag caggcctgtt 65100aggttacaaa gggccttgga tgacatgctg aggggtttta aaattttatt taaattttaa 65160ttgacaaaat ataattgtat atttctgtga ggtacaatgt gacgttatga tatatgtatg 65220caatgtagaa tgattaaatc aagctaattt gtatatctac cacctcacat acttattttt 65280tggttagaac atttaaaatt tattctctta acaactttga aatagacaac acattattat 65340caactgtagt caccatgttg tgcagatctc aaaaacttct aacaaaaact ttttaccctt 65400tgaagatatt gaactgtttt atgaacacaa tcttagaagg atttaaaaaa taatttgcta 65460ttcaccaagt acttcttacg tacactgtgc atgaaatgat tattactttt tctaatatta 65520gttttcttga ttgaggcttg gcaattatta gtttgtatgc ctttagaagg atcataagca 65580gaggtttatc ccagtaggat ttgcatttta gaatgatgac tttgggagta aaatacagag 65640aagtgaaacc agagatagtg ggatcattct ggagtctgtt gcctacactg aacagtagtt 65700gagcgaaaaa ggatgggcag aatgtgttgg ttctgggtat tgcaaattca tggcacttga 65760gtgaaaaagt ttaagccttc tattggctct ttgtgaatat cttcaacatg catgactaca 65820aatagaacac atggttttgt tgttattgtt gttgtgtttt tgtttttttt tttatttgag 65880atggagtttt gctcttcttg cccagactgg agtgcaatgg cacgaatttg gctcaccaca 65940acctccgcct cccaggttca agcgattctc ctgcctcagc ctcctgagta gctgggatta 66000gaatcatgcg ccaccacacc cggctaattt tgtattttta gtagaaacag ggtttctcca 66060tgttggtcag gctgtcttga actcccgacc tcagatgatc ctcccacctc ggcctcccaa 66120agtactgaga ttacgggcat gagccaccgc gcccggccca cacggtattt ttgaaagaac 66180agtgagcttg gattagaaca ctagtgtcca ggccctgctg ctactacata agtaattatg 66240aatccatagc catcttgttg ctcttcttct ctgagccttg gtttctttag ctataaaatg 66300ggaagttgaa actttctagc tacttctttg agttatgagt aacaagttag gtaatacact 66360taaaagagaa tgtgctatac aaatactggt tcttaagaca gctgttgtta atgtactgag 66420tattatgctt acctcacagg gttattgtga gcatcaaatg ggataatgga tttgtaagca 66480ttttgtttaa agtgtgattc aaatgttaag aattagtaaa aatagtaaaa gaacaattca 66540ttctccatcc agatgttctg tccccactgt gacttatgtg ctcattcaga gttgtacaga 66600aaaacctcca cttaattttc acaagctgga gttccacatg taacagaatc atatgggacc 66660aaaaaattct ctgtattggc ttcttccctg ccgtattttg gctctgggac caacaagaca 66720cccattttgc atgagctgcc tgccaccaac tttgcgctca catctagttc tgttgcccat 66780gtgcaagctg aatttgggcc cgggccccca gatctaacat gaaactcaag tttccttctg 66840ttcaaactgt ccaggcataa tagtcttaaa gtccgatgcc cagcagagcc gtagattttt 66900cactggccaa aaatcaacat gaaaccagat gtatctgtaa atctagtttc ataacacttt 66960gtagtcaatg gaaatacagt agcaggcaga ccagaccaga gtttactatt tgcagtggaa 67020ttaataacca catggaaact ttgcctttgg tatctgcgag atggaagata aaggtgcgaa 67080ttcaaagcag ttcccacctt accctctaaa ttccaacata aagaggcctt gaatgtcctt 67140ctatcttatt gtatatttca ttaacagaag tatgttccta gctacttagt cattctatct 67200ctattctcct ttgttttaac ttcagtggtg ccagcttaag atgctctggc tttcagcttt 67260catggagcac gtcatgtttt taaacttatc tttagggaca gaaatgttag gaagatccta 67320gttcctcatc tctttgctcc tgacaaggaa atttagaatt gcctaaagaa aggatgtatt 67380ggccaaccta ataataaatc agtattagtg aatctaaagc atatttgaaa aatttgtaac 67440atgagttgaa attcagacct gcaatgaagt gtttttaaaa gatttaaaat cgaaataata 67500taaaagaatg ttaaaaacaa gtaaaacata tcactagtta atcactctac caaaattcat 67560ttttatgttt gcatatttaa ccatttttat tttctatatt tgtccatgaa catgtgtttt 67620tatatattgt ttatattaaa catggtttta atcatggctt atttctttta tgttttactt 67680cttttccttt gacataaaat attgtatttt ttaaatttta attgcttctt ggcataccct 67740tccaatattg gtggctatat agattgaagt taaaactaat tacaatcaga gaaaattaac 67800aattcatccc ttcaatctca ttagtcacaa gttaaatact caatagccac atctatctag 67860ttgctactgt tttgaatagt acagatataa gacattttca tcaacacaga aaattcactt 67920ggaaagcatt gccctggagt aaatgtgcca gactgtacta tatcattttt ctcttgttgg 67980acatctaagt tatttcttat tttttaaata ttttatataa cttgacggtg aatataccta 68040tgtacatagc tatttgcttt ggctgaatta tttcttagaa tcaatttcaa aagtggagtt 68100attaggtcaa agagcatgag aagatttttt ggaacctgca gtgtattgcc atagtcctct 68160caaaaaagtt tatgtcaact taaagtactt ctagcagcat atgattgtac taatttcgct 68220gcaatctcaa caacactgga cattataagt ttttattcta ccctattttc cattaaaaga 68280tagcttatgc ttgattgact ttgcatttta ttttattatt aataatgatg tggtttcctt 68340ttttctagat tttattttta tttaaggcat cctttgattt taacctgatt ttttttctct 68400aaaaattatt ctaagaaaag acaaaggtga tacgaaatat atcctgagtt tttatttttt 68460tcttgcatgg gatttgtata tttgcacctt tgcccattta tactatgatt tcttagtgtc 68520ttccctggca attttaatga agacttcatg tatatcaatt tttccacaaa tataatcttt 68580ctaaaaatat gttttttcca caatataatt cagacgtatt ctccgaaatg ttggaaaaac 68640ttaagtaggc atcaaagcat ttgaagattt gtttaaaggt tgtttttata ccagttttaa 68700attgtaattt aagggtcata aaataggtga aaattaaatc atttttcagt aagggggcaa 68760gaccacttaa ctcttggaaa atacaggaaa cgtagatttc tagaggccaa gaaggaggta 68820gggattattt tgtaactgcc cccaaccttc taacctgtaa tgaaacaaac actgaaggcc 68880cttaaacatt tttaggctta attggctgtc cttgtactta gggcacatct aaaaatcctg 68940aggcaaccac tcaagagaac atgcttttgt taattcaaag ggagctgtcc tacgagtgtc 69000cagaatcctc tgtagtcttg ggcctggtgc ttgagagacc caaaggaaag gtcaatggaa 69060ttacagctta gtgttagagc tttcatgcat cacactaatt aattaatgtc ataaaggtct 69120ctctcctgtt atgggaaaaa gcagcaaata ggaacttctg gtagggtgct taaagttggt 69180ttgatatttt ttattagcat ttttaactaa tacaagtaat acatgcttat ggtagaatga 69240taaaactgaa aaaaaaggta tgaaaattta gaagttctcc tactcatgac ctcacccctt 69300ctttcactcc cagtttcact cctcagaggg taaccacagt gactagcttc ttgtgtttgg 69360ttcctgagat tttctatgta tatatattgt tagatatatg catggtatgt tttcaaaatt 69420cctgttacac tataattact gttctacaac ttaatttttt cacttaatta atagacctta 69480tatatgcttt tccatatcgg tatatataga tctatataag ttttcttaaa ggttgcacaa 69540ctttcaattg tatggctgtc ttgtaattta ctttttgttt cccttactaa tggatatttc 69600atgtttccct aactcttttg atattaagag tagtgctgca attaacatcc ttgagaggca 69660gtatatatgg tgtttaagat gaatggttct ggagccagac tactttggat tgaatattgg 69720tgccaccaat tccttgctgt atgaccttag gcaagttgct taatttcttt gcctcagtgt 69780ccttgtgtga aaaaatggag gcaataatgg tcactatcca gtagggcttt tatgaggatt 69840tagtaagtta ataatgcact ttaagaactt agttattttt agattaagta gtgaaggact 69900atataattgt tagtataatt gtataccttt attatcatac ttttgcatgt atagcaataa 69960gacaaattct tagatgttta accattggac ataaggaatg tacgcatttt aagtactggt 70020agatattacc ttttccctgc caaaaattgc aaatattgga tattaacttt ttaaatctta 70080gtaaatctga taagtataaa taacagttta tcatcatttt aagttgccta tcttaatttt 70140gtgtgaaaat gattatcttt tcacatgttt ttttggccat ttatgtttct ttccatgtga 70200actaactgtt cctggccatt gcctatttgt tgttgctgtt actatatggc ttttcatctg 70260tttcttattg gtttatggag ctctttgtat atacaggaat ttagcctcta tttatatgtg 70320tgacaaatac tttttccaat ttatctttaa aatttgttta tgttttccta ttcatcagtc 70380taaaattatg tagttaaatt catcattgtt ttttcttatg actttagagt ttggagatca 70440tgcttcaaag gtctttctag gtggggatga tttaaatcat gtactggaag tatttttgcc 70500aaaaagactc acgaattatg gatgttagag ctaaaaggga ccttagagat ttcctagttc 70560aaccaccttt tcttcatacc tttttaattt ttctctgcag atgaaaagaa gtttagtcct 70620aaagaaagaa aagagtctaa aggttctcca gtaagctaat ggcaaaaatg tagactggaa 70680cttctagctc ctgatgtgta tttcagtgat cattcaattt aaccagatgg tttcacaaaa 70740agagctttct actaaaaaat aaaatacata cttaagcaac tcagagaatt ttttttttat 70800ttttcagatt aattttcact tagagattca tcagcatatg tactatacat gtacaaatca 70860cctgtgtgtt ttggatattt agttaaacaa atgtgcaaat attttaacca aaggagcata 70920ttcatttgtg ttttattttc ttaatggttt tcgttatgaa tgtgaaatgt gtatttacct 70980taacagaaat taagtatatt tttggtctga catatatgag aactgaaaag cattggcttg 71040gctgctaact gcattctcat ctttctttct ctgctttggc aaagtctggg attaaatcta 71100atacctttta aactgtttgg gacttcagcc agagtgacct gtcttgaatt cagaactgcg 71160cagatcattc cccattctaa ggccctctca tgcctcctca ttgcctgtag gatgagatcc 71220aagtacctta gcatagctta tgcactgtag tcacttgacc tctagcacct atgcagtctt 71280ccagtcttat ttacacattc ctttgcacat gctgtttccc cgtgtggggc aacttttttc 71340ttgcctgtct gcctgcctaa gccaacttaa ataaacatca tttctgtaac ttctgtgaag 71400ccttttccaa tctctccact ccaagacgaa ggtgtttcta taggcatgac ttctggaatg 71460gcagatcaag gatctggtgg accctctact cagtgaaaca accgtttaac tagtaaaaat 71520gatcaatcaa ccatttaaaa tcttcagaaa atatcctaag ggcacatagc aaaaagagaa 71580acatttattc aagaaaagct attaagcctc agtaaaaaca gcaagagtct atggcatttg 71640agtcatgacc tgttcctaat ccttccctta tctccattct tcaggcaagt gcaaccaaga 71700agatggaggc ttcctctctc tcaaaatctt actccatagt tataatttca cccacaatgg 71760ggcagaccac aagcatctct tttttttccc ccagccctat attacagaat cactgttcta 71820ggaaggcata gcttagagga ttggagattc cttccacacc cactttctac gtatgagggc 71880tttgccccag ggatggtaag tcaagaatac agggatcctg cttgtgcctg cctcagctca 71940tatataaggt aaagcttcca cactaggaaa ggcaaattaa gaggactagg gaatataccg 72000ttatccccag ggtccacttg tagaacaggg gtgtcattct gggagaagca ggtcactgcc 72060ccacttgtgg aacaggggag tcactcgtca ctgtccctgg ttcaaattct attgcagtga 72120cagaggttct gtcccaggga aaggcaggtt gttaggatgg agaactccac agttctccct 72180gaggtgactg actttatttg gaacagagca tgaagaagtt catgcctaag ggcactgtca 72240aaaataatgg agatcttggt ggtgagcaat taagagtgga ttggtagctc catgatacta 72300gtaacaacaa gcaaaacagc agaccagcat ggaggatacc agagaaccag acaaaggaat 72360cactaagaag agcccttgtg gaattgcact cactgctggg tgtgtggaaa gttatgcatg 72420tgtgctttac tgtaccctct caaaagcaac ctaaacagga tgtggggtag gctctaaagc 72480attcctcaag ccacacatgg atccatcagt aaaatgtgga gggcttaagg ataaaaaggc 72540ttaagtacaa tctctggccc tacattttct aaatgttatg ccaccctgac caaggggcaa 72600ctcctacaaa gccaggcaaa ataataaaat catatttgtc tctagtggaa tggataacta 72660tgcctaaaac tgtgcccttt gaaaagcaac tagagagata atttctgaag tgtttgtccc 72720tacctgaatg tgtggcaaaa ttctaaactc cctgaagtgt gaaagtggtt tccaagccac 72780atgcacatcc agtagtggta aagggtgaaa atctaactgg ctaagagggc ttcatagcaa 72840cattaaccaa aaagtggttt atgtagtctt tgcctgcttc ataattccct aggcattcta 72900tgctattctg tactcagaag gcttaaagtc aggttaggga aaggaggcct atgaggttac 72960tgtgcagagg cagtgctggg aaataaatga agttaaataa atttaggcca tcgtggttta 73020aagaatggat tgtggagata agaaggataa aggaaaccca gagtcaagaa aaataaaact 73080tttcattggt gccatgccaa cccatatccg agcctgaggc aaaaggaaaa atgtgctccc 73140tgatatacac ttatacaaaa tatcaactaa ttttatttgt tggactgaat agaaaaagtc 73200aacaaaaatt aaaaataaaa aaatcatgac tatattttta ataagtggtt tatgtaaacc 73260cagagttgac caatgggatg ccagtctcaa ccataaaaac aaacaaaaca ttgtgagtaa 73320caacaccaga agtctcaaag tgtcagggaa accaatttca cagaagcagt tcagccaagt 73380cactaaacaa acaaacgact aagcaaaaaa caagaatgag tctcagaaag ggtcaagtca 73440gtatccagag ttgttacaat atagtatcta aaatattgtt ttgaactaaa aattttgagg 73500catgcaaaga atgaggaaag tatgactcat acatggtatt atatgaaaaa atcaacaaaa 73560aactatccat gaggaaacaa agatgttgaa attcactagg gaaagacttt aaaaaccagc 73620tatttaaata tattcaaaga actgaaggaa ctatgtctaa aatactaaaa taaagtataa 73680taacaatttc ttgtcaagta gagaatgcca ataaagagat agaagttata aaaaaagaaa 73740aaaatggaaa atctggagtt gaaaattata ataactgaaa tgaaaaattc actagaaaag 73800gtcacaagaa gatataactt ggcagaagaa acaatcagca aattagaaca tagatcaata 73860tagattattc attttgaagg gtagaaagaa aaaaagaatg aagaaaactg aagattccca 73920aagaaatgta ggacatctta aagacacatc attaggagaa gaaaagaagg gaaagaaaag 73980agcagaaaga atatttttta aaaaatggat aaaatcttcc aaaatttaat gaaaaacatc 74040aacctacaca tcaaagaaaa tttttttaaa acttcaagca ggaaaatgta acgatattga 74100tacttagata catcatagtc aaaatattgg agtcaaatat aaagagaaaa ttttgaaatt 74160agcaagagaa aaatgaaatg gaaccacaat aagattaaca gctgattctc atcagaaata 74220acagagagca gaaggcagtg caatcccata ttctaaacgt tgaaagaata aaaaaactgt 74280cagtcaagaa tcatatattc aacaaaacta tctttaaagg taaaaatgaa atgaagacat 74340tcctaggtaa acaaaggctg agagaatttt tcattagctg acatgccttg caagaaatac 74400taaaagcttc ctagacagta gctttaatct gcatgaaaaa aaattccaat aaagggaaat 74460ttgtaaataa taaaaataca tcattatata ttcttttcca cttaacttat ttaaaatcaa 74520tttcttaaag cactatctgt aaaattgtat tgttatttga caataaaatg taaaagaggg 74580gagtgggaat taagctaaat tggagtaagg aaatggtatc acatggtaaa ttgaatttac 74640agaaagaaat gaaaaaatta agtggcaaat atgaagagta acattaaaaa cttctataaa 74700ttaattgtgg cctcctttct tcccttagct tctgtaaaag acataagact attaaaaatg 74760acaataatta taaacacatt gttttattag taataaacat agacaaatta tctacaacaa 74820ttattattat acaaggagag ggaatggagc tgtagaggag taaagttttt ataacctact 74880ggaactaagt cagtataaat atgatgtcga ttctgttaat ttgagatata tgttagaagc 74940cccaaagtaa tcactgagaa aatgatgcaa aaatacagtt ttaaaaagtt aaaaacatag 75000tttagcttat gtgtgcctag tactccatta ttattttttt attatatttt aagttctggg 75060gtacatgtgc agaatgtgca ggtttgttac ataggcatac atgtgccatg gtggtttgct 75120gcacccatca atccgtcata tacattaggt atttctccta atactatccc tccccctgtc 75180ccctaacccc ctcaacaggc cctggtgtgt gatgttcccc tccctgtgtc catgtgttct 75240cattgttcaa ctcccactta tgagtgagaa catgcggtgt

ttcgttttct gttcttgtgt 75300tagtttgctg agaatgatgg tttccagctt catccatgtc cttgcagagg acatgaactc 75360atccttttta tggctgcata gtagtccatc gtgtatatgt gccacatttt ctttctgctt 75420gttcccagga gaaagtggct gaagattcca gagagaagct gaatgcagtt taattctttt 75480tgccataaac acgacaaccc attttcctgc aagctgtgtt agtttgctct cttcttggtt 75540cattcattca tttattcata gcttccataa atatttaaca aacactaatt aggggccaag 75600ccatgtgcta ggcacagggg ataaaactgt gaacaaaaca agccccagct actcttaagg 75660aactgataga caaatggacc agcaaacacg ctggtcctgt tttgaaggca aagcgcctgg 75720tgctcctgat ctcatgagca cagagcattt agcctaagtc tcatcctcct aaggcctcag 75780aaataaggcc ttattttaat aagtgcaagt cagtcatttg aagactaaat catagaatcc 75840tagaaaacta gtaccgggag caaggcaaaa gaatgggatg agcatgaaac atatattcag 75900aagttgtggt gtgtaggtat ataagccaag ctcttttctt cacttgcttg ctaagtcact 75960tagcttttct gcctttttgt ttgctctgtc tggaaatgga gttaatgaaa tatatctaca 76020tgatagggat attgagacga ttaaataaga tgctgctgtc acccagtatg cccttaccct 76080gctgtactta gaagtatatg aaattcattt tctaaatttt tgtatgagtg tttcatgcat 76140gcccaccacc atggaagcta ccttaagaca gtgagggact ttgtttaact tgtttgtact 76200acatcctcag tctaatggtg tctggcttat ggtaggcacc aaatataatt ttattgacag 76260aaaggatgat aatgaatgtg aaggcatttt taagtttatg aagtgttgtg catattgttg 76320ttaattttaa gctgttacgt taaagaaccc ctaatccaac tctcttgagt tttatagata 76380tcatagaaga tatatcttcc cttgacatag aagcttccct tgaaggttcc cttgactcat 76440gtatttgcct cacagtgatt gtgcagatcc cacaagataa atttatgtga atgtgcttta 76500tgtgcttgaa gtgctccaca aatatgggtt ttataagatg agaaaataga gtcagggaga 76560aaggtgactg atccaaggtc atgcaaagag ttagtgtcag aatttataat ggaatttcag 76620gctcccaact cccactccag tatactaagg cagattccag agaagaaaca gtggagagca 76680ggcactgatg agggacaaag aaaagcaggc tccgtctggc tgcaacttgt ctcttcatgg 76740caaaaagaaa ctaggaaagt gctatgccag agacgacatg ataactttgc agaatggaaa 76800gagcttgttt accacattga atactttatc tgtgtttatc taacgacagt tccaccagct 76860ctttaccact tgacttttgc ctaattcaaa aatataccaa ctatgaaaca ttttccttct 76920cagtttttat tctagattac attttgttca actttatctt aatgtgtagt gtagaaagag 76980taaggtaaga gtatagcaag tggttatttt ccatttctac tgaggacaga gaaataatct 77040aagggatttg tattagagat gaagaagtgc atggccagga catgagagat actgtgatag 77100aatggatatt gtgaagtctt tggtagtttt tgaggggaaa aaagagaagg ttttctttgt 77160ctgatatagt ttagcaacgt cttaatttag gattcaaaag ttgttcaggg tccatcttgg 77220ccttcaaatt aagatgccct ttgagagata acattgttgt tttcaaactc tgttctgtga 77280cttaagaatg agaggagaag gaagaaaaga ggagaaaatt tgagggaaaa gtgcccaagc 77340agcgtcaagg ctagacactg gaaatttatc aatgaaagcc acatggtgga tgggaatcag 77400atatgtgcat caattatttg tgttccaatc catatagaag taccgtataa tgcaccaagc 77460taataggtgc tttgaaagaa gaccatacaa gtggagatgt gttcctattc tatctaggga 77520tagagtcagg aagggcttca ttgaataagt ggtagcctct tgggctgaga cctgagttat 77580gagatgatgt ggcaaaggag acagatggct gggggcaagg tggggtcatt gaaattggag 77640gcagtagcaa tataagcaaa gctacagggg catgaaaaag caaggttaga ttagtgaatt 77700gcaacagggt ggtactgctg gaaggtcaca tggaaaagat tgtgaaggta ttgagataag 77760aagctagaaa taagctttga atgccatcct agtactttga atttgcatgc tgtaagccaa 77820gtggttttca cttggtcatt taataaaatt acagattctc aggtctcacc tgtaacttca 77880gattcagaag agtctgctaa ctgaaggtgg aatcagtgtt ccatattgct aattagctcc 77940tcagaggatt ctaatatatc agtgagttat gaccactgct gtaagccata ggtagttatt 78000gaaagctgct atggagagga gccacagaag cagatgtttt agataggatt cctctggggt 78060cctgtgtaat ttatggactg gagaggatca gacaggaagc agaaagactt gaataagaca 78120gttgcagtta ttttggaggc aaagattctc tctctctctc tctgtgtgtg tgtgtgtgtg 78180tgtaattgta ggaactattt aggcagtaaa attaacagat attagtcact gattgactga 78240gtggatggca gtgataggtg gggtgcgttg agggaagtgt attacattaa gtccaggatg 78300actcatggtt ttctaagttg agtcattggg gattgccatc caatgtgaga aactatatag 78360tcttatcata gttgatcttg gaggtagact tgaattaaaa tcttgaagcc atcaattgct 78420gtatgtgggt cttgggcaga acacttaagg tttctggacc tcagttattt cttctgtaaa 78480atgaggaaaa taatgcatac ctcatgcatt tgttgtaaag actaaatgag gttaaagtat 78540gtagagtgta gtttagtaac tgggacgtat agtggtccag taaacatcag ctgttattat 78600tgtgctatat gttgtgatgt gtactggagt gagatggggt aggggatttt ttagtctctg 78660ccaatgactc ctctccccat gatcaaaatc agaaaatcag tctcttatgt gttgaggagt 78720gagacacttc tcccaagtgt ttaaggctaa taccttgcct tgttttgcct tgggccagac 78780ctcactacac atctgtttaa gagatcaggg taagctctgt tcttggtgag tatctcaatg 78840gggctgtttt tctagttctt gtagtttctt tgggccaaca tgaaatgtct aaccttggct 78900tcttggttgt ggattctcgt caacatttca ctgctaccca agttgtgtct gcttacatga 78960tgctatcttc cttcttttgg gtttctgaag ccctcagaca cttggctgaa catttttcac 79020atttcttaag ctatatcatc tgtgttttcc ctgccacaga caaagtcaca aaaggacttt 79080aagataggtt ttggtttttt ttttccccag ggtttttata cattttgggt aagggcaagt 79140ggtaaatgct gcttttctgc cttaaccagt agtgtctgac agaggaggta gcatgatgat 79200tgcagagctc actggactga aagtcagatg ctttacccgc ctagactcta gtaccaaggg 79260gaagatggag tgagatgggg taaatgggga gaaattacca tttattttga gtgtgccagg 79320ccttttctca tgtattgtct aatgcatttg tcacaattct ctttgggttt gaaatgtgat 79380tttcttcatt ttatagataa ggaaacttat gggaagggag gttaggttca tcttgtgccc 79440aactttacat ggctagtgat caataatagt gagattcaaa ctcagatttc tctgccccaa 79500agcctttgct ttttcctctt ttgacactgt aactaatgag aagatgtatt taactctgag 79560tctcatttgc ctcaactgta aaatggagct ctgtaactct tgctctgtat gacagtaaat 79620ctcctcagac cagacttatg ataggggata aggatatttg tatctttggg cccctaatgt 79680attgaaagtg cttctaagtg cctggcacat agaagggcac tcaataaata tttaccacat 79740tttccagaaa gagggtagct ccataatggg tgagatacat tttggtggct actgtagtgt 79800ttaatgcttt taccatctgt taaaatgatt ttggagtata gctagataac tgatgatggt 79860tgttatatag attttttcat aggttgcctg ttccaaattc tatgccgtgg aagaagttaa 79920atatccagaa tttgacagga aatattattc tacaacagat ccctggcgta agaatgataa 79980cacctgtgtt ctagtctcag acttgcctct gaataactgt ttctcctggt caattctctg 80040tctctatcta ggcttgaaat ttcccccaaa tgatgaagga gttggactag tttagtgggg 80100ttcagcctcg agtggccatt aaaattattt ggggatcttt gaaaaaaatt agatgcccag 80160atttttgtcg ttgttgttgt tgtttttgtt tgtttgtttt ttaattatac tttaagttct 80220gggatacatg tgcagaacat gcaggtttgt tacataggta tacacgtgcc atggtggttt 80280gctgcaccca tcaacccgtc atctacatta ggtatttctc ctaatgctat ccctccctag 80340tcccctaacc ccagacaggc cctggtgtgt gatgttcccc tccctgtgtc tatgtgctct 80400cattgttcag ctccccctta tgagtgagaa cgtgcagtgt ttggttttct gttcctgtgt 80460tagtttgctg agaatgatgg tttccagttt catccatgtt ctttcaaagg acatgaaccc 80520atcctttttt atggtggcct gatattccat ggtgtattga actgctcact ccagttcaat 80580taaatcagaa tacagaatgt tgagaggagc atcagtattt taagaaggcc ccctagtgaa 80640gttcaatgtg cagccaaggg tgagaaacac tggactagat gattgataag ggccatccaa 80700ctttgatagt caacaagaga caatgctata gagtatggtg gacagagcat gggctttaga 80760gttagccagg tatgcattca gaccctggct ctgttactta ctagttgtgt gatcttgaag 80820aaatcaaaat ggagatacac tatgtacctg gcagtaatag ttgtggggat taagcacctt 80880caccagagct taggacataa taagccccca gtaaatagct tctttaatat cagaagttca 80940gatggaagat gtgagaaaaa tattggttca gtaagattta acaggtaaat taaaatcaag 81000tatttgaaaa cattttcctg tttctttagc aatggattcc agaaacataa tgtggaaata 81060gctctcagtc cttagatttg atgacattgc agaaagaaat ctggctagtc gtcccatggc 81120tgattggcta tgatggctag aaagccattg gaaaaaaaaa attggctcac agaagacagc 81180agatgtggct tgggaaatgc aaggacatga ctgtaataag gatttgtcta tccagcccca 81240tttatgagag tgattccagg agaaaaggac agatttgtat tgtcagtggg atacgctgtt 81300aaaaaacact tttgctacta ccactccagc tgtcttggca tgtttgttgg tgatgtaagc 81360tacagaaaat ggaaatcacc aatagggcta tagcaacctg atgcatagtg acaagtaatt 81420gttctattca tggttatgtg ttgtacagag cacttgctgc atgtcaggtt tgagacttga 81480gtatgcatta gggccatgga cacccccatc ttatctttaa gtagatttca aagtaaatat 81540ttgatgaata tgtaaaatat ttagtttggt cagtcatagg gctgagaaca tggtggcagt 81600tacctcctag tatctgcaag caaaaaaagt tttttcttcc tatagcaatt gccatctcag 81660ccacttttgc agcatttctt tttgctacac tttgcattaa ccatttgtgc acttgtctta 81720gcctcaaaca ggccatgaaa gctccttgag gataggggct atgtcttttt catctttata 81780tatgcatcat ttagcagagc tgtcccttta taatgtacta attactgaat gaagggatgc 81840atagatgaat aaatgaatga aaagtaggag tgacctgtct tctctctttc ttcacgatgg 81900ggactagtgt gtgtatataa ggggataatt tttgtgtcac ataaaatata accttactta 81960gaaggcaaga cttccagaat ggtggaatga gaaccacccc cccgccccca taaatccgcc 82020ctttcatgaa agcagtgaaa acgctagcaa acgttgtgaa aattaacttt tccagaactc 82080tggaaaggaa acagaggctt ccaacaatct gagaagaatg tattcaagaa aaacttcggt 82140aagctctctg atcacagtgg aaataataaa caattagtaa tagaaggata gttgggaaat 82200tcaccatttg tgggatataa acagtggatc aaagaagaaa tcataaggga aatgagaaaa 82260tactttgaga ttaatgaaaa tgaaaataca ttgttccaaa acttacagga tacagccaag 82320ctaaagcagt acttaaaggg aaatttgtaa ctgcgaaggc ctatatcaac aaagacaaat 82380gatctcaaat caagaaccta accttccacc ttagactagg aaaggaacag caaactacaa 82440agaaagcagg aagaaagact aataaagact aaaagggaaa taaatgaaat aatagagtag 82500aaaaacacta gaatcaatga aattaaacat tgattctttg aagagatcaa caaaactgaa 82560aaaaacttta gtcagattga ataagaaaaa aagagagaaa attcaaatta tcaaaatgag 82620caatgaaaat ggggccatca ctacctacct taaaaagaat tttcaaagga ttaaaagaaa 82680atgccattgc attagttcat tctcacacaa ctataaaaaa gctacctgag atggggtagt 82740ttatgaagaa aagcgcttta attgactcac agttccacag tctgtacagc aggcatggat 82800catgaggcct taggaaattt acatcaggtg aaaggctaag gggcatggaa gacatgtctt 82860cacacggcag caggagagag agcaaagagg gaagtgccac acacttttaa accatcagct 82920ctcatgacaa ctcactcact atcatgagaa cagcaagggg aaaatctgcc ctcatgatcc 82980aattacttcc taccaggtcc cttccccaac actggaaatt acaattcaac gtgcgatttg 83040gatggtgtga cacagagcaa aaccatatca accatactgt atgccaaaaa attagatgac 83100ctagatgaaa tggacaaata ctcagaaaaa cacaaactat ctaaagtgac cagtgaagaa 83160acagaaaatc tgagtagtcc tgtaacaagt cctgtaacaa aactggatta gtaattaaga 83220aacttcccac aaagaaaagc ccaggttcag tcttcactgg tgaatactat caaatattta 83280aggaagattt aatccttcac aaattatttc aaaacttgga agaggctgga accctttcca 83340actaattctg caaagtcagc attaccctga tgccaaaacc aaagatatga cacaaaaata 83400aaactgcagg ctaatatcac atttgaatat agataacttt ctaaaaatct caacaaaatg 83460ctagcaaaca gaattcagca acaaataaaa agggttataa agggtgacca agtaggattt 83520atctctggaa tgtaaattaa cattcaaaaa cctaagaata ggaggaaact ttcttaactt 83580tgtaatggac atctctgaaa aacacacagc taacatcata ctaaataggg aaagattgaa 83640atttttcctt gtaagatcag gaacaagaca aggatgactg ttctcaccat ttcaatttac 83700cattgtattg tagattcaag tcaaggcaat taggcaaaaa aaaaaaaaaa aaaaaaaaaa 83760aaaaagaaag aggtaaaagg cacccatatt ggaaaggaag aggtgaaaat atctatattc 83820acagatgaca tgatcttata caaagaaaac cttaaggaat ccatgataaa ctattaaaac 83880gagtaaacga gttcagcaag gtttcagaat acaagattaa tgtgcaaaaa tcaattgtat 83940ttctgtacac tagcaatgag caatctgaaa atgagattaa gaaaacagtt cactcacaat 84000ataatcaaaa taccagaata cttaaaaata aatttaacaa aagaagcgta agacttgtat 84060gctgcaaacc acaaaacact gtggaaagta attaaaaatc taaataaata gaaaaacatc 84120ccttgttcat gtactagagg actcaatatt gtcaagatgg aaatactccc caaagattga 84180aggaaatccc tatcaaaata ctggctgttt tcttagcaga aaatgaaaat ctgaccctaa 84240aattaatatt taaatacatg gaacctagga taaccaaaat aatattgaga aagaaaaaca 84300aagtcggcgt acccatgctt cctgattcca aaccttatta caaagcagtg gtaatcaaga 84360gtgtatggta ttggcataag gacaaacaga tcaataaatg gaatactatt gagaatccaa 84420aagttaactc ttacatttaa gaccaattga ctttcaaaag tgttgctaag acatttcaat 84480gaggaaagaa tagtcttttc aataaattgt actggaaaaa ttggatatcc acatgaaaat 84540aaaagatttt ggaccacttc aaacctgcaa aaaaaataaa atgatctcat ggtgtatcat 84600ggatctaaat gctatagagc taagatgata aatctcagaa gaaaatatca aagtaaatct 84660ttatgacctt gaagtaggca atggtttttt ggctataaca ccaaaagcac aagcaataag 84720agaaaaaaaa tttttttaaa aaaacccttg attattttat taaaattttg ttgtgggtac 84780aaagtaggtg tgtatattta tggggtatat gagatatttt gatacaggca tacaatgttc 84840aatgatcata ttaggataaa tgaagtatcc agtacctcaa gcatttatca tttgtgttac 84900aaacaatcca attatactct tttagttatt tttaaatgta cagtacatta ttattgtagt 84960cattcccttg tgctatcaaa tactatatgt tattcattct atctaactat attattgtac 85020ccattaacca tccccactcc cctgcctccc agctacactt cgtagcatct ggtaaccatg 85080atttcctctt atctccatga gttcagtagt ttcagctcat ggagatagac agaactaatt 85140ttattagctc ccacaaatta gctcccatgt cagaacatgt aaagtttgtc tttctgtgcc 85200aggtttattt cacataacat aacgaactct agttccaacc atgttggtgc aaatgacagg 85260ctctctcttt tttttttttt tttttttttt tgagatggag tctggctgtc tcccaggctg 85320gactgcagtg gtgcaatctc agctcactgc aagctccgcc tcccaggttc atgccattct 85380cctgcctcag cctcctgagt agctgggact acaggcaccc gccaccatgc ccgactaatt 85440ttatatatat atatatatat atatatttat tattattata ctttaagttt tagggtacat 85500gtgcacaatg tgcaggttag ttacatatgt atacatgtgc catgcaggtg cgctgcaccc 85560actaactcat catctagcat taggtatatc tcccaatgct atccctcccc cctcccccac 85620cccacaacat tccccagagt gtgatgttcc ccttcctctg tccatgtgtt ctcattgttc 85680aattcccacc tatgagtgag aacatgcggt gtttggtttt ttgttcttgc gatagtttac 85740tgagaatgat gatttccaat ttcatccatg tccctacaaa ggacatgaac tcatcctttt 85800ttatggctgc atagtattcc atggtgtata tgtgccacat tttcttaatc cagtctatca 85860ttgttggaca tttgggttgg ttccaagtct ttgctattgt gaataatgcc gcaatgaaca 85920tacgtgtgca tgtgtcttta tagcagcatg atttatagtc ctttgggtat atacccagta 85980atgggatggc tggttcaaat ggtatttcta gttctagatc cctgaggaat caccacactg 86040acttccacaa gggttgaact agtttacagt cccaccaaca gtgtcaaagt gttcctattt 86100ctccacatcc tctccagcac ctgttgtttc ctgacttttt aatgattgcc attctaactg 86160gcgtgagatg atatctcatt gtggttttga tttgcatttc tctgatggcc agtgatggtg 86220agcatttttt catgtgtttt ttgggtgcat aaatgtcttc tttttagaag tgtctgttca 86280tatccttcgc ccactttttg atggggtcgt ttgttttttt cttgtaaatt tgtttgagtt 86340cattgtagat tctggatatt agccctttgt cagatgagta cgttgcgaaa attttctctc 86400attttgtagg ttgcctgttc aatctgatgg tagtttcttt tgctgtgcag aagctcttta 86460gttgaattag atcccatttg tcaattttga cttttggtgt tttagacatg cttttggtgt 86520tttagacatg aagtccttgc ccatgcctat gtcctgaatg gtaatgccta ggttttcttc 86580tagggttttt atggttttag gtctaacgtt taagtcttta atccatctcg aattgatttt 86640tgtataaggt gtaaggaagg gatccagttt cagctttcta catatggcta gccagttttt 86700ccagcaccat ttattaaata gggaatcctt gccccattgc ttatttttgt caggtttgtc 86760aaagatcaga tagttgtaga tatgcggcat tatttctgag ggctctgttc tgtttcattg 86820atctatatct ctcttttggt accagtacca tgctgttttg attactgtag ccttgtagta 86880tagttagaag tcagggagtg tgatgcctcc agctttgttc ttttggctta ggattgactt 86940ggggatgtgg gctctttttt ggttccatat gaactttaaa gtagtttttt ccaattctgt 87000gaagaaagtc atcagtagct tgatggggat ggcattgaat ctataaatta ccttgggcag 87060tatggccatt ttcacgatat tgattcttcc tacccatgag catggaatgt tcttccattt 87120gtttgtatcc tcttttattt ccttgagcag tggtttgtag ttctccttga agaggtcctt 87180cacatccctt gaaagttgga ttcctaggta ttttattctc tttgaagcaa ttgtgaatgg 87240gagttcactc atgatttggc tctctgtttg tctgttattg gtgtataaga atgctgtgat 87300ttttgtacat tgattttgta tcctgagact ttgctgaagt tgcttatcag cttaaggaga 87360ttttgggctg agacaacggg gttttctaga tatacaatca tgtcatctgc aaacagggac 87420aatttgactt cctcttttcc taattgaata ccctttattt ccttcttctg cctaattgcc 87480ctggccagaa cttccaacac tatgttgaat aggagtggtg agagagggca tccctgtctt 87540gtgccagttt tcaaagagaa tgcttccagt ttttgaccat tcagtatgtt attggctgtg 87600ggtttgtcat agatagctct tattatttta aaatacggcc catcaatacc taatttattg 87660agagttttta gcatgaagcg ttattgaatt ttgtcaaagg ccttttctgc atctattgag 87720ataatcatgt ggtttttgtc tttggttctg tttatatgct ggattacatt tattgatttg 87780cgtatattga accagccttg catcccaagg atgaagccca cttgatcatg gtggataagc 87840tttttgatgt gctgctggat tccgtttgcc agtattttat tgaggatttt tgcatcaatg 87900ttcatcaagc atattggtct aaaattctct tttttggttg tgtctctgcc cgtctttggt 87960atcaggatga tgctggcctc ataaaatgag ttagggagga ttccctcttt ttctattgat 88020tggaatagtt tcagaaggaa tggtaccagt tcctccttgt acctctgata gaattcggct 88080gtgaatccat ctggtcctgg actctttttg gttggtaagc tattgattat tgccacaatt 88140tcagatcctg ttattggtct attcagagat tcaacttctt cctggtttag tcttgggagg 88200gtgtatgtgt caaggaattt atccatttct tctagatttt ctagtttatt tgcgtagagg 88260tgtttgtagt attctctgat ggtagtttgt atttctgtgg gatcggtggt gatatcccct 88320ttatcatttt ttattgtgtc tatttgattc ttctctcttt ttttctttat tagtcttgct 88380agcagtctat caattttgtt gatcctttca aaaaaccacc tcctggattc attaattttt 88440tgaagggttt tttgtgtctc tatttccttt agttctgctc tgattttagt tatttcttgc 88500cttctgctag cttttgaatg tgtttgctct tgcttttcta gttcttttaa ttgtgatgtt 88560agggtgtcaa ttttggatct ttcctgcttt ctcttgcggg catttagtgc tataaatttc 88620cctctacaca ctgctttgaa tgtgtcccag agattctggt atgttgtgtc tttgttctct 88680ttggtttcaa agaacatctt tatttctgcc ttcatttcgt tatgtaccca gtagtcattc 88740aggagcaggt tgttcagttt ccatgtagtt gagcggtttt gagtgagatt cttaatactg 88800agttctagtt tgattgcacg gtggtctgag agatagtttg ttataatttc tgttctttta 88860catttgctga ggagagcttt acttccaact atgtggtcaa ttttggaata ggtgtggtgt 88920ggtgctgaaa aaaatgtata ttctgttgat ttggggtaga gagttctgta gatgtctatt 88980aggtctgctt ggtgcagagc tgagttcaat tcctgggtat ccttgttaac tttctgtctc 89040gttgatctgt ctaatgttga cagtggggtg ttaaagtctc ccattattaa tgtgtgagag 89100tctaagtctc tttgtaggtc actaaggact tgctttatga atctgggtgc tcctgtattg 89160ggtgcatata tatttaggat acttagctct tcttgttgaa ttgatccctt taccattatg 89220taatggcctt ctttgtctct tttgatcttt gttggtttaa agtctgtttt atcagagact 89280agaattgtaa cccctgcctt ttttttgttt tccatttgct tggtagatct tcctccatcc 89340ttttattttg agcctatgtg tgtctctgca tatgagatgg gtttcctgaa tacagcacac 89400tgatgggtct tgactcttta tccaatttgc cagtctgtgt cttttaattg gagcatttag 89460tccatttaca tttaaagtta atattgttat gtgtgaattt tatcctgtca ttatgatttt 89520agctggttat tttgctcgtt agttgatgca gtttcttcct agtctcgatg gtctttacat 89580tttggcatga ttttgcagcg gctggtaccg gtcgttcctt tccatgttta gtgcttcctt 89640caggacctct tttagggcag gcctggtggt gacaaaatct ctcggcattt gcttgtctgt 89700aaaggatttt atttctcctt cacttatgaa gcttagtttg gctggatatg aaattctggg 89760ttgaaaattc ttttctttat gaatgttgaa tattggcccc tactctcttc tggcttgtaa 89820agtttctgcc gagagatctg ctgttagtct gatgggcttc cctttgaggg taacctgacc 89880tttctctctg gctgccctta acattttttc cttcatttca acttttttga atctgacaat 89940tatgtgtctt ggagttgctc ttctcaagga gtatctttgt ggcattctct gtatttcctg 90000aatctgaatg ttggcctgcc ttgctagact ggggaggttc tcctggataa tatcctgcag 90060agtgttttcc aacttggttc cattctcccc gtcactttca ggtacaccaa tcagacatag 90120atttggtctt ttcccatagt cccatatttc ttggaggctt tgctcgtttc tttttattct 90180tttttctcta aagttccctt ctcacttcat ttcattcatt tcatcttcca tcgctgatac 90240cctttcttcc agttgatcgc attggctcct gaggtttctg cattcttcac gtagttctcg 90300agccttagtt ttcagctcca tcagctcctt taagcacttc

tctgtattgg ttattctagt 90360tatacattct tctaaatttt tttcaaagtt ttcaacttct ttgcctttgg tttgaatgtc 90420ctcccatagc ttggagtaat ttgattgtct gaagccttct tctctcatct catcaaagtc 90480attctctgtc cagctttgtt ccgttgctgg tgaggaactg cgttcctttg gaggaggaga 90540ggcgctctgc tttttagtgt ttccagtttt tctgctctgt ttttccccat ctttgtggtt 90600ttatctactt ttggtgtttg atgatggtga tgtacagatg ggtttttggt gtggatgtcc 90660tttctgtttt ttagttttcc ttctaagaga caggaccctc agctgcaggt ctgttggagt 90720acccggccgt gtgaggtgtc agtctgcccc tgctgggggg tgcctcccag ttaggctgct 90780caggggtcag gggtcaggga cccacttgag gaggcagtct gcccattctc agatctccag 90840ctgcgtgctg ggagaaccac tgctctcttc aaagctgtcc aacagggaca tttaagtctg 90900cagaggttac tgctgtcttt ttgtttgtct atgccctgcc cccagaggtg aagcctatag 90960aggcaggcag gcctccttga gctgtggtgg gctccaccca gttcgagctt cccagctgct 91020ttgtttacct aagcaagcct gggcaatggc aggtgcccct cccccagcct cgctgccacc 91080ttgcagtttg atctcagact gctgtgctag caataagcaa gactccatgg gcgtaggacc 91140ctctgagcca tgtgcgggat ataatctcct ggtgcgccgt tttttaagcc cgtcagaaaa 91200acgcagtatt tgggtgggag tgacccaatt ttccaggtgc cgtctgtcac ccctttcttt 91260gactaggaat gggaactccc tgaccccttg cgcttcccga gtgaggcaat gcctcgccct 91320gcttcggctc acacacggtg cgctgcaccc actgacctgc gcccactgtc tggcactccc 91380tagtgagatg agcccgctac ctcagatgga aatgcagaaa tcacccgtct tctgcttcgc 91440tcatgctggg agctgtagac ctgagctgtt cctattcggc catcttggct ccagaaaaaa 91500aaattgttaa attggacttc atcaaatttg aaatttttgt gctgcaaatg ataccatcaa 91560gaaagtgaaa atctcaccca cagaatgaga gaaagtattt gcaaatcata tatctgataa 91620gggtattgaa tttagaatat ataaagaact cttgcaactc aatataaaaa gacaacccaa 91680ttttaaaatg ggcaaagtat ttgaatagaa atttcttgat agaagatata caaatttaaa 91740aatgctcaac atcattagtc attagggaaa tgcagatcaa aaccaaattg agataccggt 91800ttacacctat taagatggct atagaataaa agaacaaata acaagtattg gctttaatgt 91860ggaggagcca gaacccttat atattgctgg taaaatgtaa agtcatgcag ccctttgaaa 91920tacagtctgc aagtctttaa aaaattacta tttgttattt ggtttttctt cacttttaat 91980ttaggttcag aggtacatat gcaggtttgc tatatagcta aattgtgtgt cacaggagtt 92040tagtgtacac attatttcat cacccaggta ataagcatgg tacccaatag gtagtttttc 92100tatcctcacc ctcctcctac cctccaccat caagtaggcc ctggtgcctc ttgttctttt 92160ctttgtgttc atatgtactc aatatttagc ttccacttat cagtgagaac atgtggtatt 92220tggttttctg ttcctgcttt agtttgctta ggatactggc ctccagattc atccacgttg 92280ctgcaaagga catgatctca ttctttttgc atagtatact atggtgtaca tgtatcaaaa 92340atgttactgt ttgacctagt aattctattc caaggtaaat actcaagaga aatgaaaaca 92400tgtccacaca aatacttgta cacaaatgtt cattgcagca ttatttataa tagccaaaga 92460gtggacgaca aatgtcttcc aaatgtgggc tccaaatgtc caccaactga taaatggaaa 92520aacaaaatgt ggtatatcca tgccatggtt tatctgtcaa taataagaaa tgaagtactc 92580atacatgctc caacatggat gaaccttgaa aacattatgc taggtgaaaa aagcaactca 92640caaaagacta cactgtatga ttttatttgt attaaatgtc cataaaagaa aaatatttag 92700agatagaaag gaaattagtt tttccagggt ctgggaggag acagtatgag gagtggctgc 92760taatgggtac aggatttctt tttggagtga tataattgct ctaaaattag tttgcagtaa 92820tagatgtgag tatgctaaaa tgggtgaatt ttatagtatg tgaaatataa ctcagtaagc 92880ccattaaaaa caacctaatt aaattaaaac caagctataa cagaaatatt atatggcttt 92940ggcagtttag aatagtggga aaatatggag taagggtggg gaaatagtcc caagtataat 93000tctggttttg tcactactag tgtatggact tggacaagtc atttgctttc tctaagtatc 93060agtttgcata tatgcaaaat agaggtaatg atacctacct cagtggtacc ttttcaaaac 93120cttgttcttc ctcatctctc ctctaccact ttctcataat attattacag taataaccat 93180ttattaagca ctgtgtccgc agtggtgtgg ggctgcttta cctccacaac ttcactgaat 93240cctcactgca gtcttgtggg atctttattt ctttgcccat tttacatgta aataaattga 93300agtcaaatga gttgttcaag gtccttctgt tagcaagtgg cagagatgga catgaaaact 93360agatcttcta cctatgtgtc tttccacttc aactaaagaa tttattaaag agaattgaaa 93420agctatgaac taaatttcgg taatactttt aatagtaaac attgctgccc tcgtgaatga 93480acacacacta aatttcaaat ctcacggtgg cagggaataa agatgctacc tatcttaagc 93540cattacttca ccaacttctc caccaaaata ttccttgtaa ccacaaataa gtaagcacaa 93600tagatctata aggagagaat aattgtgaac tctgatttta tcttaaaaag tcatgtaggg 93660atgtcatgtt ccacaatgtg attaataaaa tatattttgt tactaaacac aaggaaaaat 93720attatgttcc ataaagatgt ttggtggttg cctcgacctc ttttagtttg aaaagtaggt 93780atgtatgaga aagatatgtg tttacatgtt tacccttgcc ttctctctgt ctcttcccct 93840ctctctccct ccctccccaa cccctatgcc ctacaccccc gcaaccccca catgtattta 93900cctttctcta aaagctctgc atagccaaga aaagtgctct tttttatttt taggatatta 93960gatatttcat tttcttatgg taagacaaaa gattaaggca accaagactt acaatgtgcc 94020taccatgtgg caggcacaga ggcaagggct tttacatgtt atttaatgta attgtaattc 94080tcacaaaagc cgtctagagt tgaaaatatt tccaactcta aatgaggcaa atggagcaca 94140gagagcctta attatttcac ccaaagttca gtggtagagg caggattcca acccaggtct 94200ggtgggctcc aaatccttgt tgggttgcca ttcctcttgc taacaaataa aactggtctg 94260tgacttttgc atttcacccc gcttccacag tcactggtgg gacttactta agttaatcag 94320attcttcaaa gtatccccaa gtcctccttt gaaaagaaag ttgggggaca ggaggaggag 94380cagaggagag gagataaaaa ggaaaggagt cagggagaga gagagagaga gagaaacctg 94440gtgatctcag ctgggtgcca aggtttccta agcccaagtt ccccatggtt gagcctgtat 94500tgtcaggcca acagcttcta gtaatccact tttatttaat taatagtgaa actgttgaag 94560aattgcaagt ggtgttctgg ttcagaaacc ttccgttcta tggggcactg cttttgcttc 94620agattcataa aaccaaatgc tctgcctcaa gataataagt gaacgtgtaa ccctcgggag 94680gtaagaaaaa acacaatgtc acgtgcaaat tctgcacttg ttctcaaagc aaacctctcc 94740tgtgtttgca attaggatgt tatctaggag catattcaaa acttttgagg tttttatttt 94800agtttttctt tcattatgtg ctgttttagt aatatcaaag aatacatgta atatataatt 94860tatatgtcat aacaataaaa ttaatgttga tgagcccaga ttaaagaatc aacaacatta 94920acatcatgat tgcatcaacc ctattagaat ggaagctctg tgaaggcatg gatttttgtc 94980cattttgttc actgctatat ccccaggacc tagaggagtg tcagccacat aataggagct 95040tagtcaatat tttaaaaata agagcataaa tctacttata tcctctttcc tcttaccatc 95100actcccagcc tcccctcaga ggtaaccact atcctatatt tgggctttat tattcccttg 95160cattttgata agttttcaca tgtatattcc caaataatat attgcttgct tttgcttctt 95220tttaaacttt atataatgga atcatattgt atgtatccta ttgtgaatta tgtcttttac 95280acaacattag tatttgagat tcaactatgt gtagctcgat tccattcctt ttcattgctg 95340attgtagttt attggatatg tgtgccataa attatttttc tcctgtcagt taatgtttat 95400catttatgct ttaataaaca aaactgctat gactgttcct gcatgtgcct cctagtacat 95460atgtgaccaa ctttctctag gatataagcc tgagagaggg actgcagttg gaatttacat 95520ttccaaagcc caaagtttag ctcatgagtc agagctgcaa tgtgcccttt gtccacacta 95580ggtcaggatc agtgggagtg ctacccaaaa tattttgcta gctggggagt cagggagaag 95640cagagactga cctagtgagg ccaggaggca ctatctcagg tctctagtca aaatgggttg 95700caattagtaa aagtccagat tctgaatccc cttcactatt tatcttcctc ttcctccttt 95760acagttattt ttgttcaagg tgcactttat taaactcatg cctaacaaac aaaactctaa 95820tgaatatttt gtctttcatt gattgtaaat tcaattaatt agattgcttg aaaaaatttt 95880aactgtattt tcactttagt atggatgaaa atttcgattt ctttaaaaaa cattttttaa 95940taataacaca acataaagtc taccctcata acaaaattta agggcacaac accatattgt 96000ttttttttta ttttattatt attatacttt aagttttagg gtacatgtgc acaacgtgca 96060ggtttgttgc atatgtatac atgtgccatg ttggtgtgct gcacccatta actcgtcatt 96120tagcattagg tatatctcct aatgctatcc ctcccccctc cccccacccc acaacagtcc 96180ccagtgtgtg atgttcccct tcctgtgtcc atgtgttctc aatgttcagt tcccacctat 96240gagtgagaac atgtggtgtt tggttttttg tccttgccat agtttgctga ggatgatggt 96300ttccagcttc atccatgtcc ctacaaagga catgaactca tcctttttta tggctgcata 96360gtattccacg gtgtatatgt gccacatttt cttaatccag tctatcattg ttggacattt 96420gggttggttc caagtctttg ctattgtgaa tagtgccgca ataaacatac gtgtgcatga 96480caacaccata ttgttaactg taggcacaat gttgtacagc agacgtctag aactttttct 96540tcaggcttaa ctgaaacttt atagccattg aacagcaaca ctccatttcc gtttcttaaa 96600ggtcctttac aaaatgagct ttctgcgtgt ttccattttg tttatctgat aacttttttt 96660tcttttttta ttatacttta agttctgggg tacatgtgca gaatgtacag gtttgttaca 96720taggtacaca catgccaggg tgtttggctg cacctatcaa cctgtcatct acattagata 96780tttctcctaa tgctattccc tcccttgccc ctcacccctc actggcccca gtgtgtgatg 96840ttccctagcc tgtgtccaag tgttctcatt gttcaactcc cacttttgag tgagaacatg 96900cagtgtttga ttttcttttc ttgtgttagt ttgctgagaa tgatggtttc cagcttcatc 96960catgtccctg caaaggacat gaactcttcc ttttatatgg ctgcacaata ttccatggtg 97020tatatgtgcc acaatttctt tatccaatct atcattgatg ggcatttcag ttgttccaag 97080tctttgctat tgtgaatagt gccacagtag acataagtgt gcatgtgtct ttatggtaga 97140atgatttata atcctttgtt tatataccca gtaatagaaa tgcttggtca aatggtattt 97200ctagttctag atccttgagg aattgccaca ctgtcttcca caatggttga actaatttac 97260actcccacca acaatgtaaa agcgttccta tttcttcaca tcctctccag cacctgttgt 97320ttcctgactt tttaatgatc acgattctaa ctggcgtgag atggtatttc attgtggttt 97380tgatttgcat ttctctaatg accagtgatg atgagctttt tttcatgttt gttgaccgca 97440taaatgtctt cttttgagaa gtgcctgttc atttccttca cccacttttt gatggggttg 97500tttgtctttt tcttgtaaat ttgtttaagt tcattgcaca ttctggatat taattaacct 97560ttcgtcagat ggatagactg cagaaatttt ctcccattct gtaggttgct tgttcactct 97620gatgatcgtt tcttttgctg tgcagaagct cttgagttta attagatcac atttgtcaat 97680cttggctctt gttgccattg cttttggtgt tttagtcatg tagtctttgc ccatgcctat 97740gtcctgaatg gtattgccta ggttttcttc tagggttttc atggttttag gtcttacgtg 97800actcatcttg atttaatttt tgtgtaaggt gtaaggaagg ggtccagttt cagttttctg 97860catatggcta gctagttttc ccaacaccat ttattaaata gggaatcctt tccccattgc 97920ttgtctttgt caggtttgtc aaagattaga tggttgtaga tgtgtggtat tatttctgag 97980acctctgttc tgttccattg gtctatatat ctgttttggt accagtaccg tgctattttg 98040gttactgtag ccttgtagta tagtttgaag tcaggtagca tgatgcctcc agctttgtgc 98100ttttggctta gaattgcctt ggctatgcag gctctttatt ggttccatat gaaatttaaa 98160gtagtttttt tataattctg cgaagaaagt cattggcagc ttgatggggt tagtattgaa 98220tctgtaaaac actttgggca gtttggccat tttcatgata atgattcttc ctatccatga 98280gcatggaatg gttttccatt tatttttgtc ttctcttatt tccttgagca gtggtttgta 98340attctccttg aagaggtcct tcacatccct tgtaagttgg attcctacat attttattct 98400gtttgtagca attgtgaatg ggagttcact catgatttgg ctctctgttt gtctgttatt 98460ggtgtatagg aatgcttgtg attttcgcac actgattttg tatcctgaga ctttgctgaa 98520gttgcttgtc agcttaaggt gattttgggc tgagagaatg gggttttctg aatatacatt 98580catgtcatct gcaaacagag acaatttgac ttcctgtttt cctatttgaa tatcctttat 98640tgctttctct ttcctgattg ccctggccag aacttccaat actatgttga ataggggtgg 98700tgagagacgg catccttgtc ttgttctggt tttcaaaggg agtgcttcca gtttttgacc 98760attcagtatg atattgggtg tgggtttgtc ataaatagct cttattattt tgagatatat 98820tccatcaata cctagtttat tgagagtttg agcatgaagc agtgttgtat tttgtcgaag 98880gccttttctg catctattga gataatcata tggttttgtc attggttctg ttgatgtgat 98940ggattatgtt tattgatttg tgtatgttga accagccttg catcccaggg gtgaagcgga 99000cttgatcgtg gtggataagc tttttgatgt gctgctggat tgggtttgcc agtatttttt 99060tattgaggat ttttgcactg atgttcatca gggttattgg cctgacgttt tctttttttg 99120ttgtgtctct gccaggtttt ggtatcagga tgatgctggc ccataaaatg agttagggag 99180gattccttct ttttctgttg tttggaatag tttcggaagg aatggtacca gctcctcttt 99240gtacatctgg tagaattcat ctgtgaatcc ttctggttct ggactttttt tggttggtag 99300gctattaatt acttcctcaa tttcagaact tgttatagtt ctattcaggt atttgacttc 99360ctgctttagg cttgggaggg tatatgcgtt caggaattta tctatttctt ctagattttc 99420tattttattt gccccagagg tgtttatagt attctctgat ggtaatttgt atttctgtgg 99480gatccgtggt gatatcccct ttatcatttt ttattgcatc tgtgattctt ctctcttttc 99540ttctttagta gtctggctag tggtctatct acaaaataga ctgtttatct gatatttatt 99600ttgtaattat ctaataataa ccatcattat catcatcagc attatcatta tcatctcctt 99660tacccataca tacatttgtg tctttcaaat aataatccca tctttgaagt gcatcctcat 99720ctttagcagt ctgcactctg ctttcttata tcatttatta tcttatttta taattattta 99780tttccagtcc ttcttctcta acagatagta gtttcttagg gccaaggaaa tatctcgatc 99840accactatat ccccagcacc taaccctgtg cctggtccat agggccagat gctaagagtt 99900gagttgaacc attgtaccta atcttaacct tcattagcac aacatggttt gtcagtggtt 99960aagaatctac actttggagt cagactcacc caggatggaa tcctggcatt gccacttatt 100020attaatagat gcgtgatctt gaacaagttt acttaattgt tctgagcatc agtttcctct 100080tctgcaatat agggatgata cacagctacc tggtaggttg ttgggaaaat taaatgggat 100140gatatgtatg aaatggcctg gcatatagag tgcctaaata catgttcttc tgattctatt 100200tggacagttt gtgttagtaa cagaagtcaa aaaggtggag aaaggagaaa ggtacttgtg 100260aaaattttct atttcttctc catgtttcat tcaggactga ggaagggggc acagttttta 100320cccaaggaaa tgacattttt agccaaaaga aatgatctta gcatttagct gaattatata 100380ttggaagtaa gctccttcca tgtggaactt atggccttgc tagccttggt ttgttggaag 100440tgctcttgct ggctttctag ttagggtagg gaaaggaagg cttgtgggga atgaagatag 100500gccatgatat caagccactg ggtttgcaaa tcagtagaat tttttattgc tttctgttgt 100560acttgggact tgaataaagg ctgatatttg tgtcttgctg gtaaagtgct tgtaaagtga 100620gtgaaagttt tctttgctct tgtcctgaca tagctgttca cttggggttg aggggaggat 100680aacctttcat gttttttttt tttcttcatt ctgatgactg tgctgaacat tcaaaccaaa 100740aggccattgg tggaaagtaa aggtgagtgg tgagaagaca atagggtaat ggaaactgtg 100800ttggacttgt aatcaaattg tcctgcactt cccctctcca agtcttaacg tttttcatct 100860gtacagtgga tattaaaatg agaaaataag cttgtcttca cagagttttc gttaggtgtt 100920gacacaacaa acaggctccc attagggctc attttccttc attccttagt aaggaagaag 100980tgcttataaa atatagcagt tgtgctcttg tgaatgatag catgggcagt tgtcatctcc 101040ctgaagcaga tgtaacccag aatgtcactt gagttttgtt taatgcttag gcataagaca 101100taggaatgac aaaagctgac ctttgggtag tgagaacaat gttccatttt gttcaaactt 101160gaatttttta ctataggaga ctgagaatta accttccatg aaggttttag gattggcttt 101220ctggcccttc tccttcatat ccacctgaaa gagcttgggc gcagaagttc ttgcagaaag 101280gcagttagac aaggtgactt ctgaagctcc agtggccaag tattttgatg gtagcctaaa 101340agatgtccag aatcattgta catcattttt tcaacagaag cttcaggcat agggattatg 101400cttggtactt tatgttgtgg aatggaatct ggcggatgtc catgtgatct atagaaacac 101460ctaaggaaag tgaagaaatg agggaaaaaa aagaacaaga cttttatgat aatactaatc 101520acgatccttg tgtatttatt ccaatggcat tttatccatt atctgattta tattaccact 101580cacagcagca gctcaatagg atgggagata ttatctctat tttatagatg agatttgagg 101640ctcacgaagc taaagcaagg aacatcaaat cactttgata tttggtctgg ttttgttata 101700ggtctccctt tggatgaggt aaagttacaa acctgggttc atatcattta attagtctga 101760aaatgttgcc tggacaccac cttcagttag atatcttaac ctcaggcttc ctgccttcat 101820tgctcccgca tatagacata gactatgaga ttggctaatc ccagagaact tccctaatcc 101880cttggcaaga tccaaaaagg ctcagtcaca ccctacaacc atcatcttta ggagaagtct 101940cagaaaattc agcttcacac taactaactt gagcaatgaa taatagtcat ttatgcctgc 102000aggttaatgc tgaagacctg agacttcact tgcctatttc tgccattcag tgacatgtgt 102060tgcattggtt ttttgtgtct ttccagtttg gagactgcca gggaccatgt tttgcccatt 102120gactattact ttccacccca gaagacctgc ctgatctgtg gagatgaagc ttctgggtgt 102180cactatggag ctctcacatg tggaagctgc aaggtcttct tcaaaagagc cgctgaaggt 102240aaagggtctt gcacatgcac ttctctttcc ctttctcctt taccttccag agagagacac 102300taacctttca gggcccagga ttttatcatc tcagaaatag agtcattggc aaggccctat 102360caaataactt aggagcctaa ggaagcaaat ttttgtactt gctagttccc tggtttcagc 102420agccttgttt gtacaggcaa tttaggcagt gaaggtggtc ccagctgggg cttggggctc 102480agtgggtcct agaaatgaaa gaaaaattaa tgatttgaaa agatttaatt tcctcccttc 102540ttgttttcta ctctgctggc tagtaaagga aaaatttgtc cttattagag aggttagaag 102600tggagaaacc ccaactgagt ccccagcctg ttccttggga tgaatatgag actgttcctt 102660agcaaaggct tcctggcctc ggccccagaa agggagtgtt ctcactcttc agcagactat 102720cagtctctgc acctgctccc tcctgttgtg gcctccttgg gacctgtctt tgcattaata 102780gttcctaggt aggtaagaac tcagagtgaa gaaacacatt tattctcctc tccagagacc 102840tgatctcaaa gcctgtccat tagtccctaa ccttaatcta aggtagcatc ttatatctgg 102900ctaaattggc tcaagcccta gctccttagt tttatttagc ttagaacaac tcatgtctgc 102960tcaacctcta gaggcgctca gcccacattc tgcagtagaa actcccattt tcaggcctct 103020tatatacggt aatgtctcct tcctctaacc acccagggct taagcttcct gcttatccac 103080ttcaccctgt attgagggct ttcttctcaa agagacattg atgaggagcc cctagagaga 103140gatgctgtgc tctgggacca gaccccttgt taaacaccag tattcacctc tgccccaact 103200ttccccaaag aggtacttcc tgccaaggcc tttctctttc ctctcactgg ctggaagtgt 103260tgagttccac ttcagaacca gaacagagaa cctttccttc tataagagct ataaaccttg 103320agaacagtct taaaacatag gtatgtaggc cacaccattc accacgaatg tactgatact 103380catcagaata tggaagaagc accagagagt ttgaagcatc tagagaaaag gtagaaagag 103440aatgcccttt aactgacctc ctcagtgata gccaatcaca atgatgagtg ttgattcatc 103500attttggcta ggtggcagaa atatctataa aacagaagct gccatgttgt tttcttccag 103560tcctcagggc ctacaagaag gcagctatca tttggtatta ctgaaaacat gccccatgtt 103620cagctcatac ccccaaatta cccattgcta ctgtttatgc tgggctaata tgaagcccag 103680ggccctaatg tctaggtcta ggcagtaagg cctagagcag tgcctaaaga gcctgagagc 103740agtgccttcc tttcttcaga gtactcatga aaggatggct gtcagaaaag gaaatgagga 103800tgggttccag agacttcaga ccaccccaac ttccccagtg agaccctggc acctccccat 103860accctctcac ctagcgggcc ctgtctatag agcagagaat gaaacagagc actcatctag 103920aggtagtgtg tcagcaagcc caggcactgc accacagtaa tagcagccat atcagatggg 103980aaaggagttc aagtgaacaa acaagcaaat tcaatagtca gatagattag attatacttg 104040atgcttcctc tgagttttac aaatatgggt cactaaattg ttattttcag aaaacagggg 104100aaatgctcaa tcacattgtg aaagggaaga ttttgctgtc atatcataca tcccacatgg 104160gagctttctg cagaagttag agctgaagga gggaggcagg cagaagggca actggcaggg 104220ctgcctggga ggagctctgc aatgaggtgg atcctgtgcc atttgagaac agggaagaaa 104280agaaatgagg ttttggggag ggaatcaccc aactcacaga acacacagaa atccagcaag 104340gtttcaaaac gctctacacc ttagagtctg ttaagttagg gaaactctgt gagctcatag 104400ggccaaatgc acttgcctgc ttgaaatatg aaaaatcagc aatggattcc ttgaaaaaca 104460atgaaaaggg aaccttctga gccccttggt tattttgaca tatggaccat agatttcagt 104520cctgagccct ttgaaggtag gagaaggtgg tttagaaaac acacacacac acgcacacaa 104580acacacacca gaatgaagca aaaaaaaaat tactggtgtt ttctttctcc tcccatctgt 104640gaagctgttg gattgatttt actgccatca ttatccctgt ttgaaggcag ggggctgtct 104700tattacccaa agaggacatt tattgatttg gttttctttt tccattttta caatgcatct 104760ttatcgccca tatggccttt ctggaggtgg ttttcagtct ggcttgttga aacatcaaat 104820tatacctgtc ttagagaaaa tagaaacaaa aatctttctc ttccttactt gcttgttgta 104880gtcagttaac tcggactgag tattcagagt cttgattatc acttaattca tagtttcata 104940aatctctgga atgggcatag gtacaggact taaaagcctg gcatctcaga cagaaatatg 105000tttttagctt tggtggttta taacagatgg gacttttagg ctgtcattgg tgcagggctc 105060agcacagagt cagttgtaat ctggacaggt tttgttgttg aggaagagtg ggaagaggga 105120gtcctacatt ttctccttgt cagtaatgtt ggagaattgg ggtgagggtg aggctgggca 105180gggagggtct gcatagaaaa aagggtgcgg tgagaaaaaa taatgctact aagccatgag 105240ggtaaaatga ccaaattctg gttgagagaa acttggtcaa agtgtgtatg gggagagaaa 105300gttggtcaaa gtctgtgtct gagtgcttgg tgggatgaac tctgggttag aaacaggcat 105360ggagggaaat agttggttta tggagtgggt aggatgagtg

gggtggtgaa agggaaggca 105420ttttggatgc taagagacca ggaagtcaaa gcaaggcaat acacataaac agaggtaagg 105480gctcagagag gttttagttg tgtagacttg gataagaaat tttccctttt ggacctcagt 105540tttccttgtt tgtaaaacaa cggacttgaa ctagatattt taaaatgtgc ttccagctta 105600gacattttgt gaccgttcta caaattacaa acataatcat catcatttca gcaaactcac 105660atgtatttat acctgcataa gtttttggtc ttgctttcct agaaggtgac taatcccaga 105720tcctaatcaa ttaaagaagc aatcttcaga tggggataga gccagctgag agagtgtact 105780atggatggag tgagttaaaa ctcaggactc agattttctc cttgtgatca ttgctgggta 105840acttcctttc ttttctattt tctcatctgg aaaatcagga tatgaatccc catctctacc 105900tcattatgtt tcaaagaggg ttaattaatc catcatgtgc attatgtgct caagaattta 105960ctatttttca gacattttct agtaaaacat tgaagattat atgtccattt gttttgtaca 106020catggagtgc tgtttggtac acatcataaa attgaaactg tagtttacat tctgaactca 106080aagaattaca ccatcctcac tgatgtttac aataggtccc aatttagttt ctttagcaaa 106140ttttatgtaa gtatggcttt gattctctct ctcactccag gtttttgtta gggaagaaat 106200gcaagtgaac cctcattgaa ctctttctgt cctttaaatc cattctttcc cacctcaact 106260catgtggaat tgaatgttgc ctctagtttg gagtctagca gagagttttt ggtgcatatc 106320agtgtcccct tcactccctg acttttcaag taacatttcc cagaggcaaa ttaactctgc 106380taagaggatc tgcttgcagc ttcaacagag ccttcatcag gtatctttgg ccaaggagtt 106440gactgatcct gactttgcga gtcctagaga tcttttcaca aagctcctct catgtttctg 106500cctctgattt tcttaaatgt cacagacaga ctttagattt aggggttggt taactttttt 106560tgtaaagggc catgtagtaa atattttagg ctttgtagat catatggtct ctgtgtcaac 106620tactcaactc tgcctttgta ggatgaaagc agccatagac aatactggaa ctaatgggag 106680tagctgtgtt ccaataaaac tttatgggca ctgaaatttg aatttcactt aattttcaca 106740tgtcgtttaa tattattttt cttttttacc atttaaaaat ttagaaatca ttcttagctc 106800tttgggcctc acaaaaacag atggtagagt ggatttggtt tatgggctgc agtttgttga 106860cctgtgcttt agctaatcac ttctgtactt ataaatctgc ataggtttta tgtttttcca 106920tctcttggta tcttagtagg ccagtcaaag tttgaacaac ttgttagcac agaatacctg 106980gcctagtggc ttcttggtcc tgagcttatt tactaaacaa gagaaaaaat aaataagtct 107040agaaatgcta gaagaggata cttttttgtt ttaatgatct agtagatcac tcctccttgc 107100aatacccaga ggagaaactg aaaatatttc aaacattttc tagacttctg tgttgtaaat 107160ttgtggataa ctatgaacta tatatgaatg aacttttctg gatgacacat atattccaga 107220tggtaaaaag gaagggcttt ggggactctc tggtaccaag tgtcatggaa aaactgtgtg 107280tctcatagaa agtagatccc aggaggccag cagagttgtg gatctgccat atattacctc 107340atgattctgt cttcgcacac tcaccggctt aattctgggc ctccccataa cacgactaga 107400ccacaggctt gcagaagaaa taatttagct ctgtaactca ttgaagttgg tgcccaccca 107460agtctctgtc agtgcccaat tcgggagcca tgccaagaat ttgccattgc tgcttcatgg 107520tggccttgtg cctgcttatt tatagcctgt gcattttatg aaacagggat taataagaag 107580ttgccatagc acttgcacca ttatgtaaat atctgtaatg cttacataac ttttgtcact 107640tgcaagacct tttgagtcca ttgccttctg ctaccatgcc ttaccaattt cctagtccct 107700tattattatt tttcaattca ttatatttaa cttctgtgat acacgttcag aatatgcagg 107760tttcttatat aggtatacac gtgccgtggt ggtgtgctgc aaccaacaac ccgtcatcta 107820cattaggtat ttctcctaat gctatccctc cactagccca ccacccccta ataagcccca 107880gtgtgtgatg ttcccctccc tgtgtccatg tgttctcatt gttcaactcc cacttatgag 107940tgagaacatg cagtgtttgg ttttctgttc ctgtgtttgt tttctgagaa tgatggtttc 108000cagcttcatc cgtgtccctg caaaggacat gaactcatcc ttttttatga ctgcatagta 108060ttccatggtg tatatgtgcc acattttctt tatccagtat atcattgatg ggcatttcgg 108120ttggttccaa gtctgtgcta ttgtgaatag tgctgcaata aacatacgta tgcatgcgtc 108180tttatagaag aatgacttat aatcctttgg gtatataccc agtaatggga tggctgggtc 108240aaatggcatt tcaggttcta gatccttgag gaatctccac actgtcttcc acaatggttg 108300aactgattta cacccccacc aacaatgtaa aagtgttcct atttctccat attctctcca 108360gcatctgttg tttcctgact ttttaatgat cgccattcta actggcattg acatggtatc 108420tcactgtggt tttgatttgc atttccctaa tgaccagtga tgataagctt tttttcatat 108480gtttgttggc cgcataaatg tcttcttttg agaagtgtct gttcatatcc ttcacccact 108540ttctggtgtg gttggttatt tttttcttgt aaatttgttt aagttccttg tagattctgg 108600atattagccc tttgtcagat ggatagattg cgaaaatttt ctctcattct gtaggttggt 108660tgttcactct gatgatagtt tcttttgctg tgcagaagct ctttagttta attagatttc 108720atttgtcaat tttggctttt gttgccattg cttttggtgt tttagccatg aagactttgc 108780ccattcacaa ttgctacaaa gagaataaaa tacctaggaa tacaactcac aagggatgtg 108840aaggacctct tcaaggagaa ctacaaacca ctgctcaagg caataagaga ggacacaaac 108900aaaaggagaa acattccatg ctcatggata ggaacaatca atatcgtgaa aattgccata 108960ctgcccaaag taaattatag attcaatgct atccccatta agctaccatt gactttcttc 109020acagaattag aaaatactac tttaaatttc atatggaacc aaaaagagcc catataccca 109080agacaattct aagcaaaaag aataaagctg gaggtatcaa gctacctgac ttcaaactat 109140actacaaggc tacagtaacc cttatcaatt ttttatgtgc ctctccatat tctgcagtca 109200gaagcttctt cagtcctttc agggaattgc tgggtgacta tcaaactctg gtagttcatt 109260tttgcagttg gctgctgttg tgaggataag agttagactc actttctctt cagagataga 109320aattatgtat taattctctg ggttctagac ccacagcaag gagcatactg ctcctcaaaa 109380taactgaatt ctgcgagaag ccatcattgt aaaacaacaa tatcttcagt tatagtagcc 109440atgtgtgcaa cttctggaaa ctgttattca gattttcatg ttccttccct gtctcttcat 109500agctaggcag ctgctttcag ccttgtacag atgctagtga gctttctacc tacaaacctg 109560cagaaaattg aactgagatt tggaggtgaa agactcttga taaagggaac aaggtttaga 109620attctcagtc cctttgctcc caggctgtgt tgtgactact gaggcactcc agtgaaatca 109680ctattcctcc tatctagact aatgcctgtc tctgcagagc acctcataag aacaggcctg 109740gtagtaatat cctcatgcat tcagtcagta aatatttaca gagtgcttac tacatatagg 109800gtattgggct gacatatgca agatacaggg cctgcttcca ggaggttata gcttattgat 109860cataaatgtg gcattttttt tttttgagac ggagtcttgc tctgtctgtc acccaggctg 109920gagtgcagtg gcacgatctc ggctcactgc aacctccacc tcccaggttc atgtgatttt 109980cctgcctcac cctcctgagc agctgagact acaggggctc atcaccacac ccagcttttt 110040tttttttttc tgtattttta gtagagacag ggtttcacca tattggccag gctggtctcg 110100aactcctgac ctcgtgatcc acccacctca gcctcccaaa gtgctgggat tacaggcgtg 110160aaaatgtggc aatctttaaa gctcttcagt ggatgaaagg ccaccctatc tgctgtcctt 110220ttgaacttcg caactttctt ggtacagagt gagaggttat tctcttggtt ttccatataa 110280gtaaactgag gctttgccag ttcatcaaca ggtagtaaat aatatatttg gaatttgaac 110340ccaagtcttc tggggtcaaa ggcagcattc actctgctct gtcacagcag ctcctcaaat 110400aagccaacat agaaaccaag tactatgcct aggcaacaag aaaggcagca atgaagagca 110460acagcagagt caaatatgag agaaggaagt taagaaagat gttaagtact gtggggagta 110520actgagaaac caccaagtat cgctaacatc acagggaact tgtcttccta agaaaattcc 110580aagcacttaa aaccgctggt agttcatcag caactctctt cattagatgt gcgagggaca 110640tgtgggccat agtccttcta ctaacttata ttcttcaggg gaaagttctg attctgatga 110700gacccagcat ggtagctctt aattcactgt tgtcacacga ctatagaaca ggaagcacaa 110760cttaacacct gtgctcatga gaattttgct ccttatgacc aagctaaaga aagagcttag 110820acaggatgtg tggctataaa tgtagattaa tggttccttg gctctttggt ttgagccttc 110880tcagcagagc atcccacgga gtgttttcca tggggccacg agcaagagaa atccacttcc 110940ctcctcctca atgtcagaaa atagagaata ttgtctttca ggatagaatt aaaaagtcat 111000agaggcagca acttgttttc ctatattagg gttttaaaat tctgtttttc cttcctctcc 111060tgggtcagat cattgtgtgg atggaccttg atttcattgt ggtatctgta tgtggaccct 111120gaagaccatg gacttctaac aattccttaa gttacataag cacattccta caggtcacaa 111180gctcatttac ttacaggatg gttgatttgg tcacaggtta tttcatgaaa atacttaaaa 111240gatttgcagt gttcaaaact gcagtatctt taaacactaa aacttgaagg aagggaattt 111300agaaatcaaa aaatctggtc aaaccatttc atggaaaagg aaagtgaggc tcagagagag 111360gaaattactt tcctgggttt gtatagccta taaatggcag aaatgagagc ctccctgcca 111420tttctagttt tctgtctgag agactctcct gcctaatagc taattagcag agtcacagag 111480gtcattacct tgcaattctc aagaattatg tgaggcagca tagtaagcat ttatggccct 111540tggttcctag aaggagctta gtccctgata gtcatctctg cctttgccat tgtgtgagac 111600tgtcttctgt aactgtatgt cttcctccct agtaagttaa tgagtaataa aggtattcta 111660tagtgagagg actctgtaag acatttcttg gtgtgaggat tgttccaagg ttgttttgtg 111720tgtatgtgca tgtataaact tttttaggga gcatattcat agcttttaca tggatctcag 111780aggctctata acccagagaa gattacagaa taccagtctt gtctttggta aggattttat 111840agacccatcc tgactacagt gatatccaac atggctatgt aatgactggc actttcccca 111900cataacatat atttattcca cactcagtgc ctactgtgta catgagacct ataccgggca 111960ctgggataag agacatgaaa taacagctaa aattgtttat tgagcagtca gtatgcatta 112020gatgctttgt agtcattttc ttattcaatc tgtataccct caatttacaa atgaggaaac 112080tgaggcacag aagagttgag tgatttgccc aaagtcatac aaatagtcag tggctatgtg 112140atgaatagtt accaacataa aagagtgaga ttactgctgt actaaaagta ggtacataat 112200cccctgagca gacagtatga gagaatgatt tattttacct ggaaagttta ggaaggcttc 112260acagaggagt taagggttga tctgggtctt gagggatgga taagagtttg ccagatacaa 112320aaaggtagga agagaacttc aggaggaggg aacaggctga gcaaagacac ggcgatgtga 112380aagtgggagg cttgtttggg gaacattatg gaatctggag gttattgtgg ggaatctcat 112440cagatgcagc aagctgtttg acaggccttc agttggctct ttgtaccttg ctccctccgc 112500atgctgagct gtccatagct gccctaggct ggtgtctggg attttcggaa gaaggttact 112560atccaggtag tgtaacaaga tgcagtgcaa aagcaccaga ttggggctct ggctctgctg 112620ctgacttacc acctggcctt aagcatgtct agttccctct ttgtacatta aaatctccat 112680tggaacagta acatggttgt attaaatgat cttgaagatt ttacctgcac gttttgcaca 112740tgtaccctaa aacttaaagt ataataaaaa aattaaaata aaaaataaaa atataacaat 112800ataaatcttt aacaataatt ttagtagtaa atctctacaa ttttacagat aatccagatg 112860catccattgg ccaatggttc actttgtatg cataatattt gggaaacagg cagacccaat 112920ttcaatcctt agttgtaaga cttaatacat atgtgatctc gagcaaatca cttttgtatg 112980cctctataag gataataata gctcacagaa ttattttaag aactaaatga tgtgtaataa 113040agctactggt actcagtaag ttttgtatcc ttttcctaga gtgagtcttg gtcataggca 113100tgcgtatact tgcagcgtcc ctgggtaggc cgaaagagca aataagagat ggtatctatg 113160gtattcccca ggtaaaggag gccttgggtt ggcataagat ttcacttctc tttagagtta 113220cttaattagg gaccagaaag gccatcagca tttgtatgag aatataacaa aggtcaatct 113280cttcctcttt actttttacc tcccagtaca ctgtgagtaa cattccccag ccagcccagc 113340cagcacgtgt tcattgcctc tcttgacttc cagactttgg acttgaaggt gtcagagctc 113400tctgtgtatc tttgtcccca acaagataag tctgacctcc ccagcaaatt caagtcctaa 113460gccactgtcc aggagaaaag ctagcaaggt cataaattat tctccatatt ttccagccat 113520tggtttccct tgtccagcca gaggtgtgtc tcaaagtatg ctgaggccag attcaataga 113580aacctgagcc agcacctgtg taaataattt ttaaagctcc ttttcctgaa gctggatgaa 113640tatttttaaa aactaagctg gattgtcttt tatctagcat gccgtctcct acattcctag 113700tgctatggac ctcttggagg aatgtggttt ggttatagtg gtattgtctt gtctgttgtg 113760ggggagggag acatttcttt cagaagcaag gtaatacttt ggtctggtct atgactctat 113820tttgtttaaa atgaaactat ggcagtatag tggtattcat tctgcttccc ataggttaac 113880tttacatccc tctgtcttca cccactcttc agttctgatt cttttaaaag cagccaacca 113940aaaccagcaa gtacatactg cttatctctg acttccacca gaatcaactt cagatcttgt 114000ccaaagctcc atctgaagag aggggaataa cacccagcca agagccctca gggcccatca 114060gtaagtagac atcctgtcct tgaggttcct taactctgct cagcttcaga atacagaagg 114120ggttggttct tcatttgtgt tgtttataac taaaagcctc ctactcccca cttttttgca 114180tagcttcttc tgccatccca cctgtgtagc ctcttcaact cccccaaaac tcctctgtag 114240cccatgtcac ttggaaagag ttttctttgt ctcttttgca acttgacaat gactagccag 114300caagtttaag ttcaaattat tgttccatgg gagcagagat agatatagga aacaaaaaaa 114360agggatatgg aggtatagag tgatttccca cctacctagt gagcactact gagatattca 114420agtactctct acccaagaat tctattgata taaaggtaaa aaacttgatc ttaggtctaa 114480tatccgttag tagtgtgacc ttgggaaaat gataccaccc ccaaaggctt agttttctta 114540actgtaaaat aggcatacag atgaccaccc ccagaggatt cataaggata acatgagata 114600aggcaacttg aaatttccta gcatagtgat agactttcga aaataaaatg aatcaaacac 114660tgataacagt acttcctagt acacaaatga gaaatcagtc cctcatcaaa ttacagcaca 114720ttttcaatgc tccaattatg tcactgtaga aatgctaatg tggattaaat aatttgtctg 114780ttgctattta tacggataat ttgatagtag ttatttttgg acatggatag ctttgaagcc 114840ttacagatga gtccatcccc aagtacccaa aactaaagaa agttggctag agtgatgaca 114900aggtggcagc acagagctcc ctgcgttctg ggccctgtcc cctagctaga gagaactcca 114960ggctataagc atttgtattc tcatagtcca atggcaggga agaagggctg gaggtgagta 115020gttttcactc atttattttt tcaacaagca tgtatggtat caggccttgt atgcatccag 115080agacaaatgt gaactagccg tgtcctcaag gagattccag tctggtgggc ctgccttcca 115140aggtcagttg cagctttagc actataaaga gcacctacct gcggcagata caatgtgatg 115200ggacatgaca gagaaaaaat ctataagcag agcctcccca ttcccaggca ttgaaacaat 115260cctaaccaag actggcatag tacaatgagc ctgtccctat cagcaggttt ggaagcctta 115320acaacaacaa caaaaacaat aataatggtg atgataatca tagagcctaa tgttaccaaa 115380cattttccat gtgttaagta ctatactaag tgcatactta atcctcacaa caatgctata 115440agatagtaga tactcttact actaccctga ttttacaaat gtggaaactg aggcacagaa 115500gactaagaga acaggaatac acctaattca cctcagttca acaaacatca agcatctgtt 115560ttatgtcagg cctcgtgctg gatggcaggg agagagagat gagtaaagca tagtttcagt 115620ccagtgggag caaatgacag cacacagtgg ggcaggtata ttgcagccct tctgcttgat 115680gctaagaact cagtgtcagt gatgaatgaa acacagtcat tctctcaaag atcttaaagc 115740ttagtaggag atatctgtgt ggaaacaaaa attaaatact gctgtgataa gtgtcataag 115800agataagtgg aaaatgagag agagagatca ctgtagcaat tgattggttt aaatcaaagc 115860ccccaaaaaa atgttattga gaattataaa acaactaatt gatttaaatc aaagcccaaa 115920cagaagtgtt tgctaatttt atttcaattt ggttgataat ttggttgaaa tgaatttatt 115980tcatttttta ttccatcctt acaatggaag attagtgctt gtttcccacc caaggatacc 116040aggatatttc aggggctgta ttacaatata gttaaattat tcctttatct caaagcacat 116100ccacactttc ccctatcctt acctttactc agggtatctc ttctgcctca ggtgcttttt 116160ctccacattt ccatattctt aagtcctacc ttccttcagg gcctcactca aatgcctcct 116220cctccatgaa gcattcaccc gactgaaagg taccccgccc tctcctgtac tccacatcac 116280ttcatgggtg tctccacttc ctgctttatc tttcagtaat acacttacag ttctctttcc 116340tccactagac tgagctcttc agaggaagac tcacttggct gaaaccatga ttttacttta 116400aacacattga aaacctctac tggagtgcat tgtgtctggt gggcttcaac cttaattctt 116460aagtatgtga aaacacatca cctatctgga ggtttacact ttctgctaat gactttattt 116520ttaagcccac caccctaaca caacaaatac ttaaaacttg tcttcatttc ctttaggtct 116580ggccctcatg catgcatata atttatagag tcactgtttt gctcggttgt cctcatgcct 116640ctatattatt ggaggtttag attgtttcca tatactcagg ttgtattcat gtcctttttt 116700tctttttaaa tttccttagc atccatttcc accattggaa attcagggtc aaaacagggg 116760tttgggattg gagcatgtct atcacagata accaatcatg tgttatgact taagaattta 116820tgaaagggcc ctctacctga agatatcttg ctactgatgc tgtctcacag tgtctgaaac 116880tcccatcata tgtggaattg ttttggaagg ctttgcctcc tgggacacat tcagccataa 116940tcaagaaata gtattgagca ttagactgtc agtatgtcca ttagcaagac tgtggaggaa 117000tggaatcacc aatattatat tttatagggg atacagaata caagagaagt tctgaagaga 117060aaattcttat gtagaatagg aaggcttaga tacagcatga aagctgcagg ctttgaggag 117120ccagaggtca aatgaaagca ttgagtattt gtttagatga aagaacagaa agggaaaaag 117180aagcagagga agggatagta gagagaaatg tataagtttt atccatttaa cttgtaattg 117240tgtttggcta tgggcacaat agaagcagtg agatcacttt attttatttt attctttata 117300gacagggtct tgctatgttg cccaggctgc agtgtgcagc tcttcacaag tgtgatcata 117360gcgtactaca ccctcaaact cctggactca agcaatcctc ccatctcagc ctcctgagta 117420gctgggacta caagtgcaca ccaccacgcc cagtgagatc acttgaaact agggagagat 117480gtgtgagttc tgggcaacca gtagttggct ttacatagaa ctgtaggggt caaggccaaa 117540ggggacgtcc tgttccaagt caccttcttt ggacattaga aaaccacgag gggtttggaa 117600atcagaaaac cagcagaggc aggaaaactc agggcagcat gggagattca gtatatacaa 117660aaaggttcac accagtaatc aaacagaatt ttaactgctg atgtggagta gaggcagctt 117720tgtctgctgt gtgataacca aacctttacg aatagtaggt gtatatgggg aattggaggg 117780agataggtgg ctgtgtttag taattggttg acttcactga gatggtttgg ggattgtggc 117840ttccagatga tcagattttc ttttttaggt agagactcca acatcattac agaactataa 117900attacatgtg gaaaagaaag gcctcctatg ttagaataga aaataaaatg ctgtggggtt 117960gagggacaga ggtgctgtct aggaagtcag atagcgtttt ccagttctgt ccctcagagt 118020tccttgtcct cattgagact caatttctct tacttttttt tttatacttt aagttttagg 118080gtacatgtgc acaacatgca ggtttgttac atatgtatac atgtgccatg ttggtgtgct 118140gcacccatta actcatcatt taacattagg tatatctcct aatgctatcc ttcccctctc 118200ccctctcccc accacaggcc ctagtgtgtg atgttcccct tcctgtgtcc atgtgttctc 118260attgttcaat tctcacctgt gagtgagaac atgcggtgtt tggttttttg tccttgtgat 118320agtttgctga gaatgatggt ttccagcttc atccatgtcc ctacaaagga catgaactct 118380tcatttttta tggctgcgta gtattccatg gtatatatgt gccacatttt cttaatccag 118440tttatcattg atggacattt gggttggttc caaggctttg ctattgtgaa tagtgccatg 118500ataaacatac gtgtgcatgt gtctttatag cagcatgatt tataatcctt agggtatata 118560cccagtaatg ggatggctgg gtcaaatggt atttctagtt ctagatccct gaggaatcgc 118620cacactgact tccacaatgg ttcaactagt ttacagtccc accaacagtg taaaagggtt 118680cctatttctc cacgtcctct ccagcacctg ttgtttcctg actttttaat gatcaccatt 118740ctaattggtg tgagatggta tctcgtggtt ttgatttgca tttctctgat ggccagtgat 118800gatgagcatt ttttcatgtg tctgttggct gtgtaaatgt cttctttgag acgtgtctgt 118860tcatatcctt tgcccacttt ttgatagggt tgtttgtttt tttcttgtaa atttgtttga 118920gttctttgta gattctggat attacccttt gtcagatgag tagattgcaa aagttttctc 118980ccattctgta ggttgcctgt tcactctgat ggtagtttct tttgctatgc agaagttctt 119040tagttgaatt agatcccatt tgtcaatttt ggcttttgtt gccattgctt ttggtgtttt 119100agacatgaag tccttgccca tgcctatgtc ctgaatggta ttgcgtaggt tttcttctag 119160ggtttttatg gttttaggtc taacatgtaa gtctttaatc catcttgaat taattttagt 119220ataaggtgta aggaagggat ccagtttcag ctgtctacat atggctagcc agttttccca 119280acaccattta ttaaataggg aatcctttcc ccatttcttg tttttgtcag gtttgtcaaa 119340gatcagatgg ttgtatatat gcggcattat ttctcagggc tctgttctgt tccattggtc 119400tatatctctg ttttggtacc agtaccatgc tgttttggct actgtagcct tgtagtatag 119460tttgaagtca gatagcgtga tgcctccagc tctgttcttt tggcttaggg ttgacttggc 119520gattcaggct cttttttggt tccatatgaa ctttaaagta gttttttcca tttctgtgaa 119580gaaagtcatg ggtagcttga tgaggatggc attgaatcta taaattacct tgggcagtat 119640ggccattttc acaatattga ttcttcctac ccatgagcat ggaatgttct tccatttgtt 119700tgtatcttct tttatttcat tgagcagtgg tttgtagttc tccttgaaga ggtccttcaa 119760gtcccttgta agttggattc ctaggtattt tattctctta gaagcaattg caaatgggag 119820ttcactcatg atttggctct ctgttttctg ttattggtgc ataagaatgc ttgtgatttt 119880tgcacattga ttttgtatcc tgagactttg ctgaagttgc ttatcagctt aaggagattt 119940tgggttgaga cgatggggtt ttctaggtat acaatcatgt catctgcaaa cagagacaat 120000ttgacttcct cttttcctaa ttgaatgccc tttatttcct tctcctgcct gattgccctg 120060gccagaactt ccaacagtat gttgaatagg agtggtgaga gagggcatcc ctgtcttgtg 120120ccagttttca aagggaatgc ttccagtttt tgcccattca gtatgatatt ggctgtgggt 120180ttgtcataga tagctcttat tattttgaga tacgtcccat caataactaa tttattgaga 120240gtttttagca tgaagcgctg ttgaattttg ttaaaggcct tttctgcatc tattgagata 120300atcatgtggt ttttgtcgtt ggttctgttt atatgctgga ttatgtttat tgatttgcgt 120360atattgaacc agccttgcat cccagggatg aagcccactt gatcatagtg gatacgcttt 120420ttgctggtat tttattgagg atttttgcat caatgtttat

cagggatatc ggtctaaaat 120480tctctttttt gttgtgtctc tgcctggctt tggtatcagg atgatgttgg cctcctaaaa 120540tgagttaggg aggattccct ctttttctat ttattggaat agtttcagaa ggaagggtac 120600cagctcctcc ttgtacctct ggtaggattc agctgtgaat ccatctggtt ctggactttt 120660tttgattggt aagctattag ttatatcctc aatttcagag cctgttattg gtctattcag 120720agattcaact tcttcctggt ttagtcttgg gatggtgtat gtgtcgagga atttatccat 120780ttcttctaga ttttctagtt tatttgcata caggtgttta tagtatgctc tgatggtagt 120840ttgtacttct gtgggatcgg tgattatatc ccctttatca ttttttattg cgtctatttg 120900attcttctcc cttttcttct ttattagtct tgctagtggt ctatcaattt tgttgatctt 120960ttcaaaaaac cagttcctgg attcattgat tttttgaagg gttttttaca tctctatttc 121020cttcagttct gctctgatct tagttatttc ttgccttctg ctagcttttg aatgtgtttg 121080cccttgcttc tctagttctt ttaattgtga tgttagggtt tcaattttgg atctttcctg 121140ctttctcttg tgggcattta gtgctataaa tttccctctc cacactgctt tgaatgtgtc 121200ccagagattc tggtatgttg tgtctttgtt ctcattggtt tcaaagaaca tctttatttc 121260tgccttcatt tcattatgta cctagtagtc attaaggagt aggttgttca gtttccatgt 121320agttgagcgg ttttgagtga gtttcttaat cctgagttct agtttgattg cactgtagtc 121380tgagagacag tttgttataa tttctgttct tttacatttg ctgaggagtg ctttacttcc 121440aactatgtgg tcaattttgg aataggtgtg gtgtggtgct gaaaagaatg tatattctgt 121500tgatttgggg tggagagttc tgtagatgtc tgttaggtct gcttgacagt ggagtgttaa 121560agtctcccat tattattgtg tgggagtcta agtctctttg taggtctcta aggacttgct 121620ttatgaatct gggtgctcct gtattggttg catatatatt taggatagtt agctcttctt 121680gttgaattga tccctttacc attatgtaat ggccttcttt gtctcttttg atctttgttg 121740gtttaaagtc tgttttatct gagactagga ttgcaatccc tgcctttttg tgttttccgt 121800ttgcttgata aatcttcttc catcccttta ttttgagcct atgtgtgtct ctgcatgtta 121860gacgggtttc ctgaatacag cacactgatg ggtcttgtct ctttatccaa tttgccagtc 121920tgtgtctttt aattggagca tttagcccat ttacatttaa ggttaatatt gttatgtgtg 121980aatttgatcc tgtcattatg atgttagctg gttattttgc tcgttagttg atgcagtttc 122040ttcctagcct cgacggtctt tacaatttgg tatgtttttg cagtggctgg taccggttgt 122100tcctttccat gtttagtgct tccttcagga gctcctgcag tgcaggcctg gtggtgacaa 122160aatttctcag catttgcttg tctgtaaagg attttatttc tccttcacct atgaaggtta 122220gtttggctgg atatgaaatt ctggttttaa aattcttttc tttaagaatg ttgaatattg 122280gcccccactc tcttctggct tgtagagttt ctgctgagag atcagctctt aatctgatgg 122340gcttcccttt gtggggaacc tgacctgttt ctctggctgc ctttaacatt ttttccttca 122400tttcaacttt ggtgaatctg acaattatgt gtcttggagt tgctcttctc aaggagtatc 122460tttgtggtgt tctctgtatt tcctgaattt gaatattggc ctgccttgct agattgggga 122520agttgtcctg gataatatcc tacagagtgt tttccaactt ggttccattc tccccatcac 122580tttcaggtac accaatcaga catagatttg gtcttttcac atagtcccat atttcttgga 122640ggctttgttc atttcttttt attctttttc ctctgaactt ctcgcttcat ttcattcatt 122700tgatcttcaa tcactgatac cctttcttcc agttgatcta atcggctact gaggcttgtg 122760catttgtcac gtagttctcg tgctgtgttt ttcagctcca tcaggtcctt taaggacttc 122820tctgcattgg ttattctagt tagccatttg tctaattttt tttcaaggtt tttaacttct 122880ttgccatgcg ttcgaacttc ctcctttagc tcagagtagt ttgattgtct gaagccttct 122940tctctcaact cgtcaaagtc attctccatc cagctttgtt ccattgctgg tgaggagctg 123000cattcctttg gaggaagaaa ggcactctga tttttagagt ttccggtttt tctgctctgt 123060tttttcccca tctttgtggt tttatctccc tttggtcttt gaagatggtg atgtacagat 123120gagcgtttgg tgtggatgtc ctttctgttt gttagttttc cttctgtcag gaccctcagc 123180tgcaggtctg ttggagtttg ctgcaggtcc actccagacc ctgtttgcct ggttatcagc 123240agcagaggct gcagaacagt ggatattggt gaacagaaaa tgttgctggt tgatcattcc 123300tctggaagtt ttgtctcaga ggaatacccg gatgtgtgag gtgtcagtct gcccctactt 123360gggggtgcct cccagttagg ctactcgggg ttcagggaac cacttgagga ggcagtctgt 123420ccgttctcag atctccagct gcatactggg agaaccacta ctctcttcaa agctgtcaga 123480cagggacatt taagtctgca gaggtttctg ctgccttttg ttcggctatg ccctgccccc 123540agaggtggag tctacagagg caggcaggcc tccttgagct gtggtgggct ccacccagtt 123600cgagcttccc agctgctttg tttacctact caagcttcag caatggcggg cacccctccc 123660ccagcctcgc tgctgccttg cagtttggtc tcagactgct atactagcaa tgagcgaggc 123720tctgtgggcg taggaccctc tgagccaggc acaggatata atctcctggt gtgccgtttg 123780tgaagaccat tgaaaaagtg cagtattatg gtgggagtga cccgattttc caggtgccat 123840ctgtcacccc tttctttgac taggaaaggg aattctctga tcccttgtgc ttcctgggtg 123900aggcgatgtc tcgccctgct ttggctcatg ctcggtgcgc tgcacccact gtcctgcacc 123960caccatttga cactcccctg tgagatgaac ccggtacctc agttggaaat gcagaaatca 124020cccatcttct gtgttgctca cgctgggagc tgtagactgg agctgttcct attcggccat 124080cttcacaaaa atcttacttt ggtttctagt gttaccaccc actgttcttt ctcatctcaa 124140ccctgagtat aagtacagat cacattcctt gggttcttag aaaataatag aaatgaactc 124200tcattcatca aaatgcccat tagtaaatac tgagggagaa caaactagaa atccagtata 124260gaaaataaaa ataggattat attccttgga atctcagaaa aaaacaatga agagctttct 124320ttgggcatta gacactttcc cataaggtgg ctgactctct tttagtcatg tcagcttggc 124380ccaatcttca cttggtagcc cttctttctt cttcattaat ccatctccta tgctcctatg 124440gggtcctaga gaaatgccca tcatgtacac acacatctaa taacacaaag atcactctcg 124500actagcaagc ccttttatga tggtgtgagc atttgacacc cttgttgcta gtaacatcag 124560tgagtgacct gacccatttt tggaacagaa tatgatcagt atgttgcctc aaggaggccc 124620tcactgttct aggaaatata attccagagt ttgctgactc acaccatgga atatatgcat 124680aaaatggatc ctgcagataa gcctttctct gactagtttc agacattttt ttctgggtaa 124740ttttaaagtt attttttatt tttgtgggta caaagtaggt gtatatatgt atgaggtacc 124800tgaggcattt tgatacaagc atacagtgta taataatcac cagagttaat ggggtatccc 124860tcaccacaag catttatcct ttctttgtga tacaaacaat ccaattatat tcttttagtt 124920attttaagat gtataataaa ttattgttga ctgcagtcac cctgttgagc tatcaaatac 124980tagatcttat tcattctaac tatacttttg tacccagtag ccatcccact tcctcccctc 125040ccactaccct tcccagcctc tgataaccat cattccactc tctatctcta tgagctcaat 125100tgttttaagt tttagctccc acaaatatgt gagaaaatgc caagtttgtc tttctgtgcc 125160tggcttattt cacataatat aatgtcctct agttccatcc atgttattgc aaatgacagg 125220atctctttct tttttatggc ttaatagtac tttattgtat gtatgtacca cattttcttc 125280atccatttgt ctgttgatag acaagagttg cttccaaata ttgactattg tgaatagtgc 125340tgcaataaac gtgggaatgc agatctcttt gatatactga ttttctttct ttagggtgta 125400tacccagcag tgggattgct gggtcatatg atagctctat ttttagtatt ttgtggaacc 125460tcaaatctat tctacataat ggttttactg acttacatat ccaccaacag tgtatgagga 125520tactcttttc tccacatcct caccagcatt cattactgcc tgttctttgg atgaaagcca 125580ttttaactgt ggtgaaatga gatctcattg ttgttttgat gtgcacttct ctgatgatca 125640gtgaggttga ggaccttgtc atatatctgt ttgtcatttg tatgttttat tttgagagat 125700gtctacccag atcttttgcc cattttttaa tcagattgtt agattttttt tttcctacag 125760agtgcttgag ctctttatat gccctagtta ctagtccctg gtcagatggg tagtttgcaa 125820atagttgctc tcattctgtg ggttgtctct tcactttgtt gatcgaatca cttgctgtgc 125880agaaggtttt taacttgatg tgacctcatt tgtccatttt tagttgcctg tgctggtgcg 125940gtattactca agaaattttt gcccagatta atgttctgga gagtttcccc aatgttttct 126000tgaagtagtt tcatggattg atgtcttaga tttaagtctt taatatgttt tgattttatt 126060tttgtatttg ctgagagata gggctctagt ttccttctgc atatggatat ccagtttttc 126120tagcaccttt tgttaaagag actattcatt ctctaatata cgttcttggc acctttgttg 126180aaaataagtt cactgtagat gtatggactt gtttctgggt tctctgttct gttccattgg 126240tctatgtgtc tgcttttatg tgaataccat gttgttttgg ttgcaaaagc tctgtagtat 126300aatttgaaat caggtaatgt gattcttcca gttttgctct gttctttttc ctcaagatag 126360ctttgcctat cctgggtctc ttgtggttct atataaattt taggattatt ttttctattt 126420atgtcaagaa tgtcattgat attttgatat aaattgcgtt gaatctgtag atagcttcag 126480gtagtgtgga cattttaaca atatcaattc ttgaaatcca cgaacatgga atatccttct 126540attatttgga tgtcttcttc aatttcttat attaattttt ttttagtttt cattgtagag 126600atatttcatt tatttgacta agtttattgc taggtatttt attttatttt tacctattga 126660caatgggatt gctttcttga tttctttttt agattgttca ctgttggcat acagaaatgc 126720tactgatttt tatgtgatga ttttgtatcc cgcaacttta ctgaatttgt ttatcagttc 126780taataggctt ttggtgcaga ctttaggctt ttccaaatat aagatcatat tatctgcaaa 126840caagaataat ttgacttctt tcttttcaat ttggatgcct ttcatttctt tctcttgtct 126900gattgctcta actaggactt ccagtactct gttgaataac agtggggaaa gttaacatcc 126960ttgttttgtt tcagatctta tagccaaggc cttcagtttt tctgaattta gtatgatact 127020agctatgggt ctgtcatata tggcttttat tatgttgaag tatgttccct agttttttga 127080aggtttttat attttaagga agataaaaat tgaactttat caaatgcttt tcatgcaaca 127140attgaaatga tcaagtgctt tttgtctttc attctgttga tacgatgtat cacactgatt 127200gacttgtgta tttagaacca tccttgcatc ccgtggtaaa tcccacttag tcatggtgaa 127260tgaacttttt aatgtgttgt tgaattcagt ttgctagtat tttgttgggg atttttgcat 127320cagtgtttat cagggatatt ggcctatagt tttccttttt tttatgtgtc ttttgggttt 127380tgttatcagg gtaatactgg ccttgtagaa tgagtttgga atgattctct cctctatttt 127440ttgaaatact ttgaatagga ttgatgttac ttctttaaat gtttggtaaa attctgcact 127500gaagccattg ggtcctgggc tttttactgc tggggagact tttcattaca gcttcaatct 127560tattacttgt tattggtctg ttcaggcttt agattttttt catgaatcaa tcttcacaag 127620ttgtctgttt ctcaaaattt atcaatttct tctaggtttt ccaatgtatt gtcatccagt 127680tgctcataat gccctctaat gatgccttga atttttgcag taaccactgt aatgtttcct 127740tttttaatct ctgattttat ttgagctttc tctttttttc ttagtctagc taaatatttg 127800tcaatgttgt ttgttcatcc acaaaaccaa cttttcattt cactgatctt ttgtattatt 127860ttttcctttt aattttattt atttctattc tgatatttat catttcattt cttccagtta 127920tttgagtttg gtttgctctt gcttttccag ttctttaaga tgcattgtta ggttatttat 127980ttgaactttt ttgatatagg tgcatattgc tataaacttt caccataata ttgcttttgc 128040tgtatcccat aggttttagt atgttgttta gtatgtttcc aatttggtac atttcaataa 128100atttttaaat tttcttcttt atttattgac atagtcattc cagagtatac tgtttaattt 128160ccatgtggtt tgtatagttt ccaaaattcc tcttgttatt gatttctagt tttattccat 128220tgtggtcaga gaagaagctt gatatgaatg caattgttaa taattttttt aaaacttgtt 128280ttgtgaccta agatatgatc tgtcattgag aatgatccat atgctgagga aagaatgtat 128340attctgcagc cattggataa aattgtcttt aaatatctat taggtccatt taagacataa 128400tgcagattaa agccgatgtt tcattgttca tttttctgtc tggatgatct cttcagtgct 128460gaaagtggtg tgttaaaatc tctaaatatt attgttttgg gatctttctc ttctttcaac 128520tctgataata tttgctttag atacctgggt gctccagtgt tgggtgcata tatacttaaa 128580attgttgtat cctcctgatg aattgacccc tttatcatta tataatgacc ttctttttct 128640ctttgtgtag tgtttgtctt gaaatctatt ttgtcggata ttagtattgc tgctaatttt 128700tttggtttcc atttgcatga aatatctttt tcattccttt attttcaggc agcgtgtttc 128760tttatattta ataggtgaaa tatgtttctt gtaaataaaa attattattt taaaatattt 128820ttaaaataat actatttttt aataagaaca attattattt tttaaaaaat ttcattagtt 128880ttgggggcac aagtggattt tggttaaatg ggtgagttct ttagtagtgg attttgagat 128940tttagtgcag cagccacctg agaagtgtac attacccata tattatatat atactatata 129000tgctttatat atatagtgtg tatatataat atatatacaa ctacatattg ggtaatgtac 129060acttctcagg tgactgctgc actaaaatct caaaatccac tactaaagaa ctcacccatt 129120taaccaaaat ccacttgtgc ccccaaaact aatgaaattt tttaaaaaat aataattgtt 129180cttattaaaa aatagtatta ttttaaaaat attttaaaat aataattttt atttacaaga 129240aacataattc acctattaaa tataaagaaa cacgctgcct gaaagtaaag gaatgaaaaa 129300gatatttcat gcaaatggaa accaaaaaaa ttagcagcta tactaatata ttatatatat 129360actacataaa gcatatatat agtatagtat atatataata catttataaa gcatatatat 129420agtatgtaga taatatatgt ttatatactt taagttctgg gatacatgtg cagaacgtgc 129480aggtttctta cataggtata ctcgtgccat ggtggtttgc tgcacccatc aacctgccat 129540atacattaag tatttctcct aatgctatct ttcccctagc cctaccccac tccctgacag 129600gccctggtgt atgatgttcc cctccctgtg tccatgtgtt ctcattgttc aactgccact 129660tatgagtgag aacatgtggt gtttggtttt ctgttcttgt gttttagttt gctgaggatg 129720atggtttcca gcttcatcca tgtccctgca aaggacatga actcatcctt tttgatggct 129780gcatagtatt ccatggtgta tatgtgccac gttttcttta tccagtatat cattgatggg 129840cattttggtt ggttccaagt ctttgctatt gtgaatagtg ctgcaataaa catacgtgtg 129900catttgtctt tatagaagaa tgatttataa tcttttgggt atatacccag taatgggatt 129960gctgagtcaa atgatatttc tggttctaga tccttaatga attgccacac tgtcttccac 130020aatggttgaa ctaatttatg ctcccaccaa cagtgtaaaa gcgttcctat ttcttcaaat 130080cctcaccagc atctgttgtt tcctgacttt ttaatcgcca ttctaactgg catgagatgg 130140tatctcattg tggttttgat ttgcatttct ctaatgacca gtgatgatga gctttttttc 130200atgtttgttg gcagcataaa tgtcttcttt tgagaagtgt ctgttcatat tcttcaccca 130260ctttttgatg gagttatttg ttttcttctt gtaaatttgt ttaagttcct tgtcgattct 130320ggatattagc tctttgtcag atgaatagat tgcaaaaatt ttctcccatt ctgtaagttg 130380cctgttccct ctgctgatag tttcttctgc tgtgcagaag ctctttagtt taattagatc 130440ccatttgtca attttggctt ttgttgccat tgcttctggt gttttagtca tgaagtctct 130500acccatgcct atgtcctgga tggtattgcc ttggttttct tctacagttt ttatggtttt 130560aggtcttgca tttaagtctt taatccatct tgagttaatt ttgtataacg tgtaaggaag 130620aggtccactt tcagttttct gcatgaggct aacgagtttt cccaacacca tttattaaat 130680agggaatcct ttccccattg tttgtttttg tcaagtttgt caaagatcag gtggttgtag 130740atgtgtggtg ttatttctga ggcctctgct ctgttccacg tgtctatatc tctgttttgg 130800taccagtacc atgctgtttt gggtactgta ccacttgatt ggtgagagag ggaatccttg 130860tcttgcactg gttttcaaag ggaatgcttc agcttttgcc tattcagtat gaccaatatg 130920tagtctttta ttcctcaccc tctctcaaca ccccaccccc acggagtcct caaagtccat 130980tatatcactc tgtatgtttt tgcgttctca tagcttagct cccacttata aatgagaaaa 131040tacagtattt ggttttccat tctttggtta cttaattagt ataatggcct ccagctccat 131100ccaggtgtct tgtttttcat ccattcagcc agtctataac ttttgcttgg agagtttcgt 131160ccatttagat tcagcgttat gattgataac taagggctta ctcctgccat ttggttgttt 131220tctggttatt ctgtggtctt ctcttccttt tttccttctt tcctgtctcc cttttagtga 131280aagtggtttt ctctggtggt gtattttatt ttcttccttt ttattttttt ttgtgtgtat 131340ttgttgcatg ttattgattt gaggttacca tgaggcttgt acataatatt ttctaactca 131400ttatttcaaa ctgatgacaa cactctatcg cataaaaaaa catggaaaga gaaaactaat 131460aaaaactcta cattttaact tcatctctct gcttgttgtc actttgtcgt ttctatttac 131520atcttattgt actgtttatg tcttgaaaag tagtttcagt tattactttt gattggttca 131580tctcatagtc tttctactca agatatgagt agttcacaca ccacaattac agtgttacaa 131640tattctgtgt ttttctgtgt actttcaatt acccatgagt tttgtatttt cagataattt 131700gttattgctc actaacatcc tattctttca gattaaagag ctccctttag catttcttgt 131760aggaaaagtc tggtgttaat gaattccttc agctcttgtt gatctgtgaa agtctttatt 131820tttccttcat gtttcaagga tattttcact ggatagtcta ttctagggta aaagtttttt 131880tttttttttt cttcagccct tcaggtaagt catgccactc tctcctggcc tataaggcta 131940ccactgaaaa gtctgctgcc agacatatat gagttccatt ctatgttact tgtttatttt 132000ctcttgttac ttttaggatc ctttctttat ctttgacctt tgggagtttg attattaaat 132060gccttgaggt ggtctttttt ggattaaatc ttcttcgtgt tcttgtactt ggatattaat 132120atctttctct aggtttggga agttctctgt tattatccct ttgaataaac tttctaccaa 132180gatctctctt tctctctctg tctctctctc tctctctctc tccttcttaa ggccaataac 132240ttttagattt gcccttttga ggctgttttc tagatctcgt aggtgtgctt cattgtttgc 132300tatttttttt ttttttttgt ctcttctgac tacattttca aatagcctgt tttaaaactc 132360actaattctt tcttttgcct ggtcaattat gctgttaaga gactctgagg cattcttcag 132420tgtgtcagtt gcatttttca gcaccagaat gtctgcttat ttttttttag attatttcca 132480tctctttgtt aaatatatct gatagaattc tgaattcttt cttagtgtta tctttaattt 132540ccttgaattt cctcaacaca actattttga attatctgtc tgaaaggtca catatctcta 132600tttttccagg attgctatct ggtgctttat ttagttcatt ttgtgaggtc atgttttcct 132660ggatggtgtt aatgctagta gatgtttttc agtgtctgag cattgaaaag ttagatgttt 132720attgtagtct tcacagtctg ggcttgttca tacctgccct ccttgggaga ctttccaagt 132780attcgaaggg atttggatgc tgtgatctta gtctttggtc actgcagcca tatctgcttt 132840atggagcatc ccatgctcag taatgctgtg gctctttcag actcatagag ttactgcctg 132900catgctcttg ggtaagagcc aggaaaattc cctggattac caagcagaga ctcttgttct 132960cttctctcac tttcccccaa acaaatagag tctctctctc tctctctctt tctctctctc 133020tctctccctc tcattctctg ccgacctgcc tgaatctggg gtagggatga cacaatcaca 133080tttgtagtca acaccattgg gactgtgcta ggtcagaccc aaagctggca cagcactgag 133140tctcgcccaa cgcccacaga gaccactccc tgggtaatgt ctgtgtttgc tcaaagccta 133200agggctatac aatcagtcag tggtgaagcc agcctgtctt atgtccttcc cttcagggtg 133260atgagttcct caagcaggtc cagggatggt gtccaggagc caaggcctcg agctgtgact 133320gagctggcac ccaatccata agacaaagat tttttccaca ctttccttcc ttgtcctcaa 133380gcaaaggagt ctctccctgt ggccaccacc acccccatgt tcatggcaag tattgtctgg 133440ctaccaccaa tcttcactca aggcccaggg gttctttagt tagcttatgg tgaatgctac 133500caaggctgag tctctccctt caaggaagtg ggctcctctc tggcccaggg caggtccgga 133560aatactatcc aagagccaag gcctggaatc agtttcccca agagtccatt tggtgctcta 133620cacccactgt ggcagaacca gtacccaagc tgcaagacaa agtcctcttt actcttcctt 133680ctcctttaca gagactctcc ctatagccac cacagctggg aatatgctgg gtcactcttg 133740aagcaagaac agctctgagt ctcactcaaa actcctggca agtactgcct ggctatcaca 133800ctgattattc agggcccaag ggctctttag tcagcaggag atgaatcctg ccagtactga 133860ttccttccct tcaaggcagc cggtttcttt ctggcccagt gtgtatctag aaatatcatt 133920tgggagctag ggcctggcat ggtgacctca ggactctgcc tggtgccctg ttctactgtg 133980gctgatgtag tatccaaatt gcaagaccaa gtcctcttta ctctcccctc tcctgtcttc 134040aagcagaagg aatgagtccg ccctggagtt gggagctgca ttgcctggga ttggaggagg 134100ggtggcacaa gcactctctt ggtcacccca gctggtgtct tactaggtcg catgttcccc 134160aagtccactg gctctgaggc tagcacacca ggatttgacc aagaattgca attcttgtgg 134220cttacactgc ctttcaagtt tatttgagat cccagagcac tttagcccac agtgacaggg 134280cttgccagaa tttagtttct gactgctgag atggacaatt tgcgtctgat tagggctggt 134340ctaagtgctc cttctgtggg cactggctga gttctgctcc atgttgcttt ctgctgtgac 134400agggcaacat tgagtttcaa tgcaagtccc acagtcactg caatcttcct ctcccaagcc 134460tgctctgaac accatgtggt tgctgctggg ggctggggga gggatgttgt aggcaattca 134520agaatgtctt tcctaccctt ttcggtgctt ctttccttgg tatgatatta aaaccagtta 134580ctgtgattgc tcacctgatt tttggttctt atgaaggtgc ttttttgtgt ggatcactgt 134640tcaatttgtg cctgcaagcg gggatggggg acaattgctg gaggcttctc tttggccatc 134700ttgctccacc tctaccctag tattagcaat ttcaaagcag ttgggatgga ggtagaagga 134760aagggcgctt ggaatcagaa aatccatgtc ttagctttga gccttagaaa attcatttga 134820cccttgtaag cctcagttgc ttcatctgta aaagagaaat aatataatgg ctgaaaagat 134880caaaggtgat aatgcttttg aaaacactat agaaaatgac aaaatatcac atgagtatta 134940ttttctagtt tctaggagtc tccttaccat tgtacaggac aaccatgtct atttttaaat 135000aaattattat ttgcctctga gcaaccctgc aaagagttgc ctgtaggaga aacagcttta 135060cttgcaaatc actccactgt tttctttgtg cacagcttat taatacataa ggcacatgtc 135120ctccagcctg cagtaacatt ggaatcatta cctctttgga gtacctacca gagcttctca 135180aagtgaattt tgtttatcac cacaaaaaat agtctgttgc agagataacc tccaaattca 135240atgacaatat ttccaatcac ttttgcatga tgcagaaata gacaaatata taattttgct 135300tatagagaca attattgtct cccaacaagt gatcagtagt cagaaaatgg ccaagaaata 135360ccatggggtg tgccttccca taacagctta tctttgtgtt ttagttgcaa ggttactaaa 135420agcctgtgca gggtttatgg caaaagtaaa acttgctcca ggagcaagcc cttgtttcat 135480tgtctaatgt tcttaatccc cagcagacag gatttggatc

tggcatttgg taacagggca 135540gtttccaaag ttgctgtacg caacttgagg aagagaggtg atattatcgg aatgaatttc 135600tttgttgtaa gttataaatg tatgggcttt tccaatccca tcacccttaa aactttattt 135660gttttctgca gtgagggtgt ctccgttgtc tttaatatgc ttgctttgag ttcatggatg 135720aacattcctg cctggctgac atgtggactc tctgaaattg ttataaggtc tttttctttg 135780tttttttctt gatgcccaag ctgccaaggg tagtactggc agtggtgggc agacaaggag 135840gtgatagcaa actttgtcct ctggcctccc ttgacccatt ccattcatta tctaagggac 135900tccaagccag cattccacag agtgccctca ccaaactcac taagactgaa ggcgaaccag 135960gattccaaac agccattatg aaaggaaaga gagagagact tagggtttgc aaaataagat 136020accctgttga ttctttttat tccatacaga tactactatt ctttaggaaa acgttaaaat 136080cacatgatct tccaggacct gggctgcttc tttaagaagc atgttacaga aagctttatt 136140ggccaacaac atattgaaag atagattaat caatcattca ttcaaataag gtatattcag 136200aattgaggta tattgtagcc agacagtgag actacaaaaa aagaatgcac cgtaccctta 136260tctcttgcac aatctaacga gggagataac cactctttca atttatagtg acctataaca 136320tttcgtacac tgctgaatat ctttacatgg taataacaca atggaaagct tgcaaaatag 136380acagaggcta ggggaagaag gattgagtgt gaatatagcc tcttataaat cgagaggaat 136440ggtctgtgtc ttctgatcat acagagataa taaatatgga aatgatttca aactaacaaa 136500gcaaatgtgc agaaaatact gagaatatag tgggcaggat acctgagttt tggttccatc 136560tctgttattg actcattgtg taatctgagt caggtctgtt ctgctctctg gatctcaccc 136620tttcctatct gtaaaatgag attgttggat tagatgatct ccatagaggt tctcacctat 136680tctgacattc aaaaggactc ctaatttttc ttatataata ataatatata tgatctgtag 136740agtgctttac actttatatg atatttttgc atctgttatc tcatgtgaga aaagcactgg 136800actgctggac tggcaatgag gacacctgga ttcttgtctc tgttttgaca ctgattcatg 136860gtgtgatctt caagcaaatt ctctgagttt cagtttctca atctgtaaaa taggggggta 136920tgaagattgg actaaatcag taggtctcta aaatgttcca caaagccctg gggtgggggg 136980ctcctacaga gtttcgctaa ggcaaaccac aacgctaagc ctgcatggaa gaggagaaaa 137040agagtggcct gacaagagaa gttcccagtt tcctatgcca accccaggca gattacattt 137100aattttatct gatttatata gagagtttct atgtaatgtt ttattcttaa aaatagttta 137160ctataaaaaa ctcaactggt ttgattttta aagattgcac atataagtga gatcatgcag 137220tcagtatttg tctttctatg cctggcttat ttcacttagc ataatgtctt ccagcatcat 137280ctatgttgct gcaaatgaca gacttttctt ttcattaaag gctatatagt attccatcgt 137340gtatgtacac cacattttct cttttgtaac tttcatttta ggttcagggg ttcatgtgca 137400tgtttgatat ataggtaaac tgcatgtcag agaggtttct tgtacagatt atttcatcac 137460ccaggtaata agcatagtat ctaatcaatt tttttctgat cctctccctt ctcccaccct 137520acaacctcaa gtaggccctg gtgtctattg ttcccctctt tgtgtccatt acaccacatt 137580ttctttatcc acttatccat ccatggacac ttagtttgct tccatatgtt ggctattgtg 137640aataatgctg aaaaaagtca aactcataga agcagagagt agaatggtgg ttaccaggga 137700ctgggaggca gttgactgag ctaggaaaag agagataata aaagggtaca atgtgtcagt 137760tatatagaag gaataagtta tattgaacta ttgcacagca tggtgaccat agttaataat 137820aatgtattat atgtctcagt attgctaaaa gagtaaattt aaatattcta accacaaaaa 137880attattagta ggcaaggtga tggatatgtt aatttgcttg atttaatctt tctagaatgc 137940atacatatat caaaacatcc cactgtaccc cataaatata tacaattatt atttgtcaat 138000ttagaaattt aaaaacttga tttagatgag ctctaaggcc ttaagtatta aagtattaag 138060tattaaagtg atatgtaacc aagtatattg tttggtaact tcatttttgt tattatttta 138120acaaaccaat atattgtgaa tatacttcca agtgaaaaga aaaaagacat tgcagtcatc 138180actaataact gcaaaacatt cctttgcaag aatatggaat aattcattta atcattcccc 138240taatgttaga cattcaaatg tttccaactt tttctattta aataatgcta caataaactt 138300ctattttgtg cttattgtat tattttctta caacacatcc ctagaagtgg aattcctaga 138360agtttataca catttccaat ttttttccaa atatatggca aaatttctct ctaaagtatt 138420tttattccta ccagaaatac ctcttcacca acacgtagta tttaatctgt accaatctgg 138480cttaagacaa tgatatttaa tttgtatttc tgtgatttct agctaaatta aataatcttc 138540atatgcttat tggtcatttg tacttctaac tgctttctcc tgtctgttgc ccatttttct 138600attgtgctgt ttatttttat atatcgaata tattgaccat tggttttaca tacttgatgc 138660taataattat tcttagttta tggtttgtct ttgagtttta taatggtgtt tatttcacat 138720aagaaattat aaatgttttc taatgaaatt tatcaagtct gtcttcactt atgttttctt 138780cattgtcaat aacttaaaat gaccttttct acctttaaaa attttgaaat tttcctctgt 138840attgtctaat agtacttaca tgatttcctc ttttaaattg acatatttaa tccatttgga 138900atttattttg attttaacta gtaatttaac tttattttct tctccaaatg attcactagt 138960tgttctgaca ttatttagtg aataattcat cctttcttca ctgaattgga atggcatatt 139020ccatatactg tgtctggttt tggcttttct gatctcttcc actgatcaac ctaagctgga 139080gccagtatca aactgttgta atcattatgc ctttagatac tttaaatgta cagcagggaa 139140tgtcttatta ctcttatttt tcacaaatat cttggcattg tctcatgttt tattccttca 139200gataaatttt gggattattt tgtcaagatt ttgtttgagt tgttttaaat ttttagattt 139260cattgggaaa gaactgaaat ccttgaaata ttgcttcttc ttagccagga atatggtaca 139320actttgcatt taattcagtt ctttccttaa ataccaccat gaagtttttt gttttgttca 139380tataggtcct gcattaacac catatatata aagtgtgaga aatactacat tcttcaggat 139440tctctgtagg ttaacaatga agatgatgac tcaacccttt ctttgtttgc ataatgtgat 139500gccactaata gtgggtaact tctctgcctt acctcctctg ttccaaacag gatttttcag 139560aatgaacaaa ttaaaagaat cataatcaga cactaacccc aagccatact gcatggcagc 139620accaatggga ctgacagaaa acaacagaaa taggaagaaa tcctacagag aaacaaactt 139680gaaagctgtc tcatggcctt tgaatcatac ttaagtttta tgatggaagg atacgactat 139740gaagaaagac acagagcaac atcagacagt caagaatttc agagccagct ggcatgcagt 139800ggacctcatg ccagcccatt ttatgactat ttaggtagtc aagggtttaa gatttttcta 139860ataagacagt tattatgcat ttcaatgagt gatttctttg cagctctaga gtgtggcctt 139920acctacttca acatgagaag atttttgtat tttgtcagtc atttcacaat gacttttagt 139980gagcccttca ttatagactg tggatacaac tttgctgttg gaaattaaca gtgtcaaaca 140040actgggtata atgtttgtaa tatctgagga gggggagctg cctaggaagt tgtattccct 140100gtgttaattt ttcagtctct taggttatag aggaccttct agaaccacct tacagcagga 140160ttacatccca tttacacagt tctctgtcac ttgaatacag agaagggatc cacaaggcca 140220tatgcttcct agacaaagag aaaagatttc tgccacactc agaacgcttt gtcttcagac 140280tataatcacc cacaccatat ttcctttgga tccactttcc agatttttgt gctggcacta 140340acaccaactt gctgtggctt ggggcatgta atttcaatac tttgtgccca ttttcataag 140400tgaagtgtca ggcatcacat tggacatttt aagattcttt acagcccaat gattctgtgt 140460ttctaattag gcccaatggg ttagagctaa aaggaaacag tgagtttcct ggaaggaaag 140520gacatataac acagtccaga ggtaaaatgg gctgtattca agaaaagata ggacaatact 140580ttgcagggat gctgcagaga ggattcaagc cttgtatgga ggaatggatg tgatacaacc 140640aaaaagtctt taaaaattct ttccaactaa tctgagattt gtaaccttat ggactgtgat 140700ttgcagcaaa ccaaggatgt gataaagact agtattgttt ctagaatgca aggatggttc 140760aacatatgca aatcaatagt attaacagaa tgaaggacaa aaactatatg atcatctcaa 140820tagatgcaga aaaataattt gacaaaattc aacatcattt tatgataaaa tctttcaaga 140880aattgggtat tagaaggaat gtttctcaac acaataaagg ccatatcaga caagcccaca 140940gctaacatta tattcaatga ccaggaatga gataaggatg ctcactctca ccacttctgt 141000ttaacatagt actggaagtc ctagccaatt tcatattaat gagcctcatt ttcttcatca 141060tagaatgaag tatataataa tccctgttat acttactttg cacagattat tattattatt 141120taattattat tttgagacag ggtctcactc tgtcacccag gctggagtgc agtaccacaa 141180tcacagctta cttcagccac gacctcccag gcataaagga tcctagcccc tcagcctcct 141240gagtagctgg gagtacaggt gcacaccacc acacctagct aatttttttt tttcattttt 141300ttatagagac ggagtctcac tatgctgccc aggctggtct caaactcctg tgctcaagca 141360atctttccac cttggccttc caaagtgctg ggattacagg agtgagccac tgcacctggc 141420cttgcagatt attattaaac tttgtaaact aatcaaatga gagtgattat tgttactgtt 141480aagaactctg atagcctcat ccatatattt ggagaaattg aataaataat aggaaagaaa 141540taatagcatc ccaatgattt taccttggct ctaccatcat ttggggaagt gataattcag 141600ataggagaag tgacttggaa gcagtcttga gagattgcct gttccatccc ctatctttgt 141660ccttaaacca aattgtacag ataaataagg tcttattttt aggacttaca gaaaaaagat 141720tcctttcata tccatctttg caatcctcaa ccacttctgt cactattatg tgtcatttca 141780aacattaaat tcctcattct gctttgaagg aacacatgtg tcatgtgtac ccatttgtat 141840gttttggtgt gttttatgct ttatgtgatc acccacatat gcacagataa ttccaaaatc 141900cagtgtgtgg gtgttgtatt ccctgtgtta attattcagt cacactcaaa cacctatgca 141960ctcacacata catgaataca cacatgtaca ttagcatgtt tatgcttatg ttgcatgtga 142020ctggcaacat cagtgccttt ctaaggcaat gttaactacc ttgagttttg ggagagcttt 142080agagaacaaa gacaagagac taaatgattc tagatgtaag agacaatgtt gcaataagtt 142140actatcctaa aaagacagaa tacagggaca agagactatt attttggata gtttcttgct 142200taccagtaat acttaagtcc tttacattaa aaaaaaaaaa ctctgtaaat atattgcaga 142260agaaatccag acatccttca agattcttag agctggaaaa gattttaatg actttccagt 142320ccaatctatc tcatgtaatc aatggggccc agagaggcaa aaggtcttgt ccaaggtcat 142380atagtgagtt agtgataagg ctgaacaagg attcagatgt tggggcttcc agcccactgc 142440tctttctctc atctgggatt tgtgtatttt tgttcattag agattttcct ctgtaacctc 142500aatatccaat gcagggcctt gcacataata gattatcagt aaatgttaaa ttaatatgtc 142560atggctttgg ttgtactggg cttttgcact tactcctgag taaattgtaa agaatatcta 142620cgttttaggt tgccttgttt tagaccaaga ggtacccaga gaaaaggtgt gaactatgct 142680aaggaaatta tccgagttcc aaattgaaaa aaaaaaaaaa tcatgctttt ccgctataac 142740ctctctcatt cacagagtga ttctctttca gaagggcaat ctagaactat tatgggagcc 142800atattccatt ggtggtgcaa ccatttcttg acaaactagg gtccaagaaa gtattttcct 142860ggggaagatg agatttctca aagaaggcac gcactttcta acctaagctt atttcagtaa 142920tcaatgtaac aagctggtct tgatgattgc agcagtacca atactgtggg agtgtaccag 142980ttctagaaca gctacaacat tggaattgaa cgcactagaa ttggatacag gacctgtttt 143040tgaggagcta acacccaaag gctgaacagc actcgtagca ccgtcctttc tgtgcacata 143100tggtagtcct cagtttgcaa cagaaataaa gctgttagca aattatgtgt tctatttatg 143160caaataaaat cttgtggtat gctagaaaga gcactggcct ggagacctta gttttctcat 143220atgttaaaaa cccctaacac aggcctggtt catagtaggc acccaataaa tagtagtttt 143280cttcctttgg gggcctccga ttcagtgtgc ttcttcaggt aagtcacttc cctggaactc 143340ctccttggaa tgagagttgt actgttgtga tttttaacag ttccttcaag ccaagcattt 143400tggaatcctt tcataaaggg agaaaggaag gaaagaagaa aggaaaatta aaggaaaaag 143460aacaaataaa acgttaaaaa ggaggaaagg aaaaaggatc ctttactaca ataaaactaa 143520tcttatgttc ttgcaagtag cactttaagt aaaagaagtt ctttgctgac ctggttacta 143580ctgaacctac tacataaaat agcctactat aatagatgca tttatgtgcc taatcttcac 143640tttttaggct tagtaaaggg agaggaaagc tgatgtatag ttaaatttat gtttttagtt 143700gttttttttt ctactctcaa atatcaatca ctctttagtt tctctttctt tttccgacca 143760caagcattct tcctctgctt aaagaagctt ccctaaaatc ccagtctatc cagtaagcca 143820aagcacagca ataaatttga ggaaaaaata ccagggactt agagacagaa aggagtgagg 143880ggatgcagaa gctgaagctg gagcacggtt gcaagcatga gaagttctgc gtgtttcaga 143940gcagccaagg atgtattttt gcctattcct gctggtgact ctgtgtgtct atgcatccat 144000ctgctatatt tacatgttta gtcagtcaat ccacgtttgc tgagagcctg ctgtgtgcca 144060ggattgtgct agcgtaaagg agcaaagtat tgagcaaaat atgtttgagc agctgtaatt 144120ctgaggatct ctaggtctga gcatgtgtat gtgtgtgcgc ttctatgtat ctgtgacaac 144180tccaggtgtt catgacagtg atctttgtta ctctgttggc ttcatcgaac ttccttttac 144240ttgctgtgat tcactacata gagtgggctt tatctctgat ttttataacc tgcaagactg 144300ggggtatgat caccagcaat ctaaaaacag ttagaaatcc catggagtta tcttttgtag 144360aaattttcct ctactaatat tatgaaaaat aagcatctta ttagctcgag tgtaattcta 144420tgcatgatta caggtatcaa taggaagaaa cattgactga gttcaaatct cttctacgcc 144480atgctaaagg ggtgacaagt tccacaatgg atcattttct catgggcatt tctgactttt 144540ggtaaaagta gagcacctta ttttaaaaac cattgagtag tcctaatagt ggagatatca 144600tcaggatctg aattgttcat ccctaaaaaa aacaccaatg gaaatcaaac aatatagtgc 144660caaattaaac tgtttgaata tttaggttct gtatgatcaa attgtttggt gccatactct 144720gtccactttt ttcatgtggt aggatataat ttcatatctt ttctgttcta gaaatacccg 144780aagaaagaga ctctggaaac tcattatcag gtctatcaac tcttgtattt gttctcccag 144840ggaaacagaa gtacctgtgc gccagcagaa atgattgcac tattgataaa ttccgaagga 144900aaaattgtcc atcttgtcgt cttcggaaat gttatgaagc agggatgact ctgggaggta 144960agatactttt ctttctcttc ctcctccttc ctctctcccc cttctccctc attttctagt 145020ctctctttag accagatttt cttctttgat gcttccaagg ggaccagcca tgctctagac 145080acaggctgac cctttcatag gcaacgtggc catcagccag ctggtgcctt ttttttaatc 145140cttatctata ccaatcccca ttccggggct cagcattaga gcaggcggtg tgaagcaggg 145200atcaggagcc aacagaaggt gagtgaggat gcatctgact gggcagggcc cccaggggac 145260ttaatgatac tggcctgatg ttgttcagtg gtagctagga tgagagaact aagaaatcca 145320gaacagtcag aggtgcagga tgacccaggc ataggcgcag gatgacccag gcacaggctg 145380atcctgaaca cctgggaata tcccttagct aactgctgcc tatgttgtag ggccagccac 145440ctcgaatgag aagctacttc tctttggagc ctgtgactag gctgccacac agagccaatt 145500tcctatccta tctctcccaa agatgagcag gtgttttaat aatttccttt tctttgcaaa 145560gctattgacc atttccaaaa gcattttttt tcagtagcac agtaacgtga tagatggaag 145620atacagctct ttcaagggcg ttcctctatc ataaggctct ctgtcccaca aacctgtcta 145680ccatgagtgt tgtcaccatt ccagaaaggc ttgacatcag ttgattgaga cttatatttt 145740ccctctccaa actcccccat ctcttcatgt ttacatctgc ccaatgccag ggtcctcgct 145800gctgcctgct acttccaaaa agatgtgtct ttcatgagaa aaacaagatc attaatccac 145860ttcgatttgg aaatggaatt tgaagaaagg caagcctatt tctgagtgcc tgcaactgta 145920gcctcatacc caattattca ttattagcct ggaaaaccca agtgcctaga atccaaccct 145980ctcccctctc ctcttaagtc taatttagac cagttgtcta tctctggctt tctgtgaggt 146040gttcaatacc ttgtctgcct atgtgcacat ttatagacaa caactagttc tcttatcctg 146100gagcagggcc atgtgtggat cttcatatag ataactatat cctccccatc ctcacagggc 146160agtagtatta tttaaacaga acaaagtacc tcacatgaat tgacccaggc tggatgagag 146220acaatttcaa aagaatcatc tcaagtagcg tccagtactc ccaaacatca caggtagatg 146280ttctgtgagt ggctttccaa gcatccacat caaatgagac tcagatatct gagaaaactc 146340aaccttgttt tggtttgctt ggtgcacccc aaagaaatcc aacaattgag gtctacagtg 146400gagaagaagt aggactgggg tcagggagta cagaggcaaa ggcaggaagg gtgacaaagt 146460gattgacaag aaaaaatgtt ctccatatga atgttgcagc cccatgttga gggttcttat 146520acactcaact gtcaattatt tagccttctg tgaattatgt atagtataaa agatagggac 146580tctcaagtag ggaacctctt ggcttgccat ctggcaatat gaattgcaag tccactttga 146640tgcaggtaaa gtttaatggt aacaaaagtc ctcataacat ttggatgcaa atcttaacat 146700taattccatg tctcagccaa cattctccat tattaagcag cctgtgatgt gattacagtg 146760aaccactttt gaaaaggagc ctgtgtataa cagatagttt cactatacta tataaccgtc 146820agatgcaggc ttgtaaatta atttgttggt gacaatgttt cagtacattt tcaaattgat 146880tcattggtat agtactcaaa tttgagtggg cttggtgaac acaatgaaga caagctgaga 146940agtgctgtga ctggccttca tttcagttgc aggcccatga tattttgagt gtcttccatg 147000tacaaggcac catgctaggc attagagctt gaggctggca aacttcagga agtgttcaca 147060agataccagg attcttgatg ttgtgtaaat ggccttgcct ttagagtcag gcagatctag 147120tttaaaggct cagctccttt atttactgtg tgcccctctg agcctcaatt tcctcatctc 147180tgatttagaa ataccatcct catagagtta taatgagtat cagatgacat gatgaatgtg 147240aacatccttg ataaatagca aaatgctaga caaatatggg ggcttaatat gacattgagg 147300tcactagtaa tttagctgga aagtctgtaa cacagcactt cccgatggct tttaccctaa 147360gtaacttggt atgccatata atatgtaaca gcaccaacag gcagagaatc gccagaaaac 147420actcttgatt acctcaaacg aaaaagtacc accaggatcc tgttcagaag ctaattttag 147480taattaaggg aatcatatgc tatgttcaaa taccatgcca gtaaaaaccc aattgtttac 147540cttcttaaat cactgcttga agagcaaatc tttccatttt gctgaatgaa cttatctcca 147600cgttccctgc cctactgaca caaccccctc ccaagtttat tgttaactta cacattcaat 147660gcacagcaca cctttactca aacaatggaa aagaaagaaa gtgtcaattc aaagtggccc 147720ttgtctattc cttaaggagt agacttccat tttcatcaga tttggattta gcatagacat 147780attgattacc ttgaagaaga attcatataa ttttatcttc tgattcccat cactcaaatc 147840aaaattacat aatatattcc aaaatggcaa ctaggaatgt ggccttgggc aagtcccttc 147900tctcctctga tgcttggttt tcccatcata gaactggaat tgtggcttca ccgaggacct 147960ttctggtgct aacattttgt gattctatgt aaaaagccac acagaaagga ttgtttttca 148020gccctttctt agattgtctg ttccctgctc ccagaagtat agatagtgag acttgagtgc 148080tttgatacat cgtaattgta tctacctcca ttcacaccta cttaagatat ctgtctaaaa 148140gtagactaga cagattattc agagagtgga gggcagaagg gctgtctctg tatcttaaag 148200aagctggcac tcttcagctg atggctgctt ggtcttgagg cctcaagatc tttaatctgg 148260ctttctctat agtgtttcat tcactgtttg gtgatggaat ctcttcagtt cagagatact 148320taatagatat agctttttct ttcctgcttc caggcctacc tacctgtttc ttgctttttt 148380ttctagcagc tgttgttgtt tctgaaagaa tcttgagggt gtttggagtc tcagaatggc 148440ttccttaaag actaccttca gactctcagc tgctcatcca caacagagat cagcctttct 148500ttgtagatga ttcattcctg gctgcatttg aaaaccacat attgttaatt gcttgacgaa 148560tttaaatccc ttgactactt ttcatttcag aaaacactta caaaaaaagt ccaaatgagg 148620accttccctc cagtgaatta gctgtggctt tctcacagtc catagttagg ataaatgtaa 148680agccatttct catttttctc cgcactttcc aagggtacac tccttgtttc caagatggaa 148740tgagaaataa agaagtgccc ttcctgccat cttctcccct gaccctttcc tccttcccac 148800tttcctccta ttcctcccca aacatgattt atttctgcgt tttgcaactc ttgagttctc 148860agcatttagt aaatggtgtt ggtccctgtt gattccttcc tctcctggac catggaaggt 148920agtaggcctt tcagaaattt caggtagcag ccaaacccca gaagaagaga aggaacacag 148980agacctagac catgtgagaa cctgaggtgt gcagcattta cttcacagat tcgtctagca 149040tatttgagag gtgtctttcc tactaggaga ctgaactctg catctgagaa taaaaactta 149100acatatctac aggttttgac aacctctgtg aattatctag ttgagaggat ggctcaagga 149160gcctattgcc atggtctgat gtcgttatgg acgctatgaa catccttgca gtttccattg 149220ttgaagacag ccctgatgcc agctgtctca tcattcccca tgttcaagag catcccagca 149280ttgctacctc aggatcccat gtcctgaatg caacagagtg atttcgctgc tgaattacta 149340ttcatggcat ggctcttcac agcatttatt catccatgta tctatccatt catccttcca 149400gccagccaag aagttcacgc tttcatcttt tcatccattt actcacctat ttattcattt 149460agcaaatatt tattgagtac caactatgtg ccagacactc tgctaggcat tttggggaag 149520cagaactgaa taagatacta ttcctttcct caaaaatttg agcaagagga gaaaggaagt 149580aatgaggaat attccttagc cataaaggaa aaataagaaa tcacttggaa gaagttaggt 149640gagatggaag gaaaaggaca tctaaggtaa agcgtacagt ttgaataaag gcacagagac 149700atgaacaaaa tgcattgagg gtttgaggaa cagcaattgg tttaacatgg ccagagctgg 149760ggaaatggta agggcaagct gaaaccacat tgaaagcaaa cttggttatt atactaggta 149820gtttagactt caagcagttg aaaatctttg agcatgggat aggcatgatg acattgtgtt 149880tatttgcatg tttctttaaa gaaaactggc agcagcacaa atgttttgtt gatgagggtt 149940taaattgtag aaagtgagac aattttagga aggccagcta gagagaaatt tctagcatca 150000aattttgcta aacacctagg atttgtagtt acctccattt gggttgttac ctgcaagtac 150060tgaccacgta tatgaagaag tactggttta gaccaaggca attggcttgt ataagaggcc 150120taccctcata ccaaaagcca gtttccttgg tctaggccag tgtttactgg tatgtgtcct 150180gagaaaacta gttccatgac atgttccatg aaaaatatga tttctattgt caaataagtg 150240agggaaactt gcatatcatg gtcctgctca ggaagattta caatccttat tagcatatca 150300caggtcctgg tgaatactgc ggtaaagtaa ccgaggagct ttgtaactca ggattcccga 150360agttgattca accacaggac ctcatttatt cacataacac ctgttatcct acaaaaccac 150420tgttctctgg aatacacttt cgaaaacatg ggtatagaca aaaactctat cctataggca 150480gagaatacct atacctctag ctcaggtcat cattttgcag atgtgtgtgt cattaagaat 150540cagtcaataa tgcattaatg atcaaaagca gaccatcctt

accacatggt gcataagatt 150600atgctattat gctattagct actaatgcca ctaaagttaa ttatgttggg tctgcaacgt 150660tgtcatacac aaaggatagg atgcaaaact gtcctaggcc aaagcatggt tattgcccaa 150720gttatctaat gtctgcaggt acatattcct ggcctaagga ttgtgctaaa gaagttattt 150780ctaagaaata tagtgacttc cagcatcatg cagaatgacc atttaatatt ttgaatatct 150840agacattctg ctgtagaatt taatagtcct tttatacact gtctgaccaa cattttgaca 150900tttactcaga accccatcac agtgctacca cataacctca ttgctaaagt gggaggccta 150960gaaatcacag atttgtagaa accatccaat gattgaatcc cctctacttc ctgttcagca 151020ggcagcagag tgtcataaag aattaacaac gtggaactca gttactggga tttcttccat 151080tctcctttga ttctctagac tagaattcca aagaccctca ggctggtgat gcaagtggga 151140agtctcattt ctgagaagtg ctgcttccta cccacaattc tttgatagct gagtgcttta 151200gctgatctgc ataactgagg tgtgcaccaa ggagcagaat tactctataa attttggcat 151260caacatgtgc aacttgtgac tcagcacttt gaaactctgg ggattttttt gtttggttgg 151320tttttgtttt aagatgtcct gtggtatagt ggaaatagta caatagactc agatacagag 151380aggccttgtt tctagtcttg gttctgtcac ttactatctt gatgtccttg cacaaatcac 151440cagacctctc tgagcctcag tttctccaac cacactgtgg gaataataaa atctttttta 151500cggcattgtt gtaagtatgt agagaaactg gtacacagta ggcacacaat caatgtcacc 151560gtacccttca gcccttcttt tgtggatgaa aaatggtctt tgtgctccca gtcaccactg 151620gggtctgttc tctctctctc tgctgttaca gtgtggcttt tggttcttgt ttctttgttc 151680tttggtctgt aaattaccct tgaaacaacc cttgaaattt ccactccatg acctaaatcg 151740tcatccctaa attggttaca tacatatttg gtgacacttt ggaggggaaa agctttatgt 151800ctctctaact gtagttctta agggaatttg catatggaaa aaacagagac tgcgtctctt 151860aattcctcca aaccaaatta tctgggatag cacatatatg ttgtactctg tctctgagca 151920tttgctctta gagaactatg gttagagcga agtaaatttt tctaatcata aaaattaatg 151980ataccgcata tctgatactt gaatgagtac ctccttgtaa aatttatact taaatccttg 152040agtttttaaa gtgtaatagc aatagaaaga ttttattgtt gtttactttt actgtgagtg 152100ctccaaaatc cctcagttgc tcttgaaaga gcaagatgat gccataggca atattttcca 152160aaggtagtag gcagaaaact gagtacacag cacacaatag gccatatata caaaagcaag 152220tattttgcaa ataataataa ttcaggaaaa aagcttcact ttcgttggta acctgtttgt 152280ttaaaaccat tttattattt attatttaaa aagagtgtca cttgttacag attgtgggat 152340gtgttcctta agatcacaaa aatgtaaaat attttctttt tatactgaac acatgcatag 152400acaacttacc tgagcaagct gctttttgga gacatttgca catcttttgg gatcacgttg 152460ttaagaagta gaactaaggg aaaaacacgc agccacccag aaatcggtag agccttcagc 152520tcatctgtta ttaatatttc tgtgacaaca gatatctagg aagtaaacag gaaattgcat 152580cgctatcctg catcaccttt tttggaatca ggttccattc ttctcagtcc agttcaacct 152640tgtgatactt tttagatctc aaccaaggca tagaaatata ttttcccttg cttaataccc 152700catggaacca atgcccctgt ggttgaagta aaaattgatt gttgagggac atttcagccc 152760tctagcagtc aacaattaaa aacatgtaag caccgagcac ctgcagaaaa cttggactgg 152820catttggatc taagaagaaa atctgcatct tgaccaagat gaaaagtcac cagcccaagc 152880ttgtgcagtg aagtgtcatg ttggccacaa tgaaactgaa agagactgat gactctcctc 152940agggtggaaa atgaggcatg gaagctttga ttagtgagct gttaggcaca cagacattaa 153000tttcaaagca ttctcatctc cagtctgagt aataatgctt atagtattat gcaattgttt 153060ggctgctgca agaaattcag cagactccaa caagtagtct ttcttggtct ctgagtgact 153120gtaacttaaa ttctacctcc cttctcttct cctacatctt ctcactcccc accccacccc 153180cacatacaca caattcttgt ccactatgtt cagagagatg cacgcacaca tatatatgta 153240tatatatagt atatttgtca ataaagcaga aaagaagaaa aaactccaag taaacaattt 153300tccatttccc catctcactt ctgtcttaca agtggatagg aaaagaaaaa cccccagtaa 153360aaaatggcaa ccgcccacct ccccaacttt acatgctgct tcctatgtta gaggatctgt 153420cttaggcatc tgattatgga gcctgctaga tacaagcccg tatttagact gctacagtca 153480acaatgtctc tctttcatac tagaaaaatt ccgggttggc aattgcaagc atctcaaaat 153540gaccagaccc tgaagaaagg ctgacttgcc tcattcaaaa tgagggctct agagggctct 153600agtggatagt ctggagaaac ctggcgtctg aggcttagga gcttaggttt ttgctcctca 153660acacagactt tgacgttggg gttgggggct actctcttga ttgctgactc cctccagcgg 153720gaccaatagt gttttcctac ctcacaggga tgttgtgagg acgggctgta gaagtaatag 153780tggttaccat tcatgtagtt gtgagtatca tgattattgt ttcctgtaat gtggcttggc 153840attggcaaag tgctttttga ttgttcttga tcacatatga tgggggccag gcactgactc 153900aggcggatgc agtgaagctc tggctcagtc gcttgctttt cgtggtgtgc tgccaggaag 153960aaactttgct gatgggactc aaggtgtcac cttggacaag aagcaactgt gtctgtctga 154020ggttcctgtg gccatcttta tttgtgtatt aggcaattcg tatttccccc ttaggttcta 154080gccttctgga tcccagccag tgacctagat cttagcctca ggccctgtca ctgagctgaa 154140ggtagtagct gatccacaga agttcagtaa acaaggacca gatttctgct tctccaggag 154200aagaagccag ccaacccctc tcttcaaaca cactgagaga ctacagtccg actttccctc 154260ttacatctag ccttactgta gccacactcc ttgattgctc tctcacatca catgcttctc 154320ttcatcagtt gtaagcctct cattcttctc ccaagccaga ctcaaatatt gtattgatgt 154380caaagaagaa tcacttagag tttggaatat cttgttctct ctctgctcca tagcttccat 154440attgacacca gtttctttct agtggagaag tggagtctgt gaagccaggg aaacacacat 154500gtgagagtca gaaggactct ccctgacttg cctggggcct gtctttccca ccttctccag 154560tctgtctaaa cacacacaca cacacacaca cacacacaca cacgctctct ctctctctcc 154620ccccccaaca cacacacact ctctctctct ctcacacaca cacacataca cacacacttc 154680tttctctttc ccctgactca gcaacattct ggagaaaagc caaggaagga cttcaggagg 154740ggagtttccc ccttctcagg gcagaatttt aatctccaga ccaacaagaa gttccctaat 154800gtggattgaa aggctaatga ggtttatttt taactacttt ctatttgttt gaatgttgca 154860tatttctact agtgaaattt tcccttaata aagccattaa tacaccaatc gtattttctt 154920atttacaaca gactgagaga attaatgctg ttaacattgg atcttttttc tttttttttt 154980ttcctttttt ttctctctcg tttgctttcc aggtcatgct gacctgttca gcttggactg 155040tttcacattt gtttttaatg tcagtttaaa tgtaattgta aaagcatgta tgctctaaaa 155100tcatgtagtt acttttttca gtggaaaagc ctggtattcg aaagcatttc caggctctgc 155160aatttcatat gagcaggttt ttggtaaaat cttttgtccc tcactcaggg tggtatctgg 155220acagtgagcc cctttcttct ggctcagtag tcagagagag gagacttgga gacagtttct 155280gctggatcct gtgctttggc aaggatgtgc agcattgcat atcattctat cattaattat 155340gtttactcct ccatgaacta aaaaccatta gactaaatag tccaacataa accttgaaag 155400ataaaatttg atattctttt gcctggccat ttctctgacc cagaattggg gctgggaggg 155460gattggagac ttgggggaaa gaatcaagga gccttcttgc ctgggggaat ttggcatgca 155520cttattaatc ccatttggtt gcactcccta ctaatccctc actccatacc tgccaaggat 155580tggctctgct ccctgcttct catccctgtc ctagttcttc ctcacctatc tccatttccc 155640actactgatc cttctctcca gtaagatgct attcaacccg atgaaatata aagagtagca 155700ccaccctgga agtcaggata ccttagtttt agctcctgct ctaccattat ctagctgtgt 155760gacctggggc atgacttaac ctttgctctt cagtctgaac agtctttaag aattggtttg 155820gaggaggaag gaagggatag acaagatcca aggcctttga actctttttt ggaaatgggt 155880ccttttcttc aaacaaaatt tgatgcagag tcccaaattt acctacagaa taaaatactg 155940ctgttcttgt ttgaaaggaa gtggggtgct tggagccaca tgctcaggcc cactttgccc 156000cctctcagga accctcgaaa aaacttatag gacttatagg actgttgggg atctgccaag 156060tctctcttat gttacatttc agtccttgtg aaactctata tgtttcatca gttcactttt 156120tcagaaagtt cacctgcttg gggtaaaggt catgaagtgg agaatgtggg gctcagtaac 156180tagcaatagt aaaaaacatc attgattggc ttgcagaatt tactctgttc taagcatctt 156240acacacatac tcatccgaaa actcacaaca accttgtgag gtagatctgt tattatctta 156300agattctgaa acctgccagc atgactctca atctttgact tgagaccagt tgcccaacat 156360ggaaggttat acttttcaca gtttaccacc ataagcagtc tttcagagtg atttctagct 156420agagatccat tcttagaaaa agtcagaacc tgcccattag catacactgt cacatggtgc 156480agagtacctt cactgggttc atctcatttc ctcctaaaaa tagtcctatg cagtagtcca 156540gtcatatcat caccattata tagatgagaa aaactgaggt gtaggagaaa tcaagagatc 156600tgttcaaggt cacacattcc ataagactct gaataccacc atcaagaata ataaaccttt 156660tatgtgaaaa gcattttaga acttcagtgt cattattgca ttctgcctcc tggagttcag 156720tgcacttttt caccatgctt taatcttgga gtcctggtgg tacagaatct gccttctact 156780ctcagacaac accacagtgt ctttatccct cataacaaac ttatgaatta agtaatgata 156840ttatccccat tttacaaatt agttaactga gataccaaga ggctaagtct tgcccaaagt 156900cacacagcta gtcagtgata gagccggagt tacaaatgag gcatcctgac tccagaatat 156960ttgctcttaa ctactactct ttatacatat gtaaggaaac taaaagcaaa agagggaaag 157020atgtccctga ggccccacag tgagctcccc tgactcacaa tccagtattc ctctgacctt 157080ctaatcctaa agttatacag taaggtccct tgactctaat cctagtagat ggaaagatgg 157140ctggcatgat ttaagccaga ggccacaaac tggcttcccc agagccagaa ttcacctgca 157200gaattctgtt tgtccagcac agtgtttgtt tagaaaattg acgtagactg cccctaggca 157260gggcatcaat cactgtcatt gtccccagcc ctccttattt atgtttgcca ggctttttta 157320ctcatttatg tgtctgcctg acttgtgaag gtatttgagt ttatgacttt tagatttaag 157380cattgcaata tataagcact gcacacatgc attcacaaaa gtatagccta gtctagcttc 157440acaaagaatt tgtagcccta caccaaacac acctttatgt ttacttagtg tttagaatta 157500gatttaagat cagaatttag tttcacaggc attcatgtgt ggaagaacct cagttattgt 157560tttttgtttc atactgtctc acccttgctt tccctgctgt gtctggaccc ctgtcaatcc 157620tgctttctgc cattcttcat gcctgagtta gggcccctgc aagccattca ctggttaatc 157680tttaggaatg aatggagagt gaaaaccagt ttggagggtt cactgtgtcc caagcatcct 157740ctcatttagt tctcataagt gtcctaagag acaggtagca gcacattcgt tttataaatg 157800aggaaactaa atctcagaga agctgaacaa agacctcaaa gtcattaagg tagtaattaa 157860cggagccggg atttgaacgc aagactgttg gactccagag cctattcttt tgccctacac 157920cacagttcct tacaaggaag atgtattcat tttctattac tgcataacac attgccacaa 157980atttagcagc ttcaaacatt tatcagctca ctgttttgta agtcagaagt ctggcacagc 158040atggctagat tctcagttca gggtctctga aggatgaaac tgatgtgttt accaggatgc 158100attctaatct gaagctcagg gttctcttcc aagctcatgt aattattgca ggattcagtt 158160atttgtggtt gtaggactaa ggctccctct tcctttctgg ctaccagcca agggccattc 158220tcagctcttg gaggctgccc tctttcctta tcatgtggac cccaacgcct tcaaagccaa 158280caacagagac tcttccttgt gttgaatgtt tctcactcta cggatgtctt tcctggagga 158340tcccagtccc gtaagggctc acctgatgag gtcaggtaca tcaagaatag ccacccttca 158400aattcaactg aattagcacc ttcattacat ctacctagcc tttttacaac agcatctagg 158460ttagtgcttg actgaatgac tggaaactaa ggtctcagaa tctcggggac cgtcttagaa 158520gtcagcctac tacagatgtt gattcttttc atgtgtcaaa tttcatagtg agatagggag 158580aacagaaaca tcacatcctt gaccttaggt aaagggattc aaacttccta agactttgga 158640aacttcacgc cactttcacc ttttccttaa tcatggttga gaaggcctat atcttggagt 158700ggccaggagt gagactggaa cagtacctaa aggttaagga cgctaaagaa gttacagatt 158760ggttacatct gctcctccct aggaatgatc catggaacct gatttgaaat ttttttctct 158820ggtgctatag atagctccca caggggtcta atgccccagg gctgaaaagt tagttcccca 158880taggatccat ccaggcatga tatcaggcca ggtgttacaa tctcctaaag aggaggtatg 158940gactggaaag ccccttgcca atggcccttt cttgtcactg ctctgaccca agactaacag 159000ggcagagata gtgaactcac atactattaa aactatccac ttatacttcc ccctttctct 159060ttgctttatc actccattta agtaaaccaa tgagtctctg ccttgacaca gtggcaagct 159120gacctgtatc ttatatgaaa gaattagatt tgactctggg gctcaggtgc agagggcagg 159180aggggcataa ggatggcctt catggaagaa aagaagtcct tggatactga gtaacagctg 159240agactagcaa gcctcattgt ccaggattcc aagtcgtcta gcaacatcct ggtctctgct 159300gcagacagaa cagaggatcc cccggcagaa tgaatggagt ctgatttcaa ttacgttcag 159360tatagtcact ctctttaggc agagaagcca gaacacctgg tgcagctagg gccactgtgg 159420tcacagggac aagcacacta cctgggtcct ggaggcaagt gggaatgcag tttttcttcc 159480ttaagcagat gccatatagg cctggggagg aggatgtgag aataccagcc aagttctcat 159540tggcactata cagagaaagg ggaattattt catcttgatg gattctcccc acagtctctg 159600cacatattga tcttacttgt aatgagtttg cttaggttca cgagtcatca tcccagggag 159660atctgagtca ttggtgggaa agtcgaggcg acagattata tctcactgat ctcactgtca 159720ccaattgctc tgtgtgtccc tccacctttt gaaaaagtcc atggattcat ttgtgtgtaa 159780ttcatttgga tttatttctt ctttatcaat agctttagtg gggtattgca aatgggaaag 159840ttgccccaga gaacagtgta cattcacagc attattcagt agaactttct gagatgatga 159900aaatcttcta tatcttatgt tgtacaatat aatacagcca ctaactacat gtagcttttg 159960aacactggaa atgtggcagg tgagactgag ggattatatt tttaattttt taatgttgta 160020attaatttaa ttttttaaaa tttttgcttt ctattttata gtttaataat taaactaaac 160080ttacgtagcc cacatgtggc tagttggcta ctatactgga cagtacaagt ctagaaggat 160140ctcagagaga cacatgctga gatacagcag gaataagtca aaaagagagc caatgtaaca 160200tagggaattc tggattggga attagagccc tggctctaat ctcagctctg ccactaggtg 160260accttgccct ctctggcttc agcctcccca tctttgactt gaaaggttaa actaactaac 160320gtcgaaagtc ccaaaatggt ggctatggac tgaattcaat tttgggatac acaagtttca 160380ggaatttttt aaaaatctat taatgccttc taggtgtgtg tatgcacgct tgcagacatg 160440tgcccatgca caagcatggg aaggcagtaa ggcattcatt tcaattcacc agtgtactaa 160500ccattcacac acacacacac acacacacac acacacacac atgcacacac accctactgt 160560attgcctatg tagagcctga agatctttta atctgtcacc attggataag ataatttcta 160620aggacccttc ctgttttgtc atgctgaaaa tctttaagcc actatagtgt cccaaatcta 160680ttccagtttg ggcagatgac tggagtattc tcatagcctc ctgtctattc ccttctggat 160740ttgatactag ttatgaagtt tggagtcaag ggtgaagaag ggaggcaggg atgatataac 160800cccagcccca ctcctcaact ctgcttttga gttagaagta gggttcaggg cttcagattc 160860cttggggagg cagtagagag aatatgggct ttataatcag aagatgaggt tcagatgatt 160920gggttctcac cttttttata gctgtgttac ctcagtttat tcatttgtaa aatagggata 160980agaaatatct ttaacctcct aagatcatgt ggaattaagt gatgtaatgt gatgaagcga 161040ggcacgcaga aggccctgaa aaaattagta gttaccctta aggggactaa atggtctggc 161100aactcccgag ctcaaagcta gaaaggtcca gtaatgggga agatggggtc tttctgtagg 161160aactgtagca ggggagcaga tcctgtaggc caccagtctg tggagctgtg tccaagaact 161220catgtttgca ataagcccac caaatgacaa gttattgtgg ggttcaggcc tctaactcaa 161280gaagatggtc ttggcccaga tcataccttg cagcctgtgc ctttggtggg atgtgggtgt 161340tggcagtggc tatgcatatc tccttattac tggctgtgcc aaagccccgc agaaatgatt 161400gttggacaaa gtcatcttgc actcagggct ggttttccag gcttccttgt tattttcccc 161460tgagttcttc tgtgttcctc ttgcaacacc aaccccacta ttttcctctt ccctacccta 161520gttgttggtc caaacatgta atccattctt gcagtgattt attgggtgac accatgactg 161580gagtttgcat tgaaggactt ctttttctaa ttagaactaa aagtcagttc caggctgggt 161640gtggtggctc acgcctataa tcccagcact ttgggaggcc gagatgggag gattgcttaa 161700ggccaggagt ttgagtccag cctggacaac atagtgagat cccatctcta caaaaaatgt 161760taaccaggag tggtagtgta caactctggt cccagctact tgggagactg aggagggaga 161820attgcttgag cccaggaagt tgaggctaca gtgagctttg atcgtgccac tgctctccag 161880ctgggtgaca gaggaagatc ctccttcaaa aaataaataa aaactaaaaa aaaagtcagt 161940tccaggttgt atcttttttc acaggggcca gacacagatg agagcaggtt ttgttgtatt 162000tatccattta aattgagcaa taaaattctc tctttggttt ctacctttct tatttattat 162060tattatgtta aagggattaa agtggttcat ggtctttctc agtgcaactg cttatgctag 162120acctcagaat tatgaccttt tcaattattt atatttctgt ctatataaat actggaaaaa 162180atagtacaaa gtaagcatcg gaatgcctaa ggacctctaa attgtgtgtg tgagcacatg 162240gggaagatgg ttcttaaggt ttgagttttg gattattgtg gttgtcttaa ataatgttat 162300ttctatcatt ctttccaatg actgtctcct agcatagttc ccattttaca gactgatggc 162360agaggcagaa agattctctc acttctttga tactattgag gacttcagcc tttcaccgct 162420cttctcccct ttgctaaaaa agaaaaaaat caatatgtat gttacagtgc atttttttaa 162480atatttttta ttatacttta agttctaggg tacgtgtgca caacttgcag gtttgttaca 162540tatgtataca tgtgccaagt tggtgtgctg cacccattaa ctccttattt acattaagta 162600tatctcctaa tgctatccct ccacccttcc ccaaccccac aacaggcccc agtgtgtgat 162660gttccccttc ctgtgtccag gtgttctcat tgttcaattc ccacctgtga gtgagaacat 162720gcagtgtttg gctttttgtc cttgagatag tttgctgaga atgatggttt ccagcttcat 162780ccatgtccct acaaaggaca tgaactcatc attttttatg gctgcatagt attccatggt 162840gtatatatgc cacattttct taatccagtc tatcattgat ggacatttgg gttggttcca 162900aggctttgct attgtgaata gtgccacaat aaacatatgt gtgcatgtac ctttagagca 162960gcatgacata taatcctttg ggtatatacc caataatggg atggctgggt gcaatggtat 163020ttctagttct agatccctga ggaatcacca cactgacttc cacaatggtt gaactagttt 163080acagtcccac caacagtgta aaagtgttcc tatttctcca catcctttcc agcacctgtt 163140gtttcctgac tttttaatga tcgccattct aactggtgtg agatggtatc tcattgtggt 163200tttgatttgc atttctctga tggccagtga tgatgagcat tttttcatgt gtctgttggc 163260tgcataaatg tctttttttg agaagtatct gttaatatcc tctgcccact ttttgatggg 163320gttgtttgtt tttttcttgt aaatttgttt gagttctttg tagattctgg gtatttgccc 163380tttgtcagat gagtagatgg aaaaaatttt ctcccattct gtaggttgcc tgttcactct 163440gatggtagtt tcttttgctg tgtagaagct ctttagttta attagatccc atttgtcaat 163500tttggctttt gttgccattg cttttggtgt tttagacatg aagtccttgc cggtgcctat 163560gtcatgaatg gtattgccta ggttttcttc tagggtttta tggttttagg tctaacattt 163620aagtcttgaa tccatcttga attaattttt ctataaggtg taaggaaggg atccagtttc 163680agctttctac atatggctaa ccagttttca cagcaccatt tgttaaatag ggaatctttt 163740cccaatttct tgtttttgtc aggtttgtca aagatcagat ggttgtagat acgcagcatt 163800atttctgagg gctctgttct gttccattga tctatatctc tgttttggta ccagtatcat 163860gctgttttgg ttactgtagc cttgtagtat agtttgaagt caggtagcgt gatacctcca 163920gctttgttct tttggcttag gattgtcttg gcaatgcagg ctcttttttg gttccatatg 163980aactttaaag tagttttctc caattctgtg gagaaagtca ttgatagctt gatggggatg 164040gcattgaatc tatgaattac cttgggcagt atggccattt tcacgatatt gattcttcct 164100acccatgagc atggaatgtt cttccatttc tttgtatcct cttttatttc attgagcagt 164160ggtttgtagt tctccttgaa gaggtccttc acgtcccttg taagttggat tcctaggtat 164220tttattctct tagaagcagt tgtgaatggg agttcactca tgatttggct tctgtttgtg 164280tgttattggt gtataagaat gcttgtgatt tttgcacatt gattttgtat cctgagactt 164340tgctgaagtt gcttatcagc ttaaggagat tttgggctga gacaatgggg ttttctagat 164400atacaatcat gtcatcggca aacagggaca atttgacttc ctcttttcct aattgaatac 164460cctttatttc tttctgctgc ctgattgtcc tagccagaac ttccaacact atgttgaata 164520ggaatggtga gagagggcat ccctgtcttg tgccagtttt caaagggagt gcttccagtt 164580tttgcctatt cagtatgata ttggctgtgg gtttgtcata aatagctctt attattttga 164640gatacgtccc atcaatacct aatttattga gagtttttag catgaagggc tgttgaattt 164700tgtcaaaggc cttttctgca tctattgaga taatcatgtg gtttttgtct ttggttctgt 164760ttgtatgctc aattacattt attgatttgc atatgtggaa ccagtcttgc atcccaggga 164820tgaagcccac ttgatcatgg tggataagct ttttgatgtg ctgctggatt cagtttgcca 164880gtattgtatt gaggtttttt gcatcgatat tcatcaggga tattggtgta aaattctctt 164940tttttgttgt gtctctgcca ggctttggta tcaggatgat gctggcctca taaaatgagt 165000tagggaggat tccctctttt tctagtgatt ggaatggttt cagaaggaat ggtaccagct 165060cctccttgta cctctggtag aattcagctg tgaaatccat ctagtcctgg actttttttg 165120gctggtaagc tattaattat tgcctcaatt tcagaacctg ttattggtct attaagagat 165180tcaacttcct cctagtttag tcttgggagg gtgtatgtgt cgaggaattt atccatttct 165240tctagatttt ctagtttatt tgcatagagg tatttatagt attctctgat ggtagtttgt 165300atttctgtgg gatcggtggt gatctcccct ttatcatttt ttattgcatc tatttgattt 165360ttctctcttt tcttctttat tagtcttgcc agcagtctat caattttgtt gatcttttca 165420aaaaaccagc tcctggattc attgattttt tgaagggttt cccatgtctc tatctccttc 165480agttcttctc tgatcttggt tatttcttgc cttctgctag cttttgaatg tgtttgctct 165540tccttctcta gttcttttaa ttgtgatgtt agggtgtcaa ttttagatct ttcctgcttt 165600ctcttgtggg aatttggtgc tataaatttc cctctacaca

ctactttaaa tgtgtcccag 165660agattctggt atgttgtgtc tttgttctca ttggtttcaa ggaacatctt tatttctgcc 165720ttcatttcat tatgtaccca gtagtcattc aggagcaggt tgttcagttt ccatgtagta 165780gagtggtttt gagtgagttt cttaatcctg agttccagtt tgattgcact gtggtctgag 165840agacagtttg ttataatttc tgttctttta catttgctga ggagtgtttt acttccaact 165900cagtggtcaa ttttggaata ggtgtggtgt ggtgctgaga agaatgtata ttctgttgat 165960ttggggtgga gagttctgta taagtctatt aggtccactt ggtacagagc tgagttcaat 166020tcctggatat cctttgtgtc ttgttgatct gtctaatgtt gacagtgggg tgttaaagtc 166080tcccttgatt attgtgtggg agtctaagtc tctttgtagg tctctaagta atcactttat 166140gaatctggtt gttcctgtat tggtgcatat atatttagga tagttagttc ttcttgttga 166200actgatccct ttaccattat gtaatggcct tctttgtctc ttttgatctt tgttggttta 166260aagtctgttt tatcagagac tagcattgca atccctgcct cttttggttt tccatttgct 166320tggtagatct tcctccatcc ctttgttttg agcctatatg tgtctctgca catgagatgg 166380gtttcctgaa tacagcacac tgatgggtct tgactcttta tccaatttgc cagtctgtgt 166440cttttaattg gagcatttag gttaatattt acgtttaagg ttaatattgt tatatgtgaa 166500tttgatcctg tcattgtgat gttagctggt tcttttgctc gttggttgat gcagtttctt 166560cctagcctcg atggtcttta caatttggca tgtttttgca gtggctggta ccggttgttc 166620ctttccatgt ttagtgcttc cttcaggagc tcctgtagtg caggcctggt ggtgacaaaa 166680tctctcagca tttgcttgtt tttaaagtat tttatttctc cttcacttat gaagcttagt 166740ttggctggat atgaaattct gggttgaaaa ttcttttctt taagaatgat gaatattggc 166800ccccactctc ttctggcttg tagagtttct gccaagaaat ccactgttag tctgatggct 166860tccctttgtg ggtaacccga cctttctctc tggctgccct taacattgta tccttcattt 166920caactttggc gaatctgata attatgtgtc ttggagttgc tcttctcgag gagtatcttt 166980gtggcgttct ctgtatttcc tgaatgtgaa tgttggcctg tcttgctagg ttgggtaagt 167040tctcctgggg aatatcctgc agagtgtttt ccaacttggt tccattctcc ctgtcacttt 167100caggtacacc aatcagatgt agatttggtc ttttcacata gtcccatatt tcttggaggc 167160tttgttcgtt tctttttact ctttttttct ctaaacttct cttctcgctt catttcattc 167220atttgatctt caatcactga tacccttttt tccagttgat cgaatcagct actgaagctt 167280gtgcattcgt catatagttc tcgtgccatg gttttcagct ccatcaggtc atttaaggcc 167340gtctctacat tgattattct agttagccat tcgtctaatc ttttttcaag gtttttaact 167400tctttgcgat gggttcaaac ttcctccttt agcttggaga aatttggtca tctgaagcct 167460tctctcaact catcaaagtc attctccgtc caggtttgtt ctgttgctgg tgaggagctg 167520tgttcctttg gaggagaaga ggggctctga tttttagaat gtttcagttt ttctgctctg 167580ttttttcccc atctttgtgg ttttatctac ctttggtctt tgatgatggt gacatacaga 167640tgggattttg gtgtggatgt cctttctgtt tgttagtttt ccttctaaca gtcaggaccc 167700tcagctgcag gtctgttgga gtttgctgga ggtccactct agaccctgtt tgcctgggtg 167760tcggcagcag aggctcagaa cagcgaatat tgctgaacag caaatgttgc tgcctactca 167820ttcttctgga agtttcgtct cagaggggta cctagccatg tgaggtatca gtctgcccct 167880actggtgggt gtctcccagt taggctactc gggggtcagg gagccacttg aggaggcagt 167940ctgtccgttc tcagatctcc agctgtgtgc tgggagaacc actactctct tcaaagctgt 168000cagacaggga catttaagtc tgcagaggtt tctgctgcct tttgttcggc tatgccctgc 168060ccccagaggt ggagtctaca gaggcatgca ggcctccttg agttgcggta ggctccaccc 168120agttcgagct tcccagctgc tttgtttacc tactcaagcc tcagcaatgg cgggtgcccc 168180tcccccagcc tcactgctgc cttgcagttc gatttcagac tgctctgcta gcagtgagcg 168240atgctccatg ggcgtgggac cctccgagcc aggtgtggga tataatctcc tggtgtgccg 168300tttgctaaga ccattggaaa agtgcagtat tagggtggga gtgacccaat tttccaggtg 168360ccatctgtca cagctttgct tggctaggaa agggaatttc ctgacccttt gcacttcccg 168420ggtgaggcga tgcctctccc tgctttggct cacacttggt gcactgcacc cactgtcctg 168480tacccactgt ccaacaagcc ccagtgagat gaacccggta cctcagtcgg aaatgcagaa 168540atcactcatc ttctgcgtca ctcacgctgg gagctgtaga ctggagctgt tcctattcgg 168600ccatcttatg aatcatgcat gttcaactat gagcaactat gtgtattcaa tgggaaatgg 168660aataccataa aattgtcata tgttgagccc aaaatgatag gatagaattt gatagtctga 168720ggatggaaag gaccttcaag gccactttta aaaaccccat tcccatatga tgcttgaatt 168780cttaaccact gtgtgtctag tattttctca tttccagtga tatgtgtgcc tgccaacctt 168840tccgtctcca agagctttaa ctatcaaaat gtatgtgtgt gtgtttttgt gtgtgcatgt 168900gtgtgtgagt gtgcgtgtgt gtgtgtgtgt gtttagagag agagagagag acagaaagag 168960aaggagagac taaaatccaa ttcactgttc tttctgggac ccaaagaaca agtctagtca 169020ttctccattt ctagtctctt tccctagcaa tcggctagac atgctagaca tagacacatg 169080tacatcactc ctttgaatta caacattcag tatttgtcta tcacttatat gataaaatac 169140aaacttagct tttattttta tttttttaga gacagtgttt tactatgtca cccaggctag 169200agcatcagtg gcacaatcat agcccactgc agcctggaac ccctgggctc aaggaatcct 169260tccacctctg cctcctgagt agcagagact acagatgtgc accaccagac ccagctaatt 169320tggtttttta ctattttttg tggagatggt gtattgtctt gtggtgttgc tcaggctgat 169380cttgagctcc tggcctcaag cactcctccc atctcagcct cccaaaatgc tgggattaca 169440ggcatgaacc accttaccca gccaaatttc ttaatatgat atacatgctc ctttaaaatc 169500aagcaccatc tttgctttca acctcattat taaccacttt cccatatatg caacatatgt 169560ttcagccata ctagtgtcta gtttttccct gaacactcct tggtgctttt gtttatgccc 169620tttctgccca cctttgcctg gtgaaatcct catcaatctt caaattctat caaatactat 169680cttccatata aagcattttc taaacccacc tatgtaaaaa gattagtgtt ttcctatttt 169740gttgatgcct ccattgcagc attttccagt ccaacgtttt ctagaattga ttgtggccag 169800gctaccagac tgggccaggg cctgtgtctt ttctgtcacc cagaagcaaa ggtctaacaa 169860tggatatctg ctgaatgaat gaacgaaaat gaatcattaa tatattagta aatacgttaa 169920ttaaagttcc aggtatgaat actgaaggct gcattcaggc agagctggat ccaaggatat 169980gctaggttgg tctagcacaa gaatcagagt tttcctctgc aagctatgaa aaatttgggt 170040ttagcaggta tttgggatga tgaattatac atttaaccag tgttgaatga gcacttgtcc 170100ttaaggagtt tagagtctgt gaccagggag aatggtgatt ttcttagcta gggcagtttt 170160tctaaaaagg tagttgcatt gtgtgttttt gaccactgat gataaattca agtctctctt 170220ccttcccaat agcccggaag ctgaagaaac ttggtaatct gaaactacag gaggaaggag 170280aggcttccag caccaccagc cccactgagg agacaaccca gaagctgaca gtgtcacaca 170340ttgaaggcta tgaatgtcag cccatctttc tgaatgtcct ggaagccatt gagccaggtg 170400tagtgtgtgc tggacacgac aacaaccagc ccgactcctt tgcagccttg ctctctagcc 170460tcaatgaact gggagagaga cagcttgtac acgtggtcaa gtgggccaag gccttgcctg 170520gtaaggaaaa gggaagtggg agcatgagat aagggggatc atatttagtg aacgctccta 170580tggaccagcc accatgtctg gtgcttttct gcccattaac tcaggcagtc ttcatcataa 170640ccctgtggga gagggattgt tacaagtctc aatttaaaca tacagggatc gaaactcaga 170700aagcaaagag aaagatagta ttatcgggtg tcttatgtgg cccacattga tgcacagcag 170760tcatgctttc atattcaact cacaaaaatg gtcagcaaat tttccattaa tcacaaatca 170820catagacata cccatatatg ccttaggatg ctcttctata tttgcacaca caggctcacc 170880ccaaagataa tctctagttt gactgacatt ctgtcttcaa tgtcatcttt aggagctata 170940tcatgggaac tctcataata tggtatggtg gaaagaacat gaggttggga atcagaacac 171000ttcgggtctg ctcttagctc tgctagtaac ttattgtgtg atcccttccc cttctgggtc 171060tcaatttctc tatctgtata atgtataaag cgtggtttgt atcaaattga tggtttccag 171120tttttgaaaa aaggaacgct ttttgcacct taaactacct aaggaatcat aatgagagga 171180aagattaggt aatagtgaaa gaattaccaa gtgttggtct aacagaagtt ggataacaga 171240agttcctcag tgatggggaa ctcacttctt tcttatgtca tctgttgttt aaacaagtct 171300ggttattaaa atattacagc ttaaggaatt cttagagatc ctctatccaa tgattcacaa 171360actttccttt agcagccaag tgctttattt ctcaaaagaa ttgtacacag atacaagtgg 171420agctagttta tttaaagcca gagcctgtag cttgggcctc accagttcag cctctttctc 171480tctatcccag ggaagcccta ggtcactctt gcaaaatctt agggctccaa ggaacacagt 171540ttgaaaacca gtgaagtata tgccctttaa aggttctcct aatcctgcaa ttatgattca 171600aagattcttt tgaaataaca acaaccaaac cttctcttgt ggagtcaaag attaacctgc 171660ctttcaataa taactgccat tcaggtagaa atttatagtg aacagagcaa ttttgtatgt 171720attacctgaa ttgattctta taggaatcct ataacatgag attctttctc ttattttaca 171780gaccaaatag ggaagctgtg agaatgatgt gattggccta tagttacata gtcagaaaat 171840agcaggacca gaacttgagc ccaggttctc tcctgattcc aaattctctc tattccactc 171900cacctgtagg ctgtagcacc actgcagttc tgtagctctg ggctttacag tgaggggcca 171960aggcttcatt gaaggccact tgggtcatag tatgggcttg ttgcatttga agacatttca 172020tgttggctgt caagtcttag atttgtattt ccaactcaca gggcctggtc acagccctaa 172080ccatctctta taccttctca gcttgggaag ctgaggtcga ctagccaata agaacactgg 172140gaaggaaacc caaggactct gactggatat gctctgtgcc aaaacagagg gttcactcag 172200agaggaaaaa tataaaaaag aaaaaggaga aggttgcttt aattcttatc actttttcat 172260ctggatattt tgatatcatg tgtttgacag agattcaaag tttaatcttc ccaagcagtt 172320tccaaacact tatctcattt tataggctac agagcttttt catatatatg atcccactta 172380atctttacaa caattctatg aatcatagag actattattt ccatttcaca tgccaaggct 172440caaagaggtt aactaacttg ctccatttgg tcacttaaca catggaacca gaacttgacc 172500tagaccttcg ggtttctaaa ttggttatct tgacaataac ctagtgcaaa acactatagc 172560agaatttgta tgacttggga tcactggggc tttccttggc ccaaccacca agatggaaag 172620ccccctcccc ttacattaac aaatctgcaa gccaatatca gttcaccatc tagcttgcca 172680gactaaatga tttctgaccc caagtctttt aaaagaatag cttcaaaaga aagccaatta 172740ccacattcac aagaactgtt cttcatatta tctataatta cctacaagta caagtaattt 172800gctaattcaa tagattgagt tcttgacctg taagatgaac tgtgctaggc ccctaataag 172860ataaattttg ttttaagttt tctgtgacag taaagatgta tgaaaattgc ctagtagagt 172920acctggcaca ttaataaatg ataactgtta atttggagtg ggtgagtaga ctgggtgtgc 172980acagtatatt tagaatcaaa tttatctggt ttggaatcct agctatggac tagttctgtg 173040accttgagca aatcacatgt cttctctgtg cttctgtgtc ctcatttgta agatgataga 173100ataatcacta cctttcaaat tgttgtcaac aaaaagatta tgtataaaga gcacctagta 173160acgtagcctg aaacatagtc aatgctctgt aaatggtggt ttattattat gagacttgaa 173220tgctaagcca ctgctttcac gaaactcaat tttagctacc acttgccttg cctagaagct 173280catgcatgga ccccaaggtg aaattgtgtt ctctgaagac ctcggctggc agatgtacta 173340cagcagcaaa gatttccaaa ctggcctttc tttgagccca ttctcccaga ctagacagga 173400gactacaagt ttctgctgca catgaaaaaa atatgatgtc aatcggattc tagtgagaaa 173460acagagtctc aaagaaactg cttctgctcc ctagcgtgtt taatgtgttt cagaacctga 173520gaatgactcc tctctgtttc tccagaacag cctaacacag tggcaaatgg gtgttgagtg 173580aatgcatact taaggaaatc tgtagggttg cagctactct ttcctcaagt aatcccttga 173640tagtcatgta ggctacttca gagattgggc attagagaac agagtcaggt attataatca 173700gattagactc tagggaggtt agccagccat attgctgata tgtgcacagt tactgggttt 173760gagtgctaag cagctctcat taaggacggt taattaatat tatggccaaa ttaagctttc 173820ccttttctct cctctttgtt agttcggtgg cattttaggg agaaaaaaat aagcatcagt 173880atggacaatt tgcttgatac ctgtacaatt taattctcat ccttccatgt gccttcacat 173940tcacacattc caccagaaga ccaaggttca ccagccaaaa gcttttcttg ctccccactg 174000cctcctaccc aagatattca gggtcaacct cccaggcctc ttctctaaga gatccttggt 174060tgctacatgc ttagaccctg cttcttattt cctgctgaga agggtcagtc caaggcattc 174120tgtgctacag aagggttcca agcaggaact actctgggat ctgaggctcc agccggtctg 174180tcagcgtgtc attacagtga aggtgggaag cacaggcctg ggagctaaga ctgctaagat 174240gagggactct agaatccctg atacctggaa ggcctaggat ctaaaagaaa agaacaggga 174300aatggggcta tatgagtgga cagggaccaa ccaagcagaa caatgtgtct ggataatgta 174360gacttcagac ctgatcctat ggctgacaaa agctggtgac cttggtagtt cctgagctgt 174420aaccttcatt agtggagtag aaaaaacact ggagaagaga atcagaacac ctgggttcta 174480gtattagttc agccacatat aaaccatatg accttgggta agtcagttta tttctctggc 174540cctcatgttc cttgttggta aaataagtgc cacatcacct aacctctggg attattgtga 174600gagttaaatt aggtcatcaa caggaaagtg agaagtttga tctaaatttg gggaagcatt 174660cctaatgagg tatgatgaca aaatttcaga taattctgga tttgttggtg agaagagaga 174720gtgttggtag ggacgagctc tgaggtgatg cctttataac tttaagcatc caactgtttc 174780aaaaactcca ggagaacatg gccatgtctg ttctacctgt gtattattgt agacgtagct 174840tctgggagcc tctgctctct gagcttaagg gaggtaattt ggagatcatt taattctcat 174900tttacaaaag gaaaaaaaat tgagggtctt taggccattt gtttaggtaa tatttcttaa 174960gtgcccactc aaatacgtgg actgtactaa gtactaggga ggtaaagata aataagaaga 175020tatggtccct gtcttcaaga agctccaagt cttgtggggg agacagacat gtatatacat 175080agacttcaat gctgtgtaat gactgctata attgggtgag gctacacaag gtgcaatgag 175140aatgtaaaag aagaatcttt aagccttctt cttggatgag ttgggaaagc cttcacagaa 175200gaggtagcct ttgagtgaag acttgaaaga tgagtagtgt ttaccggatg aaaggcctga 175260gaaggaggaa tgcattctag gcaaaagtaa ctgcctgtgc agagataaca gagatataga 175320ggcatgtgag agcgcaagtg gcaagagatc agtctaggta ggcaggtcat aaagggccta 175380ttcatgtata atgatggcag taagatgagg atggcagtag ggtgggaaat tagtagggcc 175440agggtaccta ttgagtagaa aagaatggag aggaaatgcc aggcagaaag aggatggacg 175500caagagaggg aacatgaaag tggtgaacag gtggcagtgg ctgtcaagac atctctccat 175560accctgtaca ctgtatgtaa tatccatctc ccagggttgt tagaagggtc aaaccagatc 175620gtagctggaa aacagctttg tgaagtgaaa actgctgttt atgtggggga aatgattgtt 175680aaactgcatc tttggaaagg tgaagtgatc aagagcacag accttggaat ctgactgctt 175740tgctttgtaa cttggtctgc caattactag ctgtatgatc ttggacaagt tccttaacct 175800ctctctgact cacttgtact ggttcacaga atggagataa taatagtact taccttactc 175860attgttgtga atgttaaatg agataatata agtaaagtgc ttagaaaaga gttaaatgta 175920ccccataaat acatacaact atcatgtacc caaaattatt tttaattttt ttaaaaaaga 175980gcaatccaat agcaaaagaa aaaaagagtt cactcatata agcagtcaat aagtgttaga 176040ttatttttct cttacaactg acaatgccct ttttgtctcc atcatcatct catttgagca 176100gctcagggaa gtagggagga taaggaatat tatcctcacc atatagtttg tgcttttccc 176160caccacccct taatggccag cctggatggt ccctggggat ccttagggga tgcccgaata 176220ccagagcatc tctgcccaac agggactcag acttagctca acccgtcagt acccagactg 176280accactgcct ctgcctcttc ttctccaggc ttccgcaact tacacgtgga cgaccagatg 176340gctgtcattc agtactcctg gatggggctc atggtgtttg ccatgggctg gcgatccttc 176400accaatgtca actccaggat gctctacttc gcccctgatc tggttttcaa tgagtaagtg 176460ctcctggggc ccagacctca ctaaaataca gcagcttggc cagacctggt tggtggtgat 176520ggtgatgggg tgacagtgaa gcttagctca tttgatctgc agttgtcgca gcggatgccc 176580cagccagcca atccagtatg aggcggcttt gccctggctt tcagccaact ggcaggagcc 176640caggaggatg gtgctgagac cacccctttc acacccaaga accaatccta gtcatatttc 176700tggtctgctt tgcagcttat ctcaaaacca catggaaaga ttcctcccct tcacatataa 176760aagaggcaga aagactctgg ctttaagggc tggagtttct tgggttcttt tgctaccacc 176820aaaggctact tctagtcacc atttgctgag caactagttt gtgccaagac tatgctagat 176880actttctaaa tcctagctca ttgagtcctc atggtgacct gacctcacct ttttatagat 176940aacactattt ttttatggat ggggaaaatc aggctcagca aaataaagtg actcacccaa 177000agtcacagag ctagtgcctg ttggagacaa gattcaaacg tatgtccctg tcgatctcag 177060ctcttctgcg tcatggtggt aactgatggg aaggagtacc tctaccgctc tctggctgtg 177120tgaccttggt actgccattt tccttccctt aaacagcttt aattaatacc tgccctgcca 177180ccagctccat ataacatcat gaatttggcc agtggctcag attttggaat tacatttttc 177240tccactaaaa tctcagttct actattttct tagtcagcat ctttgggaaa gacctttaac 177300ttttccgacc ctcaatttct tcatccatta atgataacag aaccttcata agtaatttct 177360tatgataact aaatgggaat tgacagatgt ggaatgtctg gcccatagta ggcaagaagg 177420aaaaaaaaag tccctttctg attcaccctt tccctaatag tgatacattt tttttccccg 177480agatggggtt ttgctctgcc acccaggctg gagggcagtg gcgcaatgat ctcagcccag 177540tgcaacctcc acctccctgg ttcaagcaat tctcctgcct cagcttcccg agtagctggg 177600attatagatg cccgccaccg tgtccatcta atttttgtat ttttggtaga gacgggattt 177660caccatgtta gccaggctgg tctcaaactc ctgacctcat gatctgcccg cctcagccgg 177720gcatgataat cttttctatg tctgctgtat gaggtccctc gatggcattg tgaatggagc 177780tggccagaga aatcttccca aggaccttga gctagtctca ccacagagaa tccttccagt 177840caggacagga attgaccttc ccccctcttc agccctctaa cccagaagag tcttaaaata 177900aaatctacag gccaatggtt ccttccagta cagcactgca atgcgaggga gagtgagcgt 177960ccccagctgc cctctcccaa ccctgccagc ctggtagcca aaagctaaga ataaccacta 178020ggcttttggc acaaactgct ttgtggtttt cagatctccg caaagttgcc tatgatgcca 178080tcttctgggg caggccttga aaagccccct aactgttcat ctcccatcct taaacccctg 178140ctgcccttaa gcagttgaat caactccatg agcacctgct ctaccttccc cagagccctg 178200agacctttgg agctttgaaa agtgataatt ggttgttctc taaatcctca tttccttctc 178260tgcctctaag taagcatgtg gcatcccacc tcggcttcct ggtccagtct tgttcatctt 178320ataaaaaggc ctccctacgg ggtcagaggc ctagacccat caaacccagg gctcctgaaa 178380caataggacc cctattcctc ctgtaggaag ccactgtgtt agagctctca gggtgtctac 178440aaacatctag ataagtgttt ctcaacatgg attctgttga catattggga aaaataattt 178500tgtcattatg tagaatatgg ttaacatacc tggcaccagc ctactctata ccaaatagga 178560ttccagtcat tctgacagcc caaactgctc ccacacattt ctgacaccca ctgaagaggc 178620agtactctcc agttgagtgc aactaatccc tgccagcctt cctaaggtgc taatggggag 178680cctcagaccc aaagagagag agaagaactt gtccaatgta ggtcaaccca tttgctgatc 178740tcttcaacac caagctctat tatcagccct gtttttttct ttctttctct ctttgtagag 178800atcacatgtt gtgaggataa tgagcttgaa ccttagctgt gtgaccttgg gcaaattact 178860gaacttctat gtgccgcaaa ttttatctgg agactgctga agagtattat aatagcacct 178920ttctatatgt catttattga acacctgcta tgtgtcaggc actgtgctca gtgttttcca 178980atcttcattt ctcctcttat tttctctctt gcactcccac caaccttgtt ctcttcctaa 179040attccattcc tgcctcattt ttctaccctc cattctcctc tctcttcctt cctttaactg 179100tctccctagt atttttcccc ttttccccct ttcttttccc cttcccccat gaatttcttc 179160tctttccttt ccccttctct ttcctccatt ccccactttt tctgcccctg aggcctgcag 179220caatgttaaa ggaatcctca ttccagcatt gtgatttcaa tggtaaaaag attgcagcat 179280tgtcatcaac agaggtggga aagtacattg gagactggag cagagccaga cctcagggtc 179340agccaatctt actaaaaaat tctctacagt gaaagagctt ggagcaacac tgttctgctc 179400aattgatttg tgataccatc taaacacttc ctctttctag ttgggcttca gcctgagttg 179460aataattcta caccatctgc cctcttctct ctttctccag gacagccaag atctctctga 179520gataggatgc tgagcttcca cccagacaat accaggcctg ctcatcctat ggagtaggct 179580agtggcttgg aaaccaaaat gtcaaaccat agcctttagg ctccatctgg gaggtctttg 179640tcctcaccac ttaagtgggt gtcaaatttc cttccctttc tgcacacgct gcacaatcaa 179700tttctgtctt acacacacac acacacacac acacacacac gatttttgaa gtgctgaaaa 179760ctggaaggcc tactagcatg aggatgctgt gtcttctctt agaggtatgc catggtcagc 179820catggaaccg agaggttgct cttccttgaa aagctggcca agcattggcc acttccccat 179880ataatttata ggtgataatg tggtgatctg ttcagaagtg actataataa atgcaactca 179940catatgtcta cagtttccaa actgtggtaa ggagcagcca gcatatgagg gaatgggctc 180000cccttcagca ggggacattt aaactagaca ttcaaaaaca ctccctggca gatttaacat 180060tggaactcgt tttgaaagaa caatgtggaa tctccttcac tgggagtttt tgaataagta 180120tgaaatttct agtattccag gccagaggca aaggggtcaa caggatgacc aaacacttcg 180180ggtcatttgc aaatcttgat gtcctgatgt taagagctga ctactggggc ttctcctaaa 180240aatccttcat gttgagctgc ctggaaggca ggttctcatt ctggctgtag ctgagatgtt 180300agaactgtag tcagggagac catgtgcctc ccccattgtg ttcatttggt taggctttcc 180360tgtccctgac tcagaaaaca gaaggggcac agagacctgg aaattccatg tgctaaccca 180420tatcctggcc agagaagatg agtagttatc agggtgtcag gattttggaa aacagagaga 180480gaaaaaaaac aaacaaacag acaaacaaac aaaaaaacct tttcctggtc cctggagcac 180540cagcaggaga aacagcaagc tcttcttgga aaacctggcg agggatggca atcagagaca 180600ttccctctgg gcttattgta aacttcccct cattcctttt tcctctgtgt atctccttcc 180660caggtaccgc atgcacaagt cccggatgta cagccagtgt

gtccgaatga ggcacctctc 180720tcaagagttt ggatggctcc aaatcacccc ccaggaattc ctgtgcatga aagcactgct 180780actcttcagc attagtaagt gcctagaagt gcagggaatg ccccctgagg gcacagagat 180840tcagagagga ccacttttgc cattaaaaca ttattaggga aaagccagct cctggacatt 180900tcccttcttc attccccctc cccatcccca ctctactctc tctcagcatc attttcctaa 180960caagaaacaa tttcatgact agaagccaat ttatttgcta gaagtcaacc tccatcagat 181020tccccaccta tccccagtct gtctttggga caaggccttt ttgactggtt acagcaggtc 181080tctgaatttt tccatagctt ctgctataga aacagacatg ggccaccttg tattctttgc 181140agggcagtag agcaggaggc atttcctcct ggaaagattt cctcttctgc caacaggagg 181200agatctatgt aagcaactca gataggattt gtatggcagc caaggaactt ttctttaata 181260tcttttctaa gagccctctc ttagccccta cggagggaga agggcaaaat ttgatattca 181320aagctatgtg ttttggttat ctaaatcagg gttttactgt gaatgacata aaagcttagg 181380tcctaaaaaa tgagtatctg agaagagtag aaaaagaaaa ggttcaggaa atttgattta 181440cttgactcct ttcagatcgg atccagctat cctttcccct gagatctccc tgacagactg 181500aaggccccaa gcacacagac ttcaactaac aggaagccaa gtagatggtt ccctgtgggg 181560gtgggggtca agtctgtggt cagaaaactt ggtgctttgt ctaatgctcc ttcgtgggca 181620tgcttcccct ccccattctg tcttcatccc acatcagttc cagtggatgg gctgaaaaat 181680caaaaattct ttgatgaact tcgaatgaac tacatcaagg aactcgatcg tatcattgca 181740tgcaaaagaa aaaatcccac atcctgctca agacgcttct accagctcac caagctcctg 181800gactccgtgc agcctgtaag caaacgatgg agggtgcttt atcagggaga acagcctgat 181860agagccaatg ataatatgct tctctagagt ctggcaccac ctgttgggag gtgcttccat 181920tcccctctgg ctttgagtgt ggtccaggaa gaaaatgtgg tgaagaaaag aacacgggtc 181980acagtgtccc agctggatat tgtgaaaggg gtggaggagt tgagaacaga gcagttggga 182040ctcagggaag ggacttgcag cagatgaatt ctctaggcag acaaaacaga cctggatgtt 182100tttcccctct tctttgagtc atgttcatgt gagtttgtct gtctgtgtgt gtgtgtgtgt 182160gtgtgtgtgt gtgtgtgtgt gtgtcagaga gagagagaga gagagagaga tggagtgcgg 182220aggcttgggt gagagcacaa gctggagaag tcttgagtca gagagcttac aatggtataa 182280gacatctctt gggagccctc agtgactcca tggagaccat ttctttctct ctctctcgct 182340gtctctctct aacacacaca cacacacaca cgacctcatg ggggaggacc aaggaagtac 182400ggggaagggg gaggaaacaa aaggctgaaa gaccaaaaat cagaggttgg ggaagaggct 182460agcagaggcc acctccttgt caaccctgtt tttctccctc ttattgttcc ctacagattg 182520cgagagagct gcatcagttc acttttgacc tgctaatcaa gtcacacatg gtgagcgtgg 182580actttccgga aatgatggca gagatcatct ctgtgcaagt gcccaagatc ctttctggga 182640aagtcaagcc catctatttc cacacccagt gaagcattgg aaaccctatt tccccacccc 182700agctcatgcc ccctttcaga tgtcttctgc ctgttataac tctgcactac tcctctgcag 182760tgccttgggg aatttcctct attgatgtac agtctgtcat gaacatgttc ctgaattcta 182820tttgctgggc tttttttttc tctttctctc ctttcttttt cttcttccct ccctatctaa 182880ccctcccatg gcaccttcag actttgcttc ccattgtggc tcctatctgt gttttgaatg 182940gtgttgtatg cctttaaatc tgtgatgatc ctcatatggc ccagtgtcaa gttgtgcttg 183000tttacagcac tactctgtgc cagccacaca aacgtttact tatcttatgc cacgggaagt 183060ttagagagct aagattatct ggggaaatca aaacaaaaac aagcaaacaa aaaaaaaaag 183120caaaaacaaa acaaaaaata agccaaaaaa ccttgctagt gttttttcct caaaaataaa 183180taaataaata aataaatacg tacatacata cacacataca tacaaacata tagaaatccc 183240caaagaggcc aatagtgacg agaaggtgaa aattgcaggc ccatggggag ttactgattt 183300tttcatctcc tccctccacg ggagacttta ttttctgcca atggctattg ccattagagg 183360gcagagtgac cccagagctg agttgggcag gggggtggac agagaggaga ggacaaggag 183420ggcaatggag catcagtacc tgcccacagc cttggtccct gggggctaga ctgctcaact 183480gtggagcaat tcattatact gaaaatgtgc ttgttgttga aaatttgtct gcatgttaat 183540gcctcacccc caaacccttt tctctctcac tctctgcctc caacttcaga ttgactttca 183600atagtttttc taagaccttt gaactgaatg ttctcttcag ccaaaacttg gcgacttcca 183660cagaaaagtc tgaccactga gaagaaggag agcagagatt taaccctttg taaggcccca 183720tttggatcca ggtctgcttt ctcatgtgtg agtcagggag gagctggagc cagaggagaa 183780gaaaatgata gcttggctgt tctcctgctt aggacactga ctgaatagtt aaactctcac 183840tgccactacc ttttccccac ctttaaaaga cctgaatgaa gttttctgcc aaactccgtg 183900aagccacaag caccttatgt cctcccttca gtgttttgtg ggcctgaatt tcatcacact 183960gcatttcagc catggtcatc aagcctgttt gcttcttttg ggcatgttca cagattctct 184020gttaagagcc cccaccacca agaaggttag caggccaaca gctctgacat ctatctgtag 184080atgccagtag tcacaaagat ttcttaccaa ctctcagatc gctggagccc ttagacaaac 184140tggaaagaag gcatcaaagg gatcaggcaa gctgggcgtc ttgcccttgt cccccagaga 184200tgataccctc ccagcaagtg gagaagttct cacttccttc tttagagcag ctaaaggggc 184260tacccagatc agggttgaag agaaaactca attaccaggg tgggaagaat gaaggcacta 184320gaaccagaaa ccctgcaaat gctcttcttg tcacccagca tatccacctg cagaagtcat 184380gagaagagag aaggaacaaa gaggagactc tgactactga attaaaatct tcagcggcaa 184440agcctaaagc cagatggaca ccatctggtg agtttactca tcatcctcct ctgctgctga 184500ttctgggctc tgacattgcc catactcact cagattcccc acctttgttg ctgcctctta 184560gtcagaggga ggccaaacca ttgagacttt ctacagaacc atggcttctt tcggaaaggt 184620ctggttggtg tggctccaat actttgccac ccatgaactc agggtgtgcc ctgggacact 184680ggttttatat agtcttttgg cacacctgtg ttctgttgac ttcgttcttc aagcccaagt 184740gcaagggaaa atgtccacct actttctcat cttggcctct gcctccttac ttagctctta 184800atctcatctg ttgaactcaa gaaatcaagg gccagtcatc aagctgccca ttttaattga 184860ttcactctgt ttgttgagag gatagtttct gagtgacatg atatgatcca caagggtttc 184920cttccctgat ttctgcattg atattaatag ccaaacgaac ttcaaaacag ctttaaataa 184980caagggagag gggaacctaa gatgagtaat atgccaatcc aagactgctg gagaaaacta 185040aagctgacag gttccctttt tggggtggga tagacatgtt ctggttttct ttattattac 185100acaatctggc tcatgtacag gatcactttt agctgtttta aacagaaaaa aatatccacc 185160actcttttca gttacactag gttacatttt aataggtcct ttacatctgt tttggaatga 185220ttttcatctt ttgtgataca cagattgaat tatatcattt tcatatctct ccttgtaaat 185280actagaagct ctcctttaca tttctctatc aaatttttca tctttatggg tttcccaatt 185340gtgactcttg tcttcatgaa tatatgtttt tcatttgcaa aagccaaaaa tcagtgaaac 185400agcagtgtaa ttaaaagcaa caactggatt actccaaatt tccaaatgac aaaactaggg 185460aaaaatagcc tacacaagcc tttaggccta ctctttctgt gcttgggttt gagtgaacaa 185520aggagatttt agcttggctc tgttctccca tggatgaaag gaggaggatt ttttttttct 185580tttggccatt gatgttctag ccaatgtaat tgacagaagt ctcattttgc atgcgctctg 185640ctctacaaac agagttggta tggttggtat actgtactca cctgtgaggg actggccact 185700cagacccact tagctggtga gctagaagat gaggatcact cactggaaaa gtcacaagga 185760ccatctccaa acaagttggc agtgctcgat gtggacgaag agtgaggaag agaaaaagaa 185820ggagcaccag ggagaaggct ccgtctgtgc tgggcagcag acagctgcca ggatcacgaa 185880ctctgtagtc aaagaaaaga gtcgtgtggc agtttcagct ctcgttcatt gggcagctcg 185940cctaggccca gcctctgagc tgacatggga gttgttggat tctttgtttc atagcttttt 186000ctatgccata ggcaatattg ttgttcttgg aaagtttatt atttttttaa ctcccttact 186060ctgagaaagg gatattttga aggactgtca tatatctttg aaaaaagaaa atctgtaata 186120catatatttt tatgtatgtt cactggcact aaaaaatata gagagcttca ttctgtcctt 186180tgggtagttg ctgaggtaat tgtccaggtt gaaaaataat gtgctgatgc tagagtccct 186240ctctgtccat actctacttc taaatacata taggcataca tagcaagttt tatttgactt 186300gtactttaag agaaaatatg tccaccatcc acatgatgca caaatgagct aacattgagc 186360ttcaagtagc ttctaagtgt ttgtttcatt aggcacagca cagatgtggc ctttcccccc 186420ttctctccct tgatatctgg cagggcataa aggcccaggc cacttcctct gccccttccc 186480agccctgcac caaagctgca tttcaggaga ctctctccag acagcccagt aactacccga 186540gcatggcccc tgcatagccc tggaaaaata agaggctgac tgtctacgaa ttatcttgtg 186600ccagttgccc aggtgagagg gcactgggcc aagggagtgg ttttcatgtt tgacccacta 186660caaggggtca tgggaatcag gaatgccaaa gcaccagatc aaatccaaaa cttaaagtca 186720aaataagcca ttcagcatgt tcagtttctt ggaaaaggaa gtttctaccc ctgatgcctt 186780tgtaggcaga tctgttctca ccattaatct ttttgaaaat cttttaaagc agtttttaaa 186840aagagagatg aaagcatcac attatataac caaagattac attgtacctg ctaagatacc 186900aaaattcata agggcagggg gggagcaagc attagtgcct ctttgataag ctgtccaaag 186960acagactaaa ggactctgct ggtgactgac ttataagagc tttgtgggtt tttttttccc 187020taataatata catgtttaga agaattgaaa ataatttcgg gaaaatggga ttatgggtcc 187080ttcactaagt gattttataa gcagaactgg ctttcctttt ctctagtagt tgctgagcaa 187140attgttgaag ctccatcatt gcatggttgg aaatggagct gttcttagcc actgtgtttg 187200ctagtgccca tgttagctta tctgaagatg tgaaaccctt gctgataagg gagcatttaa 187260agtactagat tttgcactag agggacagca ggcagaaatc cttatttctg cccactttgg 187320atggcacaaa aagttatctg cagttgaagg cagaaagttg aaatacattg taaatgaata 187380tttgtatcca tgtttcaaaa ttgaaatata tatatatata tatatatata tatatatata 187440tatatagtgt gtgtgtgtgt tctgatagct ttaactttct ctgcatcttt atatttggtt 187500ccagatcaca cctgatgcca tgtacttgtg agagaggatg cagttttgtt ttggaagctc 187560tctcagaaca aacaagacac ctggattgat cagttaacta aaagttttct cccctattgg 187620gtttgaccca caggtcctgt gaaggagcag agggataaaa agagtagagg acatgataca 187680ttgtacttta ctagttcaag acagatgaat gtggaaagca taaaaactca atggaactga 187740ctgagattta ccacagggaa ggcccaaact tggggccaaa agcctaccca agtgattgac 187800cagtggcccc ctaatgggac ctgagctgtt ggaagaagag aactgttcct tggtcttcac 187860catccttgtg agagaagggc agtttcctgc attggaacct ggagcaagcg ctctatcttt 187920cacacaaatt ccctcacctg agattgaggt gctcttgtta ctgggtgtct gtgtgctgta 187980attctggttt tggatatgtt ctgtaaagat tttgacaaat gaaaatgtgt ttttctctgt 188040taaaacttgt cagagtacta gaagttgtat ctctgtaggt gcaggtccat ttctgcccac 188100aggtagggtg tttttctttg attaagagat tgacacttct gttgcctagg acctcccaac 188160tcaaccattt ctaggtgaag gcagaaaaat ccacattagt tactcctctt cagacatttc 188220agctgagata acaaatcttt tggaattttt tcacccatag aaagagtggt agatatttga 188280atttagcagg tggagtttca tagtaaaaac agcttttgac tcagctttga tttatcctca 188340tttgatttgg ccagaaagta ggtaatatgc attgattggc ttctgattcc aattcagtat 188400agcaaggtgc taggtttttt cctttcccca cctgtctctt agcctgggga attaaatgag 188460aagccttaga atgggtggcc cttgtgacct gaaacacttc ccacataagc tacttaacaa 188520gattgtcatg gagctgcaga ttccattgcc caccaaagac tagaacacac acatatccat 188580acaccaaagg aaagacaatt ctgaaatgct gtttctctgg tggttccctc tctggctgct 188640gcctcacagt atgggaacct gtactctgca gaggtgacag gccagatttg cattatctca 188700caaccttagc ccttggtgct aactgtccta cagtgaagtg cctggggggt tgtcctatcc 188760cataagccac ttggatgctg acagcagcca ccatcagaat gacccacgca aaaaaaagaa 188820aaaaaaaatt aaaaagtccc ctcacaaccc agtgacacct ttctgctttc ctctagactg 188880gaacattgat tagggagtgc ctcagacatg acattcttgt gctgtccttg gaattaatct 188940ggcagcagga gggagcagac tatgtaaaca gagataaaaa ttaattttca atattgaagg 189000aaaaaagaaa taagaagaga gagagaaaga aagcatcaca caaagatttt cttaaaagaa 189060acaattttgc ttgaaatctc tttagatggg gctcatttct cacggtggca cttggcctcc 189120actgggcagc aggaccagct ccaagcgcta gtgttctgtt ctctttttgt aatcttggaa 189180tcttttgttg ctctaaatac aattaaaaat ggcagaaact tgtttgttgg actacatgtg 189240tgactttggg tctgtctctg cctctgcttt cagaaatgtc atccattgtg taaaatattg 189300gcttactggt ctgccagcta aaacttggcc acatcccctg ttatggctgc aggatcgagt 189360tattgttaac aaagagaccc aagaaaagct gctaatgtcc tcttatcatt gttgttaatt 189420tgttaaaaca taaagaaatc taaaatttca gatgaatgtc atcagagttc ttttaattag 189480ctctttttat tggctgtttt tattgaagtc aagagttggt atcatgcccg gttgcgtttt 189540atgctatttt gattttcata tatttttaaa agtctttgca caagggttac aaatttgccc 189600tgtggtggcc ttagcataag ctgacctggg accaccaaaa taacaaggaa tttgggctag 189660aaagcacaga tggacactgg tgacccatca caacttctct tgaaaaaccc caaacttgtc 189720agctggggaa aagccacaca aagcccagct gcccaccttc acatccttat ccttgtagga 189780gcataaaatg gtgtcatcac tgcccagttc taaccaagct tcagttaaag aatgggtacc 189840ttcacatctt cactattttt caggggcctt accgtccttg accacccaag taaaatctaa 189900atcagccttc ttttgggttc ttcagttcaa gcaaggcctc ttcttgtggc ctctcagtat 189960taatatttat gaggttgcag attgaatttt tgggcctgag atacaagcca tcaatgaggt 190020gtgacaaagc atgtcaatga ataataagaa aattatctat tcttccatat cctcccctgt 190080aataagggtt gtcagaatgc cttctttctg ggctgggttg aggattcagt gagaacatat 190140gtgacacagc tggtgggcta ttaagctctg gctttgctcc ctgttaaaat gccagaaccc 190200ttgagaggga tcccacattg agccatgttt atcactgacc accttagaat ggatggattt 190260ctcagatttt tcctgagatc aatgcttgat ggagaggaga ggagaacaat agattcttgg 190320gatgtgtgtt atgcatgtgt ttaagtaaga gacagagagt atgtttattt gcaggttgtg 190380tgtgtaaagt cagagcctgc ctccagagga tcttctctaa ccaccattgc ttaggtcctg 190440ttcgtttgca tctacagcga atgaccttac agccatctga cttggcttca ctcaccactc 190500agctcctgcc taaacagacg aggtggttag catccaccat aagttttcca aggagtagca 190560aagcacaaag gacacctatt gggttgaaaa gagcctagag gcatgagtcc tgtgtgtgac 190620ttgttcatag tcatgcagct agtgtatagc taggattctc ccctgctgat ttactatgtg 190680acactaggca gcaatctgcc cttgctggac ctcggttttc taatctgtaa aatgtgtgga 190740gtaaaactac atgagatggg aagtcccttc tagtgcagat gccatggtta ttgaaaactg 190800cagcaacatc tttcttaatc gtaaggggaa agaaaaagac catttactac tcctagaaca 190860gttttggagc tagaatattc acatttgcac tcaataatta tttacaaaac aactagtgtg 190920gagagggtca aaacaacagc tgagtcctgt gtaatagata ttgtcaaccc cttgatggat 190980gaggaagggg ctcaaaggga a 191001210661DNAHomo sapiensCDS(1116)...(3878) 2cgagatcccg gggagccagc ttgctgggag agcgggacgg tccggagcaa gcccagaggc 60agaggaggcg acagagggaa aaagggccga gctagccgct ccagtgctgt acaggagccg 120aagggacgca ccacgccagc cccagcccgg ctccagcgac agccaacgcc tcttgcagcg 180cggcggcttc gaagccgccg cccggagctg ccctttcctc ttcggtgaag tttttaaaag 240ctgctaaaga ctcggaggaa gcaaggaaag tgcctggtag gactgacggc tgcctttgtc 300ctcctcctct ccaccccgcc tccccccacc ctgccttccc cccctccccc gtcttctctc 360ccgcagctgc ctcagtcggc tactctcagc caacccccct caccaccctt ctccccaccc 420gcccccccgc ccccgtcggc ccagcgctgc cagcccgagt ttgcagagag gtaactccct 480ttggctgcga gcgggcgagc tagctgcaca ttgcaaagaa ggctcttagg agccaggcga 540ctggggagcg gcttcagcac tgcagccacg acccgcctgg ttaggctgca cgcggagaga 600accctctgtt ttcccccact ctctctccac ctcctcctgc cttccccacc ccgagtgcgg 660agccagagat caaaagatga aaaggcagtc aggtcttcag tagccaaaaa acaaaacaaa 720caaaaacaaa aaagccgaaa taaaagaaaa agataataac tcagttctta tttgcaccta 780cttcagtgga cactgaattt ggaaggtgga ggattttgtt tttttctttt aagatctggg 840catcttttga atctaccctt caagtattaa gagacagact gtgagcctag cagggcagat 900cttgtccacc gtgtgtcttc ttctgcacga gactttgagg ctgtcagagc gctttttgcg 960tggttgctcc cgcaagtttc cttctctgga gcttcccgca ggtgggcagc tagctgcagc 1020gactaccgca tcatcacagc ctgttgaact cttctgagca agagaagggg aggcggggta 1080agggaagtag gtggaagatt cagccaagct caagg atg gaa gtg cag tta ggg 1133 Met Glu Val Gln Leu Gly 1 5ctg gga agg gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct 1181Leu Gly Arg Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala 10 15 20ttc cag aat ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc 1229Phe Gln Asn Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly 25 30 35ccc agg cac cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg 1277Pro Arg His Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu 40 45 50ctg ctg ctg cag cag cag cag cag cag cag cag cag cag cag cag cag 1325Leu Leu Leu Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 55 60 65 70cag cag cag cag cag cag cag cag cag caa gag act agc ccc agg cag 1373Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro Arg Gln 75 80 85cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat cgt aga 1421Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His Arg Arg 90 95 100ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct tca cag 1469Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro Ser Gln 105 110 115ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc cca gag 1517Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val Pro Glu 120 125 130cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag ctg cca 1565Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln Leu Pro135 140 145 150gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg tcc ctg 1613Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu Ser Leu 155 160 165ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac ctt aaa 1661Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp Leu Lys 170 175 180gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa cag cag 1709Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln Gln Gln 185 190 195cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg gag gcc 1757Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg Glu Ala 200 205 210tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc act tcg 1805Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly Thr Ser215 220 225 230acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg gtg tcc 1853Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser Val Ser 235 240 245atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg gaa cag 1901Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly Glu Gln 250 255 260ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca ccc gct 1949Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro Pro Ala 265 270 275gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt tct ctg 1997Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly Ser Leu 280 285 290cta gac gac agc gca ggc aag agc act gaa gat act gct gag tat tcc 2045Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu Tyr Ser295 300 305 310cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc cta ggc 2093Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser Leu Gly 315 320 325tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa ctg ccg 2141Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu Leu Pro 330 335 340tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca gct gcg 2189Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala Ala Ala 345 350 355tac cag

agt cgc gac tac tac aac ttt cca ctg gct ctg gcc gga ccg 2237Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala Gly Pro 360 365 370ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag ctg gag 2285Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys Leu Glu375 380 385 390aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg cag tgc 2333Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala Gln Cys 395 400 405cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg gga ccc 2381Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala Gly Pro 410 415 420ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac act ctc 2429Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His Thr Leu 425 430 435ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt ggt ggg 2477Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly Gly Gly 440 445 450ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 2525Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly455 460 465 470ggc ggc ggc gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc 2573Gly Gly Gly Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro 475 480 485cct cag ggg ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg 2621Pro Gln Gly Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val 490 495 500tgg tac cct ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act 2669Trp Tyr Pro Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr 505 510 515tgt gtc aaa agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct 2717Cys Val Lys Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro 520 525 530tac ggg gac atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att 2765Tyr Gly Asp Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile535 540 545 550gac tat tac ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa 2813Asp Tyr Tyr Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu 555 560 565gct tct ggg tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc 2861Ala Ser Gly Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val 570 575 580ttc ttc aaa aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc 2909Phe Phe Lys Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser 585 590 595aga aat gat tgc act att gat aaa ttc cga agg aaa aat tgt cca tct 2957Arg Asn Asp Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser 600 605 610tgt cgt ctt cgg aaa tgt tat gaa gca ggg atg act ctg gga gcc cgg 3005Cys Arg Leu Arg Lys Cys Tyr Glu Ala Gly Met Thr Leu Gly Ala Arg615 620 625 630aag ctg aag aaa ctt ggt aat ctg aaa cta cag gag gaa gga gag gct 3053Lys Leu Lys Lys Leu Gly Asn Leu Lys Leu Gln Glu Glu Gly Glu Ala 635 640 645tcc agc acc acc agc ccc act gag gag aca acc cag aag ctg aca gtg 3101Ser Ser Thr Thr Ser Pro Thr Glu Glu Thr Thr Gln Lys Leu Thr Val 650 655 660tca cac att gaa ggc tat gaa tgt cag ccc atc ttt ctg aat gtc ctg 3149Ser His Ile Glu Gly Tyr Glu Cys Gln Pro Ile Phe Leu Asn Val Leu 665 670 675gaa gcc att gag cca ggt gta gtg tgt gct gga cac gac aac aac cag 3197Glu Ala Ile Glu Pro Gly Val Val Cys Ala Gly His Asp Asn Asn Gln 680 685 690ccc gac tcc ttt gca gcc ttg ctc tct agc ctc aat gaa ctg gga gag 3245Pro Asp Ser Phe Ala Ala Leu Leu Ser Ser Leu Asn Glu Leu Gly Glu695 700 705 710aga cag ctt gta cac gtg gtc aag tgg gcc aag gcc ttg cct ggc ttc 3293Arg Gln Leu Val His Val Val Lys Trp Ala Lys Ala Leu Pro Gly Phe 715 720 725cgc aac tta cac gtg gac gac cag atg gct gtc att cag tac tcc tgg 3341Arg Asn Leu His Val Asp Asp Gln Met Ala Val Ile Gln Tyr Ser Trp 730 735 740atg ggg ctc atg gtg ttt gcc atg ggc tgg cga tcc ttc acc aat gtc 3389Met Gly Leu Met Val Phe Ala Met Gly Trp Arg Ser Phe Thr Asn Val 745 750 755aac tcc agg atg ctc tac ttc gcc cct gat ctg gtt ttc aat gag tac 3437Asn Ser Arg Met Leu Tyr Phe Ala Pro Asp Leu Val Phe Asn Glu Tyr 760 765 770cgc atg cac aag tcc cgg atg tac agc cag tgt gtc cga atg agg cac 3485Arg Met His Lys Ser Arg Met Tyr Ser Gln Cys Val Arg Met Arg His775 780 785 790ctc tct caa gag ttt gga tgg ctc caa atc acc ccc cag gaa ttc ctg 3533Leu Ser Gln Glu Phe Gly Trp Leu Gln Ile Thr Pro Gln Glu Phe Leu 795 800 805tgc atg aaa gca ctg cta ctc ttc agc att att cca gtg gat ggg ctg 3581Cys Met Lys Ala Leu Leu Leu Phe Ser Ile Ile Pro Val Asp Gly Leu 810 815 820aaa aat caa aaa ttc ttt gat gaa ctt cga atg aac tac atc aag gaa 3629Lys Asn Gln Lys Phe Phe Asp Glu Leu Arg Met Asn Tyr Ile Lys Glu 825 830 835ctc gat cgt atc att gca tgc aaa aga aaa aat ccc aca tcc tgc tca 3677Leu Asp Arg Ile Ile Ala Cys Lys Arg Lys Asn Pro Thr Ser Cys Ser 840 845 850aga cgc ttc tac cag ctc acc aag ctc ctg gac tcc gtg cag cct att 3725Arg Arg Phe Tyr Gln Leu Thr Lys Leu Leu Asp Ser Val Gln Pro Ile855 860 865 870gcg aga gag ctg cat cag ttc act ttt gac ctg cta atc aag tca cac 3773Ala Arg Glu Leu His Gln Phe Thr Phe Asp Leu Leu Ile Lys Ser His 875 880 885atg gtg agc gtg gac ttt ccg gaa atg atg gca gag atc atc tct gtg 3821Met Val Ser Val Asp Phe Pro Glu Met Met Ala Glu Ile Ile Ser Val 890 895 900caa gtg ccc aag atc ctt tct ggg aaa gtc aag ccc atc tat ttc cac 3869Gln Val Pro Lys Ile Leu Ser Gly Lys Val Lys Pro Ile Tyr Phe His 905 910 915acc cag tga agcattggaa accctatttc cccaccccag ctcatgcccc 3918Thr Gln 920ctttcagatg tcttctgcct gttataactc tgcactactc ctctgcagtg ccttggggaa 3978tttcctctat tgatgtacag tctgtcatga acatgttcct gaattctatt tgctgggctt 4038tttttttctc tttctctcct ttctttttct tcttccctcc ctatctaacc ctcccatggc 4098accttcagac tttgcttccc attgtggctc ctatctgtgt tttgaatggt gttgtatgcc 4158tttaaatctg tgatgatcct catatggccc agtgtcaagt tgtgcttgtt tacagcacta 4218ctctgtgcca gccacacaaa cgtttactta tcttatgcca cgggaagttt agagagctaa 4278gattatctgg ggaaatcaaa acaaaaacaa gcaaacaaaa aaaaaaagca aaaacaaaac 4338aaaaaataag ccaaaaaacc ttgctagtgt tttttcctca aaaataaata aataaataaa 4398taaatacgta catacataca cacatacata caaacatata gaaatcccca aagaggccaa 4458tagtgacgag aaggtgaaaa ttgcaggccc atggggagtt actgattttt tcatctcctc 4518cctccacggg agactttatt ttctgccaat ggctattgcc attagagggc agagtgaccc 4578cagagctgag ttgggcaggg gggtggacag agaggagagg acaaggaggg caatggagca 4638tcagtacctg cccacagcct tggtccctgg gggctagact gctcaactgt ggagcaattc 4698attatactga aaatgtgctt gttgttgaaa atttgtctgc atgttaatgc ctcaccccca 4758aacccttttc tctctcactc tctgcctcca acttcagatt gactttcaat agtttttcta 4818agacctttga actgaatgtt ctcttcagcc aaaacttggc gacttccaca gaaaagtctg 4878accactgaga agaaggagag cagagattta accctttgta aggccccatt tggatccagg 4938tctgctttct catgtgtgag tcagggagga gctggagcca gaggagaaga aaatgatagc 4998ttggctgttc tcctgcttag gacactgact gaatagttaa actctcactg ccactacctt 5058ttccccacct ttaaaagacc tgaatgaagt tttctgccaa actccgtgaa gccacaagca 5118ccttatgtcc tcccttcagt gttttgtggg cctgaatttc atcacactgc atttcagcca 5178tggtcatcaa gcctgtttgc ttcttttggg catgttcaca gattctctgt taagagcccc 5238caccaccaag aaggttagca ggccaacagc tctgacatct atctgtagat gccagtagtc 5298acaaagattt cttaccaact ctcagatcgc tggagccctt agacaaactg gaaagaaggc 5358atcaaaggga tcaggcaagc tgggcgtctt gcccttgtcc cccagagatg ataccctccc 5418agcaagtgga gaagttctca cttccttctt tagagcagct aaaggggcta cccagatcag 5478ggttgaagag aaaactcaat taccagggtg ggaagaatga aggcactaga accagaaacc 5538ctgcaaatgc tcttcttgtc acccagcata tccacctgca gaagtcatga gaagagagaa 5598ggaacaaaga ggagactctg actactgaat taaaatcttc agcggcaaag cctaaagcca 5658gatggacacc atctggtgag tttactcatc atcctcctct gctgctgatt ctgggctctg 5718acattgccca tactcactca gattccccac ctttgttgct gcctcttagt cagagggagg 5778ccaaaccatt gagactttct acagaaccat ggcttctttc ggaaaggtct ggttggtgtg 5838gctccaatac tttgccaccc atgaactcag ggtgtgccct gggacactgg ttttatatag 5898tcttttggca cacctgtgtt ctgttgactt cgttcttcaa gcccaagtgc aagggaaaat 5958gtccacctac tttctcatct tggcctctgc ctccttactt agctcttaat ctcatctgtt 6018gaactcaaga aatcaagggc cagtcatcaa gctgcccatt ttaattgatt cactctgttt 6078gttgagagga tagtttctga gtgacatgat atgatccaca agggtttcct tccctgattt 6138ctgcattgat attaatagcc aaacgaactt caaaacagct ttaaataaca agggagaggg 6198gaacctaaga tgagtaatat gccaatccaa gactgctgga gaaaactaaa gctgacaggt 6258tccctttttg gggtgggata gacatgttct ggttttcttt attattacac aatctggctc 6318atgtacagga tcacttttag ctgttttaaa cagaaaaaaa tatccaccac tcttttcagt 6378tacactaggt tacattttaa taggtccttt acatctgttt tggaatgatt ttcatctttt 6438gtgatacaca gattgaatta tatcattttc atatctctcc ttgtaaatac tagaagctct 6498cctttacatt tctctatcaa atttttcatc tttatgggtt tcccaattgt gactcttgtc 6558ttcatgaata tatgtttttc atttgcaaaa gccaaaaatc agtgaaacag cagtgtaatt 6618aaaagcaaca actggattac tccaaatttc caaatgacaa aactagggaa aaatagccta 6678cacaagcctt taggcctact ctttctgtgc ttgggtttga gtgaacaaag gagattttag 6738cttggctctg ttctcccatg gatgaaagga ggaggatttt ttttttcttt tggccattga 6798tgttctagcc aatgtaattg acagaagtct cattttgcat gcgctctgct ctacaaacag 6858agttggtatg gttggtatac tgtactcacc tgtgagggac tggccactca gacccactta 6918gctggtgagc tagaagatga ggatcactca ctggaaaagt cacaaggacc atctccaaac 6978aagttggcag tgctcgatgt ggacgaagag tgaggaagag aaaaagaagg agcaccaggg 7038agaaggctcc gtctgtgctg ggcagcagac agctgccagg atcacgaact ctgtagtcaa 7098agaaaagagt cgtgtggcag tttcagctct cgttcattgg gcagctcgcc taggcccagc 7158ctctgagctg acatgggagt tgttggattc tttgtttcat agctttttct atgccatagg 7218caatattgtt gttcttggaa agtttattat ttttttaact cccttactct gagaaaggga 7278tattttgaag gactgtcata tatctttgaa aaaagaaaat ctgtaataca tatattttta 7338tgtatgttca ctggcactaa aaaatataga gagcttcatt ctgtcctttg ggtagttgct 7398gaggtaattg tccaggttga aaaataatgt gctgatgcta gagtccctct ctgtccatac 7458tctacttcta aatacatata ggcatacata gcaagtttta tttgacttgt actttaagag 7518aaaatatgtc caccatccac atgatgcaca aatgagctaa cattgagctt caagtagctt 7578ctaagtgttt gtttcattag gcacagcaca gatgtggcct ttcccccctt ctctcccttg 7638atatctggca gggcataaag gcccaggcca cttcctctgc cccttcccag ccctgcacca 7698aagctgcatt tcaggagact ctctccagac agcccagtaa ctacccgagc atggcccctg 7758catagccctg gaaaaataag aggctgactg tctacgaatt atcttgtgcc agttgcccag 7818gtgagagggc actgggccaa gggagtggtt ttcatgtttg acccactaca aggggtcatg 7878ggaatcagga atgccaaagc accagatcaa atccaaaact taaagtcaaa ataagccatt 7938cagcatgttc agtttcttgg aaaaggaagt ttctacccct gatgcctttg taggcagatc 7998tgttctcacc attaatcttt ttgaaaatct tttaaagcag tttttaaaaa gagagatgaa 8058agcatcacat tatataacca aagattacat tgtacctgct aagataccaa aattcataag 8118ggcagggggg gagcaagcat tagtgcctct ttgataagct gtccaaagac agactaaagg 8178actctgctgg tgactgactt ataagagctt tgtgggtttt tttttcccta ataatataca 8238tgtttagaag aattgaaaat aatttcggga aaatgggatt atgggtcctt cactaagtga 8298ttttataagc agaactggct ttccttttct ctagtagttg ctgagcaaat tgttgaagct 8358ccatcattgc atggttggaa atggagctgt tcttagccac tgtgtttgct agtgcccatg 8418ttagcttatc tgaagatgtg aaacccttgc tgataaggga gcatttaaag tactagattt 8478tgcactagag ggacagcagg cagaaatcct tatttctgcc cactttggat ggcacaaaaa 8538gttatctgca gttgaaggca gaaagttgaa atacattgta aatgaatatt tgtatccatg 8598tttcaaaatt gaaatatata tatatatata tatatatata tatatatata tatagtgtgt 8658gtgtgtgttc tgatagcttt aactttctct gcatctttat atttggttcc agatcacacc 8718tgatgccatg tacttgtgag agaggatgca gttttgtttt ggaagctctc tcagaacaaa 8778caagacacct ggattgatca gttaactaaa agttttctcc cctattgggt ttgacccaca 8838ggtcctgtga aggagcagag ggataaaaag agtagaggac atgatacatt gtactttact 8898agttcaagac agatgaatgt ggaaagcata aaaactcaat ggaactgact gagatttacc 8958acagggaagg cccaaacttg gggccaaaag cctacccaag tgattgacca gtggccccct 9018aatgggacct gagctgttgg aagaagagaa ctgttccttg gtcttcacca tccttgtgag 9078agaagggcag tttcctgcat tggaacctgg agcaagcgct ctatctttca cacaaattcc 9138ctcacctgag attgaggtgc tcttgttact gggtgtctgt gtgctgtaat tctggttttg 9198gatatgttct gtaaagattt tgacaaatga aaatgtgttt ttctctgtta aaacttgtca 9258gagtactaga agttgtatct ctgtaggtgc aggtccattt ctgcccacag gtagggtgtt 9318tttctttgat taagagattg acacttctgt tgcctaggac ctcccaactc aaccatttct 9378aggtgaaggc agaaaaatcc acattagtta ctcctcttca gacatttcag ctgagataac 9438aaatcttttg gaattttttc acccatagaa agagtggtag atatttgaat ttagcaggtg 9498gagtttcata gtaaaaacag cttttgactc agctttgatt tatcctcatt tgatttggcc 9558agaaagtagg taatatgcat tgattggctt ctgattccaa ttcagtatag caaggtgcta 9618ggttttttcc tttccccacc tgtctcttag cctggggaat taaatgagaa gccttagaat 9678gggtggccct tgtgacctga aacacttccc acataagcta cttaacaaga ttgtcatgga 9738gctgcagatt ccattgccca ccaaagacta gaacacacac atatccatac accaaaggaa 9798agacaattct gaaatgctgt ttctctggtg gttccctctc tggctgctgc ctcacagtat 9858gggaacctgt actctgcaga ggtgacaggc cagatttgca ttatctcaca accttagccc 9918ttggtgctaa ctgtcctaca gtgaagtgcc tggggggttg tcctatccca taagccactt 9978ggatgctgac agcagccacc atcagaatga cccacgcaaa aaaaagaaaa aaaaaattaa 10038aaagtcccct cacaacccag tgacaccttt ctgctttcct ctagactgga acattgatta 10098gggagtgcct cagacatgac attcttgtgc tgtccttgga attaatctgg cagcaggagg 10158gagcagacta tgtaaacaga gataaaaatt aattttcaat attgaaggaa aaaagaaata 10218agaagagaga gagaaagaaa gcatcacaca aagattttct taaaagaaac aattttgctt 10278gaaatctctt tagatggggc tcatttctca cggtggcact tggcctccac tgggcagcag 10338gaccagctcc aagcgctagt gttctgttct ctttttgtaa tcttggaatc ttttgttgct 10398ctaaatacaa ttaaaaatgg cagaaacttg tttgttggac tacatgtgtg actttgggtc 10458tgtctctgcc tctgctttca gaaatgtcat ccattgtgta aaatattggc ttactggtct 10518gccagctaaa acttggccac atcccctgtt atggctgcag gatcgagtta ttgttaacaa 10578agagacccaa gaaaagctgc taatgtcctc ttatcattgt tgttaatttg ttaaaacata 10638aagaaatcta aaatttcaaa aaa 1066138112DNAHomo sapiensCDS(163)...(1329) 3gctgcgagca gagagggatt cctcggaggt catctgttcc atcttcttgc ctatgcaaat 60gcctgcctga agctgctgga ggctggcttt gtaccggact ttgtacaggg aaccagggaa 120acgaatgcag agtgctcctg acattgcctg tcactttttc cc atg ata ctc tgg 174 Met Ile Leu Trp 1ctt cac agt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat 222Leu His Ser Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr 5 10 15 20tac ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa gct tct 270Tyr Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser 25 30 35ggg tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc 318Gly Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe 40 45 50aaa aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc aga aat 366Lys Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser Arg Asn 55 60 65gat tgc act att gat aaa ttc cga agg aaa aat tgt cca tct tgt cgt 414Asp Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser Cys Arg 70 75 80ctt cgg aaa tgt tat gaa gca ggg atg act ctg gga gcc cgg aag ctg 462Leu Arg Lys Cys Tyr Glu Ala Gly Met Thr Leu Gly Ala Arg Lys Leu 85 90 95 100aag aaa ctt ggt aat ctg aaa cta cag gag gaa gga gag gct tcc agc 510Lys Lys Leu Gly Asn Leu Lys Leu Gln Glu Glu Gly Glu Ala Ser Ser 105 110 115acc acc agc ccc act gag gag aca acc cag aag ctg aca gtg tca cac 558Thr Thr Ser Pro Thr Glu Glu Thr Thr Gln Lys Leu Thr Val Ser His 120 125 130att gaa ggc tat gaa tgt cag ccc atc ttt ctg aat gtc ctg gaa gcc 606Ile Glu Gly Tyr Glu Cys Gln Pro Ile Phe Leu Asn Val Leu Glu Ala 135 140 145att gag cca ggt gta gtg tgt gct gga cac gac aac aac cag ccc gac 654Ile Glu Pro Gly Val Val Cys Ala Gly His Asp Asn Asn Gln Pro Asp 150 155 160tcc ttt gca gcc ttg ctc tct agc ctc aat gaa ctg gga gag aga cag 702Ser Phe Ala Ala Leu Leu Ser Ser Leu Asn Glu Leu Gly Glu Arg Gln165 170 175 180ctt gta cac gtg gtc aag tgg gcc aag gcc ttg cct ggc ttc cgc aac 750Leu Val His Val Val Lys Trp Ala Lys Ala Leu Pro Gly Phe Arg Asn 185 190 195tta cac gtg gac gac cag atg gct gtc att cag tac tcc tgg atg ggg 798Leu His Val Asp Asp Gln Met Ala Val Ile Gln Tyr Ser Trp Met Gly 200 205 210ctc atg gtg ttt gcc atg ggc tgg cga tcc ttc acc aat gtc aac tcc 846Leu Met Val Phe Ala Met Gly Trp Arg Ser Phe Thr Asn Val Asn Ser 215 220 225agg atg ctc tac ttc gcc cct gat ctg gtt ttc aat gag tac cgc atg 894Arg Met Leu Tyr Phe Ala Pro Asp Leu Val Phe Asn Glu Tyr Arg Met 230 235 240cac aag tcc cgg atg tac agc cag tgt gtc cga atg agg cac ctc tct 942His Lys Ser Arg Met Tyr Ser Gln Cys Val Arg

Met Arg His Leu Ser245 250 255 260caa gag ttt gga tgg ctc caa atc acc ccc cag gaa ttc ctg tgc atg 990Gln Glu Phe Gly Trp Leu Gln Ile Thr Pro Gln Glu Phe Leu Cys Met 265 270 275aaa gca ctg cta ctc ttc agc att att cca gtg gat ggg ctg aaa aat 1038Lys Ala Leu Leu Leu Phe Ser Ile Ile Pro Val Asp Gly Leu Lys Asn 280 285 290caa aaa ttc ttt gat gaa ctt cga atg aac tac atc aag gaa ctc gat 1086Gln Lys Phe Phe Asp Glu Leu Arg Met Asn Tyr Ile Lys Glu Leu Asp 295 300 305cgt atc att gca tgc aaa aga aaa aat ccc aca tcc tgc tca aga cgc 1134Arg Ile Ile Ala Cys Lys Arg Lys Asn Pro Thr Ser Cys Ser Arg Arg 310 315 320ttc tac cag ctc acc aag ctc ctg gac tcc gtg cag cct att gcg aga 1182Phe Tyr Gln Leu Thr Lys Leu Leu Asp Ser Val Gln Pro Ile Ala Arg325 330 335 340gag ctg cat cag ttc act ttt gac ctg cta atc aag tca cac atg gtg 1230Glu Leu His Gln Phe Thr Phe Asp Leu Leu Ile Lys Ser His Met Val 345 350 355agc gtg gac ttt ccg gaa atg atg gca gag atc atc tct gtg caa gtg 1278Ser Val Asp Phe Pro Glu Met Met Ala Glu Ile Ile Ser Val Gln Val 360 365 370ccc aag atc ctt tct ggg aaa gtc aag ccc atc tat ttc cac acc cag 1326Pro Lys Ile Leu Ser Gly Lys Val Lys Pro Ile Tyr Phe His Thr Gln 375 380 385tga agcattggaa accctatttc cccaccccag ctcatgcccc ctttcagatg 1379tcttctgcct gttataactc tgcactactc ctctgcagtg ccttggggaa tttcctctat 1439tgatgtacag tctgtcatga acatgttcct gaattctatt tgctgggctt tttttttctc 1499tttctctcct ttctttttct tcttccctcc ctatctaacc ctcccatggc accttcagac 1559tttgcttccc attgtggctc ctatctgtgt tttgaatggt gttgtatgcc tttaaatctg 1619tgatgatcct catatggccc agtgtcaagt tgtgcttgtt tacagcacta ctctgtgcca 1679gccacacaaa cgtttactta tcttatgcca cgggaagttt agagagctaa gattatctgg 1739ggaaatcaaa acaaaaacaa gcaaacaaaa aaaaaaagca aaaacaaaac aaaaaataag 1799ccaaaaaacc ttgctagtgt tttttcctca aaaataaata aataaataaa taaatacgta 1859catacataca cacatacata caaacatata gaaatcccca aagaggccaa tagtgacgag 1919aaggtgaaaa ttgcaggccc atggggagtt actgattttt tcatctcctc cctccacggg 1979agactttatt ttctgccaat ggctattgcc attagagggc agagtgaccc cagagctgag 2039ttgggcaggg gggtggacag agaggagagg acaaggaggg caatggagca tcagtacctg 2099cccacagcct tggtccctgg gggctagact gctcaactgt ggagcaattc attatactga 2159aaatgtgctt gttgttgaaa atttgtctgc atgttaatgc ctcaccccca aacccttttc 2219tctctcactc tctgcctcca acttcagatt gactttcaat agtttttcta agacctttga 2279actgaatgtt ctcttcagcc aaaacttggc gacttccaca gaaaagtctg accactgaga 2339agaaggagag cagagattta accctttgta aggccccatt tggatccagg tctgctttct 2399catgtgtgag tcagggagga gctggagcca gaggagaaga aaatgatagc ttggctgttc 2459tcctgcttag gacactgact gaatagttaa actctcactg ccactacctt ttccccacct 2519ttaaaagacc tgaatgaagt tttctgccaa actccgtgaa gccacaagca ccttatgtcc 2579tcccttcagt gttttgtggg cctgaatttc atcacactgc atttcagcca tggtcatcaa 2639gcctgtttgc ttcttttggg catgttcaca gattctctgt taagagcccc caccaccaag 2699aaggttagca ggccaacagc tctgacatct atctgtagat gccagtagtc acaaagattt 2759cttaccaact ctcagatcgc tggagccctt agacaaactg gaaagaaggc atcaaaggga 2819tcaggcaagc tgggcgtctt gcccttgtcc cccagagatg ataccctccc agcaagtgga 2879gaagttctca cttccttctt tagagcagct aaaggggcta cccagatcag ggttgaagag 2939aaaactcaat taccagggtg ggaagaatga aggcactaga accagaaacc ctgcaaatgc 2999tcttcttgtc acccagcata tccacctgca gaagtcatga gaagagagaa ggaacaaaga 3059ggagactctg actactgaat taaaatcttc agcggcaaag cctaaagcca gatggacacc 3119atctggtgag tttactcatc atcctcctct gctgctgatt ctgggctctg acattgccca 3179tactcactca gattccccac ctttgttgct gcctcttagt cagagggagg ccaaaccatt 3239gagactttct acagaaccat ggcttctttc ggaaaggtct ggttggtgtg gctccaatac 3299tttgccaccc atgaactcag ggtgtgccct gggacactgg ttttatatag tcttttggca 3359cacctgtgtt ctgttgactt cgttcttcaa gcccaagtgc aagggaaaat gtccacctac 3419tttctcatct tggcctctgc ctccttactt agctcttaat ctcatctgtt gaactcaaga 3479aatcaagggc cagtcatcaa gctgcccatt ttaattgatt cactctgttt gttgagagga 3539tagtttctga gtgacatgat atgatccaca agggtttcct tccctgattt ctgcattgat 3599attaatagcc aaacgaactt caaaacagct ttaaataaca agggagaggg gaacctaaga 3659tgagtaatat gccaatccaa gactgctgga gaaaactaaa gctgacaggt tccctttttg 3719gggtgggata gacatgttct ggttttcttt attattacac aatctggctc atgtacagga 3779tcacttttag ctgttttaaa cagaaaaaaa tatccaccac tcttttcagt tacactaggt 3839tacattttaa taggtccttt acatctgttt tggaatgatt ttcatctttt gtgatacaca 3899gattgaatta tatcattttc atatctctcc ttgtaaatac tagaagctct cctttacatt 3959tctctatcaa atttttcatc tttatgggtt tcccaattgt gactcttgtc ttcatgaata 4019tatgtttttc atttgcaaaa gccaaaaatc agtgaaacag cagtgtaatt aaaagcaaca 4079actggattac tccaaatttc caaatgacaa aactagggaa aaatagccta cacaagcctt 4139taggcctact ctttctgtgc ttgggtttga gtgaacaaag gagattttag cttggctctg 4199ttctcccatg gatgaaagga ggaggatttt ttttttcttt tggccattga tgttctagcc 4259aatgtaattg acagaagtct cattttgcat gcgctctgct ctacaaacag agttggtatg 4319gttggtatac tgtactcacc tgtgagggac tggccactca gacccactta gctggtgagc 4379tagaagatga ggatcactca ctggaaaagt cacaaggacc atctccaaac aagttggcag 4439tgctcgatgt ggacgaagag tgaggaagag aaaaagaagg agcaccaggg agaaggctcc 4499gtctgtgctg ggcagcagac agctgccagg atcacgaact ctgtagtcaa agaaaagagt 4559cgtgtggcag tttcagctct cgttcattgg gcagctcgcc taggcccagc ctctgagctg 4619acatgggagt tgttggattc tttgtttcat agctttttct atgccatagg caatattgtt 4679gttcttggaa agtttattat ttttttaact cccttactct gagaaaggga tattttgaag 4739gactgtcata tatctttgaa aaaagaaaat ctgtaataca tatattttta tgtatgttca 4799ctggcactaa aaaatataga gagcttcatt ctgtcctttg ggtagttgct gaggtaattg 4859tccaggttga aaaataatgt gctgatgcta gagtccctct ctgtccatac tctacttcta 4919aatacatata ggcatacata gcaagtttta tttgacttgt actttaagag aaaatatgtc 4979caccatccac atgatgcaca aatgagctaa cattgagctt caagtagctt ctaagtgttt 5039gtttcattag gcacagcaca gatgtggcct ttcccccctt ctctcccttg atatctggca 5099gggcataaag gcccaggcca cttcctctgc cccttcccag ccctgcacca aagctgcatt 5159tcaggagact ctctccagac agcccagtaa ctacccgagc atggcccctg catagccctg 5219gaaaaataag aggctgactg tctacgaatt atcttgtgcc agttgcccag gtgagagggc 5279actgggccaa gggagtggtt ttcatgtttg acccactaca aggggtcatg ggaatcagga 5339atgccaaagc accagatcaa atccaaaact taaagtcaaa ataagccatt cagcatgttc 5399agtttcttgg aaaaggaagt ttctacccct gatgcctttg taggcagatc tgttctcacc 5459attaatcttt ttgaaaatct tttaaagcag tttttaaaaa gagagatgaa agcatcacat 5519tatataacca aagattacat tgtacctgct aagataccaa aattcataag ggcagggggg 5579gagcaagcat tagtgcctct ttgataagct gtccaaagac agactaaagg actctgctgg 5639tgactgactt ataagagctt tgtgggtttt tttttcccta ataatataca tgtttagaag 5699aattgaaaat aatttcggga aaatgggatt atgggtcctt cactaagtga ttttataagc 5759agaactggct ttccttttct ctagtagttg ctgagcaaat tgttgaagct ccatcattgc 5819atggttggaa atggagctgt tcttagccac tgtgtttgct agtgcccatg ttagcttatc 5879tgaagatgtg aaacccttgc tgataaggga gcatttaaag tactagattt tgcactagag 5939ggacagcagg cagaaatcct tatttctgcc cactttggat ggcacaaaaa gttatctgca 5999gttgaaggca gaaagttgaa atacattgta aatgaatatt tgtatccatg tttcaaaatt 6059gaaatatata tatatatata tatatatata tatatatata tatagtgtgt gtgtgtgttc 6119tgatagcttt aactttctct gcatctttat atttggttcc agatcacacc tgatgccatg 6179tacttgtgag agaggatgca gttttgtttt ggaagctctc tcagaacaaa caagacacct 6239ggattgatca gttaactaaa agttttctcc cctattgggt ttgacccaca ggtcctgtga 6299aggagcagag ggataaaaag agtagaggac atgatacatt gtactttact agttcaagac 6359agatgaatgt ggaaagcata aaaactcaat ggaactgact gagatttacc acagggaagg 6419cccaaacttg gggccaaaag cctacccaag tgattgacca gtggccccct aatgggacct 6479gagctgttgg aagaagagaa ctgttccttg gtcttcacca tccttgtgag agaagggcag 6539tttcctgcat tggaacctgg agcaagcgct ctatctttca cacaaattcc ctcacctgag 6599attgaggtgc tcttgttact gggtgtctgt gtgctgtaat tctggttttg gatatgttct 6659gtaaagattt tgacaaatga aaatgtgttt ttctctgtta aaacttgtca gagtactaga 6719agttgtatct ctgtaggtgc aggtccattt ctgcccacag gtagggtgtt tttctttgat 6779taagagattg acacttctgt tgcctaggac ctcccaactc aaccatttct aggtgaaggc 6839agaaaaatcc acattagtta ctcctcttca gacatttcag ctgagataac aaatcttttg 6899gaattttttc acccatagaa agagtggtag atatttgaat ttagcaggtg gagtttcata 6959gtaaaaacag cttttgactc agctttgatt tatcctcatt tgatttggcc agaaagtagg 7019taatatgcat tgattggctt ctgattccaa ttcagtatag caaggtgcta ggttttttcc 7079tttccccacc tgtctcttag cctggggaat taaatgagaa gccttagaat gggtggccct 7139tgtgacctga aacacttccc acataagcta cttaacaaga ttgtcatgga gctgcagatt 7199ccattgccca ccaaagacta gaacacacac atatccatac accaaaggaa agacaattct 7259gaaatgctgt ttctctggtg gttccctctc tggctgctgc ctcacagtat gggaacctgt 7319actctgcaga ggtgacaggc cagatttgca ttatctcaca accttagccc ttggtgctaa 7379ctgtcctaca gtgaagtgcc tggggggttg tcctatccca taagccactt ggatgctgac 7439agcagccacc atcagaatga cccacgcaaa aaaaagaaaa aaaaaattaa aaagtcccct 7499cacaacccag tgacaccttt ctgctttcct ctagactgga acattgatta gggagtgcct 7559cagacatgac attcttgtgc tgtccttgga attaatctgg cagcaggagg gagcagacta 7619tgtaaacaga gataaaaatt aattttcaat attgaaggaa aaaagaaata agaagagaga 7679gagaaagaaa gcatcacaca aagattttct taaaagaaac aattttgctt gaaatctctt 7739tagatggggc tcatttctca cggtggcact tggcctccac tgggcagcag gaccagctcc 7799aagcgctagt gttctgttct ctttttgtaa tcttggaatc ttttgttgct ctaaatacaa 7859ttaaaaatgg cagaaacttg tttgttggac tacatgtgtg actttgggtc tgtctctgcc 7919tctgctttca gaaatgtcat ccattgtgta aaatattggc ttactggtct gccagctaaa 7979acttggccac atcccctgtt atggctgcag gatcgagtta ttgttaacaa agagacccaa 8039gaaaagctgc taatgtcctc ttatcattgt tgttaatttg ttaaaacata aagaaatcta 8099aaatttcaaa aaa 811243641DNAHomo sapiensCDS(328)...(2265) 4gacactgaat ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt 60gaatctaccc ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca 120ccgtgtgtct tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct 180cccgcaagtt tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg 240catcatcaca gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt 300aggtggaaga ttcagccaag ctcaagg atg gaa gtg cag tta ggg ctg gga agg 354 Met Glu Val Gln Leu Gly Leu Gly Arg 1 5gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct ttc cag aat 402Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala Phe Gln Asn 10 15 20 25ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc ccc agg cac 450Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly Pro Arg His 30 35 40cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg ctg ctg cag 498Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu Leu Leu Gln 45 50 55cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 546Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 60 65 70cag cag cag cag cag cag cag cag cag cag cag caa gag act agc ccc 594Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro 75 80 85agg cag cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat 642Arg Gln Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His 90 95 100 105cgt aga ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct 690Arg Arg Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro 110 115 120tca cag ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc 738Ser Gln Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val 125 130 135cca gag cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag 786Pro Glu Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln 140 145 150ctg cca gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg 834Leu Pro Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu 155 160 165tcc ctg ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac 882Ser Leu Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp170 175 180 185ctt aaa gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa 930Leu Lys Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln 190 195 200cag cag cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg 978Gln Gln Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg 205 210 215gag gcc tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc 1026Glu Ala Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly 220 225 230act tcg acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg 1074Thr Ser Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser 235 240 245gtg tcc atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg 1122Val Ser Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly250 255 260 265gaa cag ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca 1170Glu Gln Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro 270 275 280ccc gct gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt 1218Pro Ala Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly 285 290 295tct ctg cta gac gac agc gca ggc aag agc act gaa gat act gct gag 1266Ser Leu Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu 300 305 310tat tcc cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc 1314Tyr Ser Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser 315 320 325cta ggc tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa 1362Leu Gly Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu330 335 340 345ctg ccg tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca 1410Leu Pro Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala 350 355 360gct gcg tac cag agt cgc gac tac tac aac ttt cca ctg gct ctg gcc 1458Ala Ala Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala 365 370 375gga ccg ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag 1506Gly Pro Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys 380 385 390ctg gag aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg 1554Leu Glu Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala 395 400 405cag tgc cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg 1602Gln Cys Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala410 415 420 425gga ccc ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac 1650Gly Pro Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His 430 435 440act ctc ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt 1698Thr Leu Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly 445 450 455ggt ggg ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 1746Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 460 465 470ggc gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc cct cag 1794Gly Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro Pro Gln 475 480 485ggg ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg tgg tac 1842Gly Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val Trp Tyr490 495 500 505cct ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act tgt gtc 1890Pro Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr Cys Val 510 515 520aaa agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct tac ggg 1938Lys Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro Tyr Gly 525 530 535gac atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat 1986Asp Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr 540 545 550tac ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa gct tct 2034Tyr Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser 555 560 565ggg tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc 2082Gly Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe570 575 580 585aaa aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc aga aat 2130Lys Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser Arg Asn 590 595 600gat tgc act att gat aaa ttc cga agg aaa aat tgt cca tct tgt cgt 2178Asp Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser Cys Arg 605 610 615ctt cgg aaa tgt tat gaa gca ggg atg act ctg gga gaa aaa ttc cgg 2226Leu Arg Lys Cys Tyr Glu Ala Gly Met Thr Leu Gly Glu Lys Phe Arg 620 625 630gtt ggc aat tgc aag cat ctc aaa atg acc aga ccc tga agaaaggctg 2275Val Gly Asn Cys Lys His Leu Lys Met Thr Arg Pro 635 640 645acttgcctca ttcaaaatga gggctctaga gggctctagt ggatagtctg gagaaacctg 2335gcgtctgagg cttaggagct taggtttttg ctcctcaaca cagactttga cgttggggtt 2395gggggctact ctcttgattg ctgactccct ccagcgggac caatagtgtt

ttcctacctc 2455acagggatgt tgtgaggacg ggctgtagaa gtaatagtgg ttaccactca tgtagttgtg 2515agtatcatga ttattgtttc ctgtaatgtg gcttggcatt ggcaaagtgc tttttgattg 2575ttcttgatca catatgatgg gggccaggca ctgactcagg cggatgcagt gaagctctgg 2635ctcagtcgct tgcttttcgt ggtgtgctgc caggaagaaa ctttgctgat gggactcaag 2695gtgtcacctt ggacaagaag caactgtgtc tgtctgaggt tcctgtggcc atctttattt 2755gtgtattagg caattcgtat ttccccctta ggttctagcc ttctggatcc cagccagtga 2815cctagatctt agcctcaggc cctgtcactg agctgaaggt agtagctgat ccacagaagt 2875tcagtaaaca aggaccagat ttctgcttct ccaggagaag aagccagcca acccctctct 2935tcaaacacac tgagagacta cagtccgact ttccctctta catctagcct tactgtagcc 2995acactccttg attgctctct cacatcacat gcttctcttc atcagttgta agcctctcat 3055tcttctccca agccagactc aaatattgta ttgatgtcaa agaagaatca cttagagttt 3115ggaatatctt gttctctctc tgctccatag cttccatatt gacaccagtt tctttctagt 3175ggagaagtgg agtctgtgaa gccagggaaa cacacatgtg agagtcagaa ggactctccc 3235tgacttgcct ggggcctgtc tttcccacct tctccagtct gtctaaacac acacacacac 3295acacacacac acacacacac acacacacac gctctctctc tctctccccc cccaacacac 3355acacactctc tctctcacac acacacacat acacacacac ttctttctct ttcccctgac 3415tcagcaacat tctggagaaa agccaaggaa ggacttcagg aggggagttt cccccttctc 3475agggcagaat tttaatctcc agaccaacaa gaagttccct aatgtggatt gaaaggctaa 3535tgaggtttat ttttaactac tttctatttg tttgaatgtt gcatatttct actagtgaaa 3595ttttccctta ataaagccat taatacaccc aaaaaaaaaa aaaaaa 364152430DNAHomo sapiensCDS(328)...(2274) 5gacactgaat ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt 60gaatctaccc ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca 120ccgtgtgtct tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct 180cccgcaagtt tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg 240catcatcaca gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt 300aggtggaaga ttcagccaag ctcaagg atg gaa gtg cag tta ggg ctg gga agg 354 Met Glu Val Gln Leu Gly Leu Gly Arg 1 5gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct ttc cag aat 402Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala Phe Gln Asn 10 15 20 25ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc ccc agg cac 450Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly Pro Arg His 30 35 40cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg ctg ctg cag 498Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu Leu Leu Gln 45 50 55cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 546Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 60 65 70cag cag cag cag cag cag cag cag cag cag caa gag act agc ccc agg 594Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro Arg 75 80 85cag cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat cgt 642Gln Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His Arg 90 95 100 105aga ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct tca 690Arg Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro Ser 110 115 120cag ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc cca 738Gln Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val Pro 125 130 135gag cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag ctg 786Glu Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln Leu 140 145 150cca gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg tcc 834Pro Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu Ser 155 160 165ctg ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac ctt 882Leu Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp Leu170 175 180 185aaa gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa cag 930Lys Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln Gln 190 195 200cag cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg gag 978Gln Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg Glu 205 210 215gcc tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc act 1026Ala Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly Thr 220 225 230tcg acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg gtg 1074Ser Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser Val 235 240 245tcc atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg gaa 1122Ser Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly Glu250 255 260 265cag ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca ccc 1170Gln Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro Pro 270 275 280gct gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt tct 1218Ala Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly Ser 285 290 295ctg cta gac gac agc gca ggc aag agc act gaa gat act gct gag tat 1266Leu Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu Tyr 300 305 310tcc cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc cta 1314Ser Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser Leu 315 320 325ggc tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa ctg 1362Gly Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu Leu330 335 340 345ccg tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca gct 1410Pro Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala Ala 350 355 360gcg tac cag agt cgc gac tac tac aac ttt cca ctg gct ctg gcc gga 1458Ala Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala Gly 365 370 375ccg ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag ctg 1506Pro Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys Leu 380 385 390gag aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg cag 1554Glu Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala Gln 395 400 405tgc cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg gga 1602Cys Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala Gly410 415 420 425ccc ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac act 1650Pro Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His Thr 430 435 440ctc ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt ggt 1698Leu Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly Gly 445 450 455ggg ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 1746Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 460 465 470gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc cct cag ggg 1794Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro Pro Gln Gly 475 480 485ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg tgg tac cct 1842Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val Trp Tyr Pro490 495 500 505ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act tgt gtc aaa 1890Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr Cys Val Lys 510 515 520agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct tac ggg gac 1938Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro Tyr Gly Asp 525 530 535atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat tac 1986Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr Tyr 540 545 550ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa gct tct ggg 2034Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser Gly 555 560 565tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc aaa 2082Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe Lys570 575 580 585aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc aga aat gat 2130Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser Arg Asn Asp 590 595 600tgc act att gat aaa ttc cga agg aaa aat tgt cca tct tgt cgt ctt 2178Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser Cys Arg Leu 605 610 615cgg aaa tgt tat gaa gca ggg atg act ctg gga gca gct gtt gtt gtt 2226Arg Lys Cys Tyr Glu Ala Gly Met Thr Leu Gly Ala Ala Val Val Val 620 625 630tct gaa aga atc ttg agg gtg ttt gga gtc tca gaa tgg ctt cct taa 2274Ser Glu Arg Ile Leu Arg Val Phe Gly Val Ser Glu Trp Leu Pro 635 640 645agactacctt cagactctca gctgctcatc cacaacagag atcagccctt ctttgtagat 2334gattcattcc tggctgcatt tgaaaaccac atattgttaa ttgcttgacg aatttaaatc 2394ccttgactac ttttcatttc aaaaaaaaaa aaaaaa 243062427DNAHomo sapiensCDS(328)...(2271) 6gacactgaat ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt 60gaatctaccc ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca 120ccgtgtgtct tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct 180cccgcaagtt tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg 240catcatcaca gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt 300aggtggaaga ttcagccaag ctcaagg atg gaa gtg cag tta ggg ctg gga agg 354 Met Glu Val Gln Leu Gly Leu Gly Arg 1 5gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct ttc cag aat 402Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala Phe Gln Asn 10 15 20 25ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc ccc agg cac 450Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly Pro Arg His 30 35 40cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg ctg ctg cag 498Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu Leu Leu Gln 45 50 55cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 546Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 60 65 70cag cag cag cag cag cag cag cag cag cag caa gag act agc ccc agg 594Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro Arg 75 80 85cag cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat cgt 642Gln Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His Arg 90 95 100 105aga ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct tca 690Arg Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro Ser 110 115 120cag ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc cca 738Gln Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val Pro 125 130 135gag cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag ctg 786Glu Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln Leu 140 145 150cca gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg tcc 834Pro Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu Ser 155 160 165ctg ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac ctt 882Leu Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp Leu170 175 180 185aaa gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa cag 930Lys Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln Gln 190 195 200cag cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg gag 978Gln Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg Glu 205 210 215gcc tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc act 1026Ala Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly Thr 220 225 230tcg acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg gtg 1074Ser Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser Val 235 240 245tcc atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg gaa 1122Ser Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly Glu250 255 260 265cag ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca ccc 1170Gln Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro Pro 270 275 280gct gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt tct 1218Ala Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly Ser 285 290 295ctg cta gac gac agc gca ggc aag agc act gaa gat act gct gag tat 1266Leu Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu Tyr 300 305 310tcc cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc cta 1314Ser Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser Leu 315 320 325ggc tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa ctg 1362Gly Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu Leu330 335 340 345ccg tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca gct 1410Pro Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala Ala 350 355 360gcg tac cag agt cgc gac tac tac aac ttt cca ctg gct ctg gcc gga 1458Ala Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala Gly 365 370 375ccg ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag ctg 1506Pro Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys Leu 380 385 390gag aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg cag 1554Glu Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala Gln 395 400 405tgc cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg gga 1602Cys Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala Gly410 415 420 425ccc ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac act 1650Pro Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His Thr 430 435 440ctc ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt ggt 1698Leu Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly Gly 445 450 455ggg ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 1746Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 460 465 470gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc cct cag ggg 1794Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro Pro Gln Gly 475 480 485ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg tgg tac cct 1842Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val Trp Tyr Pro490 495 500 505ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act tgt gtc aaa 1890Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr Cys Val Lys 510 515 520agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct tac ggg gac 1938Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro Tyr Gly Asp 525 530 535atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat tac 1986Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr Tyr 540 545 550ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa gct tct ggg 2034Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser Gly 555 560 565tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc aaa 2082Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe Lys570 575 580 585aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc aga aat gat 2130Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser Arg Asn Asp 590 595 600tgc act att gat aaa ttc cga agg aaa aat tgt cca tct tgt cgt ctt 2178Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser Cys Arg Leu 605 610 615cgg aaa tgt tat gaa gca ggg att ctg gga gca gct gtt gtt gtt tct 2226Arg Lys Cys Tyr Glu Ala Gly Ile Leu Gly Ala Ala Val Val Val Ser 620 625 630gaa aga atc ttg agg gtg ttt gga gtc tca gaa tgg ctt cct taa 2271Glu Arg Ile Leu Arg Val Phe Gly Val Ser Glu Trp Leu Pro 635 640 645agactacctt cagactctca gctgctcatc cacaacagag atcagccctt ctttgtagat 2331gattcattcc tggctgcatt tgaaaaccac atattgttaa ttgcttgacg aatttaaatc 2391ccttgactac ttttcatttc aaaaaaaaaa aaaaaa 242774039DNAHomo

sapiensCDS(328)...(2376) 7gacactgaat ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt 60gaatctaccc ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca 120ccgtgtgtct tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct 180cccgcaagtt tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg 240catcatcaca gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt 300aggtggaaga ttcagccaag ctcaagg atg gaa gtg cag tta ggg ctg gga agg 354 Met Glu Val Gln Leu Gly Leu Gly Arg 1 5gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct ttc cag aat 402Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala Phe Gln Asn 10 15 20 25ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc ccc agg cac 450Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly Pro Arg His 30 35 40cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg ctg ctg cag 498Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu Leu Leu Gln 45 50 55cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 546Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 60 65 70cag cag cag cag cag cag cag cag cag cag cag caa gag act agc ccc 594Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro 75 80 85agg cag cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat 642Arg Gln Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His 90 95 100 105cgt aga ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct 690Arg Arg Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro 110 115 120tca cag ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc 738Ser Gln Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val 125 130 135cca gag cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag 786Pro Glu Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln 140 145 150ctg cca gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg 834Leu Pro Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu 155 160 165tcc ctg ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac 882Ser Leu Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp170 175 180 185ctt aaa gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa 930Leu Lys Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln 190 195 200cag cag cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg 978Gln Gln Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg 205 210 215gag gcc tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc 1026Glu Ala Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly 220 225 230act tcg acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg 1074Thr Ser Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser 235 240 245gtg tcc atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg 1122Val Ser Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly250 255 260 265gaa cag ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca 1170Glu Gln Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro 270 275 280ccc gct gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt 1218Pro Ala Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly 285 290 295tct ctg cta gac gac agc gca ggc aag agc act gaa gat act gct gag 1266Ser Leu Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu 300 305 310tat tcc cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc 1314Tyr Ser Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser 315 320 325cta ggc tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa 1362Leu Gly Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu330 335 340 345ctg ccg tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca 1410Leu Pro Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala 350 355 360gct gcg tac cag agt cgc gac tac tac aac ttt cca ctg gct ctg gcc 1458Ala Ala Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala 365 370 375gga ccg ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag 1506Gly Pro Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys 380 385 390ctg gag aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg 1554Leu Glu Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala 395 400 405cag tgc cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg 1602Gln Cys Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala410 415 420 425gga ccc ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac 1650Gly Pro Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His 430 435 440act ctc ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt 1698Thr Leu Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly 445 450 455ggt ggg ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 1746Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 460 465 470ggc gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc cct cag 1794Gly Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro Pro Gln 475 480 485ggg ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg tgg tac 1842Gly Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val Trp Tyr490 495 500 505cct ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act tgt gtc 1890Pro Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr Cys Val 510 515 520aaa agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct tac ggg 1938Lys Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro Tyr Gly 525 530 535gac atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat 1986Asp Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr 540 545 550tac ttt cca ccc cag aag acc tgc ctg atc tgt gga gat gaa gct tct 2034Tyr Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser 555 560 565ggg tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc 2082Gly Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe570 575 580 585aaa aga gcc gct gaa ggg aaa cag aag tac ctg tgc gcc agc aga aat 2130Lys Arg Ala Ala Glu Gly Lys Gln Lys Tyr Leu Cys Ala Ser Arg Asn 590 595 600gat tgc act att gat aaa ttc cga agg aaa aat tgt cca tct tgt cgt 2178Asp Cys Thr Ile Asp Lys Phe Arg Arg Lys Asn Cys Pro Ser Cys Arg 605 610 615ctt cgg aaa tgt tat gaa gca ggg atg act ctg gga gga ttt ttc aga 2226Leu Arg Lys Cys Tyr Glu Ala Gly Met Thr Leu Gly Gly Phe Phe Arg 620 625 630atg aac aaa tta aaa gaa tca tca gac act aac ccc aag cca tac tgc 2274Met Asn Lys Leu Lys Glu Ser Ser Asp Thr Asn Pro Lys Pro Tyr Cys 635 640 645atg gca gca cca atg gga ctg aca gaa aac aac aga aat agg aag aaa 2322Met Ala Ala Pro Met Gly Leu Thr Glu Asn Asn Arg Asn Arg Lys Lys650 655 660 665tcc tac aga gaa aca aac ttg aaa gct gtc tca tgg cct ttg aat cat 2370Ser Tyr Arg Glu Thr Asn Leu Lys Ala Val Ser Trp Pro Leu Asn His 670 675 680act taa gttttatgat ggaaggatac gactatgaag aaagacacag agcaacatca 2426Thrgacagtcaag aatttcagag ccagctggca tgcagtggac ctcatgccag cccattttat 2486gactatttag ggaaacagaa gtacctgtgc gccagcagaa atgattgcac tattgataaa 2546ttccgaagga aaaattgtcc atcttgtcgt cttcggaaat gttatgaagc agggatgact 2606ctgggagaaa aattccgggt tggcaattgc aagcatctca aaatgaccag accctgaaga 2666aaggctgact tgcctcattc aaaatgaggg ctctagaggg ctctagtgga tagtctggag 2726aaacctggcg tctgaggctt aggagcttag gtttttgctc ctcaacacag actttgacgt 2786tggggttggg ggctactctc ttgattgctg actccctcca gcgggaccaa tagtgttttc 2846ctacctcaca gggatgttgt gaggacgggc tgtagaagta atagtggtta ccactcatgt 2906agttgtgagt atcatgatta ttgtttcctg taatgtggct tggcattggc aaagtgcttt 2966ttgattgttc ttgatcacat atgatggggg ccaggcactg actcaggcgg atgcagtgaa 3026gctctggctc agtcgcttgc ttttcgtggt gtgctgccag gaagaaactt tgctgatggg 3086actcaaggtg tcaccttgga caagaagcaa ctgtgtctgt ctgaggttcc tgtggccatc 3146tttatttgtg tattaggcaa ttcgtatttc ccccttaggt tctagccttc tggatcccag 3206ccagtgacct agatcttagc ctcaggccct gtcactgagc tgaaggtagt agctgatcca 3266cagaagttca gtaaacaagg accagatttc tgcttctcca ggagaagaag ccagccaacc 3326cctctcttca aacacactga gagactacag tccgactttc cctcttacat ctagccttac 3386tgtagccaca ctccttgatt gctctctcac atcacatgct tctcttcatc agttgtaagc 3446ctctcattct tctcccaagc cagactcaaa tattgtattg atgtcaaaga agaatcactt 3506agagtttgga atatcttgtt ctctctctgc tccatagctt ccatattgac accagtttct 3566ttctagtgga gaagtggagt ctgtgaagcc agggaaacac acatgtgaga gtcagaagga 3626ctctccctga cttgcctggg gcctgtcttt cccaccttct ccagtctgtc taaacacaca 3686cacacacaca cacacacaca cacacacaca cacacacgct ctctctctct ctcccccccc 3746aacacacaca cactctctct ctcacacaca cacacataca cacacacttc tttctctttc 3806ccctgactca gcaacattct ggagaaaagc caaggaagga cttcaggagg ggagtttccc 3866ccttctcagg gcagaatttt aatctccaga ccaacaagaa gttccctaat gtggattgaa 3926aggctaatga ggtttatttt taactacttt ctatttgttt gaatgttgca tatttctact 3986agtgaaattt tcccttaata aagccattaa tacacccaaa aaaaaaaaaa aaa 403983922DNAHomo sapiensCDS(328)...(2259) 8gacactgaat ttggaaggtg gaggattttg tttttttctt ttaagatctg ggcatctttt 60gaatctaccc ttcaagtatt aagagacaga ctgtgagcct agcagggcag atcttgtcca 120ccgtgtgtct tcttctgcac gagactttga ggctgtcaga gcgctttttg cgtggttgct 180cccgcaagtt tccttctctg gagcttcccg caggtgggca gctagctgca gcgactaccg 240catcatcaca gcctgttgaa ctcttctgag caagagaagg ggaggcgggg taagggaagt 300aggtggaaga ttcagccaag ctcaagg atg gaa gtg cag tta ggg ctg gga agg 354 Met Glu Val Gln Leu Gly Leu Gly Arg 1 5gtc tac cct cgg ccg ccg tcc aag acc tac cga gga gct ttc cag aat 402Val Tyr Pro Arg Pro Pro Ser Lys Thr Tyr Arg Gly Ala Phe Gln Asn 10 15 20 25ctg ttc cag agc gtg cgc gaa gtg atc cag aac ccg ggc ccc agg cac 450Leu Phe Gln Ser Val Arg Glu Val Ile Gln Asn Pro Gly Pro Arg His 30 35 40cca gag gcc gcg agc gca gca cct ccc ggc gcc agt ttg ctg ctg cag 498Pro Glu Ala Ala Ser Ala Ala Pro Pro Gly Ala Ser Leu Leu Leu Gln 45 50 55cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag 546Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 60 65 70cag cag cag cag cag cag cag cag cag cag cag caa gag act agc ccc 594Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Glu Thr Ser Pro 75 80 85agg cag cag cag cag cag cag ggt gag gat ggt tct ccc caa gcc cat 642Arg Gln Gln Gln Gln Gln Gln Gly Glu Asp Gly Ser Pro Gln Ala His 90 95 100 105cgt aga ggc ccc aca ggc tac ctg gtc ctg gat gag gaa cag caa cct 690Arg Arg Gly Pro Thr Gly Tyr Leu Val Leu Asp Glu Glu Gln Gln Pro 110 115 120tca cag ccg cag tcg gcc ctg gag tgc cac ccc gag aga ggt tgc gtc 738Ser Gln Pro Gln Ser Ala Leu Glu Cys His Pro Glu Arg Gly Cys Val 125 130 135cca gag cct gga gcc gcc gtg gcc gcc agc aag ggg ctg ccg cag cag 786Pro Glu Pro Gly Ala Ala Val Ala Ala Ser Lys Gly Leu Pro Gln Gln 140 145 150ctg cca gca cct ccg gac gag gat gac tca gct gcc cca tcc acg ttg 834Leu Pro Ala Pro Pro Asp Glu Asp Asp Ser Ala Ala Pro Ser Thr Leu 155 160 165tcc ctg ctg ggc ccc act ttc ccc ggc tta agc agc tgc tcc gct gac 882Ser Leu Leu Gly Pro Thr Phe Pro Gly Leu Ser Ser Cys Ser Ala Asp170 175 180 185ctt aaa gac atc ctg agc gag gcc agc acc atg caa ctc ctt cag caa 930Leu Lys Asp Ile Leu Ser Glu Ala Ser Thr Met Gln Leu Leu Gln Gln 190 195 200cag cag cag gaa gca gta tcc gaa ggc agc agc agc ggg aga gcg agg 978Gln Gln Gln Glu Ala Val Ser Glu Gly Ser Ser Ser Gly Arg Ala Arg 205 210 215gag gcc tcg ggg gct ccc act tcc tcc aag gac aat tac tta ggg ggc 1026Glu Ala Ser Gly Ala Pro Thr Ser Ser Lys Asp Asn Tyr Leu Gly Gly 220 225 230act tcg acc att tct gac aac gcc aag gag ttg tgt aag gca gtg tcg 1074Thr Ser Thr Ile Ser Asp Asn Ala Lys Glu Leu Cys Lys Ala Val Ser 235 240 245gtg tcc atg ggc ctg ggt gtg gag gcg ttg gag cat ctg agt cca ggg 1122Val Ser Met Gly Leu Gly Val Glu Ala Leu Glu His Leu Ser Pro Gly250 255 260 265gaa cag ctt cgg ggg gat tgc atg tac gcc cca ctt ttg gga gtt cca 1170Glu Gln Leu Arg Gly Asp Cys Met Tyr Ala Pro Leu Leu Gly Val Pro 270 275 280ccc gct gtg cgt ccc act cct tgt gcc cca ttg gcc gaa tgc aaa ggt 1218Pro Ala Val Arg Pro Thr Pro Cys Ala Pro Leu Ala Glu Cys Lys Gly 285 290 295tct ctg cta gac gac agc gca ggc aag agc act gaa gat act gct gag 1266Ser Leu Leu Asp Asp Ser Ala Gly Lys Ser Thr Glu Asp Thr Ala Glu 300 305 310tat tcc cct ttc aag gga ggt tac acc aaa ggg cta gaa ggc gag agc 1314Tyr Ser Pro Phe Lys Gly Gly Tyr Thr Lys Gly Leu Glu Gly Glu Ser 315 320 325cta ggc tgc tct ggc agc gct gca gca ggg agc tcc ggg aca ctt gaa 1362Leu Gly Cys Ser Gly Ser Ala Ala Ala Gly Ser Ser Gly Thr Leu Glu330 335 340 345ctg ccg tct acc ctg tct ctc tac aag tcc gga gca ctg gac gag gca 1410Leu Pro Ser Thr Leu Ser Leu Tyr Lys Ser Gly Ala Leu Asp Glu Ala 350 355 360gct gcg tac cag agt cgc gac tac tac aac ttt cca ctg gct ctg gcc 1458Ala Ala Tyr Gln Ser Arg Asp Tyr Tyr Asn Phe Pro Leu Ala Leu Ala 365 370 375gga ccg ccg ccc cct ccg ccg cct ccc cat ccc cac gct cgc atc aag 1506Gly Pro Pro Pro Pro Pro Pro Pro Pro His Pro His Ala Arg Ile Lys 380 385 390ctg gag aac ccg ctg gac tac ggc agc gcc tgg gcg gct gcg gcg gcg 1554Leu Glu Asn Pro Leu Asp Tyr Gly Ser Ala Trp Ala Ala Ala Ala Ala 395 400 405cag tgc cgc tat ggg gac ctg gcg agc ctg cat ggc gcg ggt gca gcg 1602Gln Cys Arg Tyr Gly Asp Leu Ala Ser Leu His Gly Ala Gly Ala Ala410 415 420 425gga ccc ggt tct ggg tca ccc tca gcc gcc gct tcc tca tcc tgg cac 1650Gly Pro Gly Ser Gly Ser Pro Ser Ala Ala Ala Ser Ser Ser Trp His 430 435 440act ctc ttc aca gcc gaa gaa ggc cag ttg tat gga ccg tgt ggt ggt 1698Thr Leu Phe Thr Ala Glu Glu Gly Gln Leu Tyr Gly Pro Cys Gly Gly 445 450 455ggt ggg ggt ggt ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc ggc 1746Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 460 465 470ggc gag gcg gga gct gta gcc ccc tac ggc tac act cgg ccc cct cag 1794Gly Glu Ala Gly Ala Val Ala Pro Tyr Gly Tyr Thr Arg Pro Pro Gln 475 480 485ggg ctg gcg ggc cag gaa agc gac ttc acc gca cct gat gtg tgg tac 1842Gly Leu Ala Gly Gln Glu Ser Asp Phe Thr Ala Pro Asp Val Trp Tyr490 495 500 505cct ggc ggc atg gtg agc aga gtg ccc tat ccc agt ccc act tgt gtc 1890Pro Gly Gly Met Val Ser Arg Val Pro Tyr Pro Ser Pro Thr Cys Val 510 515 520aaa agc gaa atg ggc ccc tgg atg gat agc tac tcc gga cct tac ggg 1938Lys Ser Glu Met Gly Pro Trp Met Asp Ser Tyr Ser Gly Pro Tyr Gly 525 530 535gac atg cgt ttg gag act gcc agg gac cat gtt ttg ccc att gac tat 1986Asp Met Arg Leu Glu Thr Ala Arg Asp His Val Leu Pro Ile Asp Tyr 540 545 550tac ttt cca ccc cag aag acc tgc ctg atc tgt gga gac gaa gct tct 2034Tyr Phe Pro Pro Gln Lys Thr Cys Leu Ile Cys Gly Asp Glu Ala Ser 555 560 565ggg tgt cac tat gga gct ctc aca tgt gga agc tgc aag gtc ttc ttc 2082Gly Cys His Tyr Gly Ala Leu Thr Cys Gly Ser Cys Lys Val Phe Phe570 575 580 585aaa aga gcc gct gaa gga ttt ttc aga atg aac aaa tta aaa gaa tca 2130Lys Arg Ala Ala Glu Gly Phe Phe Arg Met Asn Lys Leu Lys Glu Ser 590 595 600tca gac act aac ccc aag cca tac tgc atg

gca gca cca atg gga ctg 2178Ser Asp Thr Asn Pro Lys Pro Tyr Cys Met Ala Ala Pro Met Gly Leu 605 610 615aca gaa aac aac aga aat agg aag aaa tcc tac aga gaa aca aac ttg 2226Thr Glu Asn Asn Arg Asn Arg Lys Lys Ser Tyr Arg Glu Thr Asn Leu 620 625 630aaa gct gtc tca tgg cct ttg aat cat act taa gttttatgat ggaaggatac 2279Lys Ala Val Ser Trp Pro Leu Asn His Thr 635 640gactatgaag aaagacacag agcaacatca gacagtcaag aatttcagag ccagctggca 2339tgcagtggac ctcatgccag cccattttat gactatttag ggagacagaa gtacctgtgc 2399gccagcagaa atgattgcac tattgataaa ttccgaagga aaaattgtcc atcttgtcgt 2459cttcggaaat gttatgaagc aggggtgact ctgggagaaa aattccgggt tggcaattgc 2519aagcatctca aaatgaccag accctgaaga aaggctgact tgcctcattc aaaatgaggg 2579ctctagaggg ctctagtgga tagtctggag aaacctggcg tctgaggctt aggagcttag 2639gtttttgctc ctcaacacag actttgacgt tggggttggg ggctactctc ttgattgctg 2699actccctcca gcgggaccaa tagtgttttc ctacctcaca gggatgttgt gaggacgggc 2759tgtagaagta atagtggtta ccactcatgt agttgtgagt atcatgatta ttgtttcctg 2819taatgtggct tggcattggc aaagtgcttt ttgattgttc ttgatcacat atgatggggg 2879ccaggcactg actcaggcgg atgcagtgaa gctctggctc agtcgcttgc ttttcgtggt 2939gtgctgccag gaagaaactt tgctgatggg actcaaggtg tcaccttgga caagaagcaa 2999ctgtgtctgt ctgaggttcc tgtggccatc tttatttgtg tattaggcaa ttcgtatttc 3059ccccttaggt tctagccttc tggatcccag ccagtgacct agatcttagc ctcaggccct 3119gtcactgagc tgaaggtagt agctgatcca cagaagttca gtaaacaagg accagatttc 3179tgcttctcca ggagaagaag ccagccaacc cctctcttca aacacactga gagactacag 3239tccgactttc cctcttacat ctagccttac tgtagccaca ctccttgatt gctctctcac 3299atcacatgct tctcttcatc agttgtaagc ctctcattct tctcccaagc cagactcaaa 3359tattgtattg atgtcaaaga agaatcactt agagtttgga atatcttgtt ctctctctgc 3419tccatagctt ccatattgac accagtttct ttctagtgga gaagtggagt ctgtgaagcc 3479agggaaacac acatgtgaga gtcagaagga ctctccctga cttgcctggg gcctgtcttt 3539cccaccttct ccagtctgtc taaacacaca cacacacaca cacacacaca cacacacaca 3599cacacacgct ctctctctct ctcccccccc aacacacaca cactctctct ctcacacaca 3659cacacataca cacacacttc tttctctttc ccctgactca gcaacattct ggagaaaagc 3719caaggaagga cttcaggagg ggagtttccc ccttctcagg gcagaatttt aatctccaga 3779ccaacaagaa gttccctaat gtggattgaa aggctaatga ggtttatttt taactacttt 3839ctatttgttt gaatgttgca tatttctact agtgaaattt tcccttaata aagccattaa 3899tacacccaaa aaaaaaaaaa aaa 3922921DNAArtificial SequencePrimer 9tccttcacca atgtcaactc c 211021DNAArtificial SequencePrimer 10gagccatcca aactcttgag a 211122DNAArtificial SequenceProbe 11agtaccgcat gcacaagtcc cg 221216DNAArtificial SequenceSynthetic Oligonucleotide 12gcgctctgac agcctc 161316DNAArtificial SequenceSynthetic Oligonucleotide 13cacctgcggg aagctc 161416DNAArtificial SequenceSynthetic Oligonucleotide 14ggctgtgatg atgcgg 161516DNAArtificial SequenceSynthetic Oligonucleotide 15cttcgcgcac gctctg 161616DNAArtificial SequenceSynthetic Oligonucleotide 16atggtgctgg cctcgc 161716DNAArtificial SequenceSynthetic Oligonucleotide 17ggtcgaagtg ccccct 161816DNAArtificial SequenceSynthetic Oligonucleotide 18gacaccgaca ctgcct 161916DNAArtificial SequenceSynthetic Oligonucleotide 19cccgaagctg ttcccc 162016DNAArtificial SequenceSynthetic Oligonucleotide 20cttgcctgcg ctgtcg 162116DNAArtificial SequenceSynthetic Oligonucleotide 21gttgtagtag tcgcga 162216DNAArtificial SequenceSynthetic Oligonucleotide 22aagttgtagt agtcgc 162316DNAArtificial SequenceSynthetic Oligonucleotide 23gcgctgccgt agtcca 162416DNAArtificial SequenceSynthetic Oligonucleotide 24aggatgagga agcggc 162516DNAArtificial SequenceSynthetic Oligonucleotide 25gctcccgcct cgccgc 162616DNAArtificial SequenceSynthetic Oligonucleotide 26cgctttcctg gcccgc 162716DNAArtificial SequenceSynthetic Oligonucleotide 27gccgccaggg taccac 162816DNAArtificial SequenceSynthetic Oligonucleotide 28ccaaacgcat gtcccc 162916DNAArtificial SequenceSynthetic Oligonucleotide 29agcttcatct ccacag 163016DNAArtificial SequenceSynthetic Oligonucleotide 30tcccttcagc ggctct 163116DNAArtificial SequenceSynthetic Oligonucleotide 31tttctgctgg cgcaca 163216DNAArtificial SequenceSynthetic Oligonucleotide 32gttcattcga agttca 163316DNAArtificial SequenceSynthetic Oligonucleotide 33gaggatcatc acagat 163416DNAArtificial SequenceSynthetic Oligonucleotide 34ctaaacttcc cgtggc 163516DNAArtificial SequenceSynthetic Oligonucleotide 35ttgatttaat ggttgc 163616DNAArtificial SequenceSynthetic Oligonucleotide 36gttgatttaa tggttg 163716DNAArtificial SequenceSynthetic Oligonucleotide 37atggttgatt taatgg 163820DNAArtificial SequenceSynthetic Oligonucleotide 38tggttgattt aatggttgca 203916DNAArtificial SequenceSynthetic Oligonucleotide 39tgatttaatg gttgca 164016DNAArtificial SequenceSynthetic Oligonucleotide 40ggttgattta atggtt 164116DNAArtificial SequenceSynthetic Oligonucleotide 41tggttgattt aatggt 164216DNAArtificial SequenceSynthetic Oligonucleotide 42agttgtagta gtcgcg 164316DNAArtificial SequenceSynthetic Oligonucleotide 43gatttaatgg ttgcaa 164416DNAArtificial SequenceSynthetic Oligonucleotide 44acagcactgg agcggc 164516DNAArtificial SequenceSynthetic Oligonucleotide 45aacttcaccg aagagg 164616DNAArtificial SequenceSynthetic Oligonucleotide 46agtctttagc agcttt 164716DNAArtificial SequenceSynthetic Oligonucleotide 47gcttcctccg agtctt 164816DNAArtificial SequenceSynthetic Oligonucleotide 48ccttgcttcc tccgag 164916DNAArtificial SequenceSynthetic Oligonucleotide 49gcactttcct tgcttc 165016DNAArtificial SequenceSynthetic Oligonucleotide 50tcagtcctac caggca 165116DNAArtificial SequenceSynthetic Oligonucleotide 51gactgaggca gctgcg 165216DNAArtificial SequenceSynthetic Oligonucleotide 52ccgactgagg cagctg 165316DNAArtificial SequenceSynthetic Oligonucleotide 53gctagctcgc ccgctc 165416DNAArtificial SequenceSynthetic Oligonucleotide 54cagctagctc gcccgc 165516DNAArtificial SequenceSynthetic Oligonucleotide 55gcaatgtgca gctagc 165616DNAArtificial SequenceSynthetic Oligonucleotide 56gtcgcctggc tcctaa 165716DNAArtificial SequenceSynthetic Oligonucleotide 57ctggctccgc actcgg 165816DNAArtificial SequenceSynthetic Oligonucleotide 58atctctggct ccgcac 165916DNAArtificial SequenceSynthetic Oligonucleotide 59tgatctctgg ctccgc 166016DNAArtificial SequenceSynthetic Oligonucleotide 60agtgtccact gaagta 166116DNAArtificial SequenceSynthetic Oligonucleotide 61aggctcacag tctgtc 166216DNAArtificial SequenceSynthetic Oligonucleotide 62gacacacggt ggacaa 166316DNAArtificial SequenceSynthetic Oligonucleotide 63agaagacaca cggtgg 166416DNAArtificial SequenceSynthetic Oligonucleotide 64cgctctgaca gcctca 166516DNAArtificial SequenceSynthetic Oligonucleotide 65gtcgctgcag ctagct 166616DNAArtificial SequenceSynthetic Oligonucleotide 66ggtagtcgct gcagct 166716DNAArtificial SequenceSynthetic Oligonucleotide 67gcggtagtcg ctgcag 166816DNAArtificial SequenceSynthetic Oligonucleotide 68atgcggtagt cgctgc 166916DNAArtificial SequenceSynthetic Oligonucleotide 69gtgatgatgc ggtagt 167016DNAArtificial SequenceSynthetic Oligonucleotide 70ctgtgatgat gcggta 167116DNAArtificial SequenceSynthetic Oligonucleotide 71gaagagttca acaggc 167216DNAArtificial SequenceSynthetic Oligonucleotide 72gcttggctga atcttc 167316DNAArtificial SequenceSynthetic Oligonucleotide 73ccttgagctt ggctga 167416DNAArtificial SequenceSynthetic Oligonucleotide 74atccttgagc ttggct 167516DNAArtificial SequenceSynthetic Oligonucleotide 75tccatccttg agcttg 167616DNAArtificial SequenceSynthetic Oligonucleotide 76gtaggtcttg gacggc 167716DNAArtificial SequenceSynthetic Oligonucleotide 77gattctggaa agctcc 167816DNAArtificial SequenceSynthetic Oligonucleotide 78gctctggaac agattc 167916DNAArtificial SequenceSynthetic Oligonucleotide 79cgcgcacgct ctggaa 168016DNAArtificial SequenceSynthetic Oligonucleotide 80tcacttcgcg cacgct 168116DNAArtificial SequenceSynthetic Oligonucleotide 81tggatcactt cgcgca 168216DNAArtificial SequenceSynthetic Oligonucleotide 82gttctggatc acttcg 168316DNAArtificial SequenceSynthetic Oligonucleotide 83cgctcgcggc ctctgg 168416DNAArtificial SequenceSynthetic Oligonucleotide 84tgcgctcgcg gcctct 168516DNAArtificial SequenceSynthetic Oligonucleotide 85gctgcgctcg cggcct 168616DNAArtificial SequenceSynthetic Oligonucleotide 86aggtgctgcg ctcgcg 168716DNAArtificial SequenceSynthetic Oligonucleotide 87gctgttcctc atccag 168816DNAArtificial SequenceSynthetic Oligonucleotide 88tgctgcggca gcccct 168916DNAArtificial SequenceSynthetic Oligonucleotide 89ggtgctggcc tcgctc 169016DNAArtificial SequenceSynthetic Oligonucleotide 90tgcatggtgc tggcct 169116DNAArtificial SequenceSynthetic Oligonucleotide 91gttgcatggt gctggc 169216DNAArtificial SequenceSynthetic Oligonucleotide 92tgctgttgct gaagga 169316DNAArtificial SequenceSynthetic Oligonucleotide 93ggatactgct tcctgc 169416DNAArtificial SequenceSynthetic Oligonucleotide 94tcggatactg cttcct 169516DNAArtificial SequenceSynthetic Oligonucleotide 95tgccttcgga tactgc 169616DNAArtificial SequenceSynthetic Oligonucleotide 96ctcgctctcc cgctgc 169716DNAArtificial SequenceSynthetic Oligonucleotide 97tgtccttgga ggaagt 169816DNAArtificial SequenceSynthetic Oligonucleotide 98tggtcgaagt gccccc 169916DNAArtificial SequenceSynthetic Oligonucleotide 99cagaaatggt cgaagt 1610016DNAArtificial SequenceSynthetic Oligonucleotide 100tgttcccctg gactca 1610116DNAArtificial SequenceSynthetic Oligonucleotide 101agctgttccc ctggac 1610216DNAArtificial SequenceSynthetic Oligonucleotide 102gaagctgttc ccctgg 1610316DNAArtificial SequenceSynthetic Oligonucleotide 103ccgaagctgt tcccct 1610416DNAArtificial SequenceSynthetic Oligonucleotide 104gtacatgcaa tccccc 1610516DNAArtificial SequenceSynthetic Oligonucleotide 105acagcgggtg gaactc 1610616DNAArtificial SequenceSynthetic Oligonucleotide 106ggacgcacag cgggtg 1610716DNAArtificial SequenceSynthetic Oligonucleotide 107gtgggacgca cagcgg 1610816DNAArtificial SequenceSynthetic Oligonucleotide 108tgcattcggc caatgg 1610916DNAArtificial SequenceSynthetic Oligonucleotide 109cctttgcatt cggcca 1611016DNAArtificial SequenceSynthetic Oligonucleotide 110aacctttgca ttcggc 1611116DNAArtificial SequenceSynthetic Oligonucleotide 111gctcttgcct gcgctg 1611216DNAArtificial SequenceSynthetic Oligonucleotide 112cagtgctctt gcctgc 1611316DNAArtificial SequenceSynthetic Oligonucleotide 113ttcagtgctc ttgcct 1611416DNAArtificial SequenceSynthetic Oligonucleotide 114tcttcagtgc tcttgc 1611516DNAArtificial SequenceSynthetic Oligonucleotide 115actcagcagt atcttc 1611616DNAArtificial SequenceSynthetic Oligonucleotide 116atactcagca gtatct 1611716DNAArtificial SequenceSynthetic Oligonucleotide 117tttggtgtaa cctccc 1611816DNAArtificial SequenceSynthetic Oligonucleotide 118cctttggtgt aacctc 1611916DNAArtificial SequenceSynthetic Oligonucleotide 119ctaggctctc gccttc 1612016DNAArtificial SequenceSynthetic Oligonucleotide 120cagcctaggc tctcgc 1612116DNAArtificial SequenceSynthetic Oligonucleotide 121agcagcctag gctctc 1612216DNAArtificial SequenceSynthetic Oligonucleotide 122ctgccagagc agccta 1612316DNAArtificial SequenceSynthetic Oligonucleotide 123tcgcgactct ggtacg 1612416DNAArtificial SequenceSynthetic Oligonucleotide 124agtcgcgact ctggta 1612516DNAArtificial SequenceSynthetic Oligonucleotide 125gtagtcgcga ctctgg 1612616DNAArtificial SequenceSynthetic Oligonucleotide 126tagtagtcgc gactct 1612716DNAArtificial SequenceSynthetic Oligonucleotide 127tctccagctt gatgcg 1612816DNAArtificial SequenceSynthetic Oligonucleotide 128cagcgggttc tccagc

1612916DNAArtificial SequenceSynthetic Oligonucleotide 129ccttcttcgg ctgtga 1613016DNAArtificial SequenceSynthetic Oligonucleotide 130ggtccataca actggc 1613116DNAArtificial SequenceSynthetic Oligonucleotide 131acacatcagg tgcggt 1613216DNAArtificial SequenceSynthetic Oligonucleotide 132cgccagggta ccacac 1613316DNAArtificial SequenceSynthetic Oligonucleotide 133catgccgcca gggtac 1613416DNAArtificial SequenceSynthetic Oligonucleotide 134accatgccgc cagggt 1613516DNAArtificial SequenceSynthetic Oligonucleotide 135ctgctcacca tgccgc 1613616DNAArtificial SequenceSynthetic Oligonucleotide 136acacaagtgg gactgg 1613716DNAArtificial SequenceSynthetic Oligonucleotide 137cccttcagcg gctctt 1613816DNAArtificial SequenceSynthetic Oligonucleotide 138cagagtcatc cctgct 1613916DNAArtificial SequenceSynthetic Oligonucleotide 139caccctcaag attctt 1614016DNAArtificial SequenceSynthetic Oligonucleotide 140aaggtagtct ttaagg 1614116DNAArtificial SequenceSynthetic Oligonucleotide 141gttttcaaat gcagcc 1614216DNAArtificial SequenceSynthetic Oligonucleotide 142gccatgagac agcttt 1614316DNAArtificial SequenceSynthetic Oligonucleotide 143attcttgact gtctga 1614416DNAArtificial SequenceSynthetic Oligonucleotide 144gcatgccagc tggctc 1614516DNAArtificial SequenceSynthetic Oligonucleotide 145cgcgcaggta ggagcc 1614616DNAArtificial SequenceSynthetic Oligonucleotide 146tctaaacatg acggtt 1614716DNAArtificial SequenceSynthetic Oligonucleotide 147atgcaattgc ctgcca 1614816DNAArtificial SequenceSynthetic Oligonucleotide 148atgggagtaa cttttg 1614916DNAArtificial SequenceSynthetic Oligonucleotide 149catattattg tgctgc 1615016DNAArtificial SequenceSynthetic Oligonucleotide 150gtcaatatca aagcac 1615116DNAArtificial SequenceSynthetic Oligonucleotide 151gagttgtgat ttcagg 1615216DNAArtificial SequenceSynthetic Oligonucleotide 152ttgatggaat gctgat 1615316DNAArtificial SequenceSynthetic Oligonucleotide 153ggttaacttt ctctga 1615416DNAArtificial SequenceSynthetic Oligonucleotide 154tggattgtaa attacg 1615516DNAArtificial SequenceSynthetic Oligonucleotide 155gaacattatt aggcta 1615616DNAArtificial SequenceSynthetic Oligonucleotide 156tcaatctaga taccat 1615716DNAArtificial SequenceSynthetic Oligonucleotide 157cacatcagaa ggagta 1615816DNAArtificial SequenceSynthetic Oligonucleotide 158gagtgttaat gaagac 1615916DNAArtificial SequenceSynthetic Oligonucleotide 159ctgattagct atgacc 1616016DNAArtificial SequenceSynthetic Oligonucleotide 160atgagtcctc agaatc 1616116DNAArtificial SequenceSynthetic Oligonucleotide 161gtagattcta gctttg 1616216DNAArtificial SequenceSynthetic Oligonucleotide 162acaggctctg actagg 1616316DNAArtificial SequenceSynthetic Oligonucleotide 163tgtgtgaccc ttggac 1616416DNAArtificial SequenceSynthetic Oligonucleotide 164aagtatgagc atggtt 1616516DNAArtificial SequenceSynthetic Oligonucleotide 165ggattctcta cacaca 1616616DNAArtificial SequenceSynthetic Oligonucleotide 166ccatttgtgc caaacc 1616716DNAArtificial SequenceSynthetic Oligonucleotide 167aggttaggga gtaggc 1616816DNAArtificial SequenceSynthetic Oligonucleotide 168tagggtttgg tcagaa 1616916DNAArtificial SequenceSynthetic Oligonucleotide 169ccttatggat gctgct 1617016DNAArtificial SequenceSynthetic Oligonucleotide 170gttatcttac tctccc 1617116DNAArtificial SequenceSynthetic Oligonucleotide 171gattgtgtat agctgc 1617216DNAArtificial SequenceSynthetic Oligonucleotide 172ggttatggtt ctgtct 1617316DNAArtificial SequenceSynthetic Oligonucleotide 173cttcattgca ggtctg 1617416DNAArtificial SequenceSynthetic Oligonucleotide 174tagccaactt tcttta 1617516DNAArtificial SequenceSynthetic Oligonucleotide 175cattgtacta tgccag 1617616DNAArtificial SequenceSynthetic Oligonucleotide 176tttggtaaca ttaggc 1617716DNAArtificial SequenceSynthetic Oligonucleotide 177atggttgtcc tgtaca 1617816DNAArtificial SequenceSynthetic Oligonucleotide 178accaagtttc ttcagc 1617920DNAArtificial SequenceSynthetic Oligonucleotide 179tcttatgttt ccgaaccgtt 2018021DNAArtificial SequencePrimer 180gcccctggat ggatagctac t 2118121DNAArtificial SequencePrimer 181ccacagatca ggcaggtctt c 2118224DNAArtificial SequenceProbe 182actgccaggg accatgtttt gccc 2418318DNAArtificial SequencePrimer 183cttgcgcccc aggagtct 1818427DNAArtificial SequencePrimer 184ctcagagtaa gctctagcac acatgtc 2718528DNAArtificial SequenceProbe 185agtgtgtgag cctccatctc ctgtccaa 2818619DNAArtificial SequencePrimer 186gccaaggagg gagggtctt 1918721DNAArtificial SequencePrimer 187ccccccatag tgaatcagct t 2118828DNAArtificial SequenceProbe 188atgaagtaag gagagggact ggaccccc 28189174000DNAMacaca mulattamisc_feature(1)...(174000)n = A,T,C or G 189aagttgtggt gggattaaat gttgcaatga gtattcaaat aaggttgaag tatctatgca 60ttctacttac atatggttga ggtatattca aggaagcctg tagccattaa aatctcaggg 120aacaattttt cacctcctca ggtgaaaggg tcttcaggcc tttgtgttct ggaaggttca 180tttatagcca tttcccaaat aacattgaga cggatgagtc tagagtctag ctcaaatggc 240aatgggctgg aagactagtt tagtttttac taatgtggaa catagaacaa aattatgtcc 300ttgtttcagc ctgctcatct gtgaagtaga gcctatcata tccagtctcc cttgccttta 360ggtttgagtt accttctttg gtcaaggtaa gtaaatgcct atgatgtttt gctgtgcaca 420agataaagct acaacaaagc tacaacctgt cttttctctg tagaagacgg caaaaagcaa 480aagagaccca ggcaaaaatc tcggaatgac ttttgaaaca gacagcctcc ctagaatcag 540aagtcaaagg aatttaaaac atagggaggc ccagggtctc tactgacata aaagaaagct 600gttttcgtta taggtttact tttacatttt ctctctcttt ccattcccac ctgcctctcc 660acctttacac agggcttatg ggacctcctc cacaaaagag cagttgcaat aacccacatc 720atcctccacg cctggctgtc catcaagagg cgaaaagcag ccctatatag gttctatcct 780tggatagttc cggttggaaa gtttaaaata tgcaaaggca acttggaaaa gcaagcggct 840gcatacaaca caaacctttg caaagctctg cacaaaattg agggcctatg cgtacatggc 900aagtgttttt agtgtttgcg tgtttacctg cttgtctggg tggttttgcc tttgcaagtc 960tggatgagaa atgcatggtt aaaggcaatt ccagacagga agaaaggcag agaagagggt 1020agaaatgacc tctgattctt ggggctgagg gttcctagag caaatggcac aatgccagga 1080ggcccgatct atccctatga cggaatctaa ggtttcagct agtatctgct ggcttggtca 1140tggcttgctc ctcagtttgt aggagactct cccgtctgca cgctcttatc agtcctgaaa 1200agaacccctg gcagccatta ggagcaggta ctcctatcgt ccttttcctc cctcctcctc 1260tacaccccgt tggtttttta gattgggctt tggaaccaaa tttggtgagt gctggcctcc 1320aggaaatctg gatctctggc gcttaaagct tggtttagca aagcaggagc tattcaggaa 1380gcaggggtcc tccagggcta cagctagcct ctcctgccct cgcccacgct gcgccagcac 1440ttgtttctcc aaagccacta ggcaggcgtt agcgcgcgat gaggggaggg gagaaaaaga 1500aaggggaggg gagggaaaag gaggtgggaa ggcaaggagg ccggcccggc gggggcggga 1560cccgactcgc aaactgttgc atttgctctc cacctcccag cgccccctcc gagatcccgg 1620ggagccagct tgctgggaga gcgggacggt ccggagcaag cccagaggca gaggaggcga 1680cagagggaaa aacggccgag ctagccgctc cagtgctgta caggagccga agggacgcac 1740cacgacagcc ccagcccggc tccagcgaca gccaacgcct tttgcagcgc ggcgacttcg 1800aagccgccgc cccggagctg ccctttcctc ttcggtgaag tttttaaaag ctgctaaaga 1860ctcggaggaa gcaaggaaag tgcctggtag gactgacggc tgcctttgtc ctcctcctct 1920ccaccccgcc tccccccacc ctgctccccc ccccgccccg cgtcttctct cccgcagctg 1980cctcagtcgg ctactctccg ccaacccccc ttactgcccc tctccccacc ctccctcccc 2040cgtcggccca gcgctgccag cccgagtttg cagagaggta actccctttg gctgcgagcg 2100ggcgagctag ctgcacattg caaagaaggc tcttaggagc caggcgactg gggagcggct 2160tcagcactgc agccacgacc tgcctggtta ggctgcacgc ggagagaacc ctccgtttcc 2220ccccactctc tctctacttc ctcctgcttt ccccaccccg agtgcggagc cagagatcaa 2280aagatgaaaa gacagtcagg gcttcagtag ccaaaaaata aaacaaacaa aaacaaaaca 2340aaacaaaaaa acgaaataaa agaaaaagat aataactcag ttcttatttg cacctacttc 2400agtggacact gaatttggaa ggtggaggat tttgtttttt cttttaagat tcgggcatct 2460tttgaatcta cccttcaagt gttaagagac agactgtgag cctagcaggg cagatcttgt 2520ccaccgtgtg tcttcttctg caggagactt tgaggctgtc agagcgcttt ttgcgtggtt 2580gctcccgcaa gtttccttct ctggagcttc ccgcaggtgg gcagctagct gcagcgacta 2640ccgcatcatc acagcctgtt gaactcttct gagcaagaga aggggaggcg gggtaaggga 2700agtaggtgga agattcagcc aagctcaagg atggaggtgc agttagggct ggggagggtc 2760taccctcggc cgccgtccaa gacctaccga ggagctttcc agaatctgtt ccagagcgtg 2820cgcgaagtga tccagaaccc gggccccagg cacccagagg ccgcgagcgc agcacctccc 2880ggcgccagtt tgcagcagca gcagcagcag cagcaagaaa ctagcccccg gcaacagcag 2940cagcagcagc agggtgagga tggttctccc caagcccatc gtagaggccc cacaggctac 3000ctggtcctgg atgaggaaca gcagccttca cagcctcagt cagccccgga gtgccacccc 3060gagagaggtt gcgtcccaga gcctggagcc gccgtggccg ccggcaaggg gctgccgcag 3120cagctgccag cacctccgga cgaggatgac tcagctgccc catccacgtt gtctctgctg 3180ggccccactt tccccggctt aagcagctgc tccgccgacc ttaaagacat cctgagcgag 3240gccagcacca tgcaactcct tcagcaacag cagcaggaag cagtatccga aggcagcagc 3300agcgggagag cgagggaggc ctcgggggct cccacttcct ccaaggacaa ttacttaggg 3360ggcacttcga ccatttctga cagcgccaag gagctgtgta aggcagtgtc ggtgtccatg 3420ggcttgggtg tggaggcgtt ggagcatctg agtccagggg aacagcttcg gggggattgc 3480atgtacgccc cagttttggg agttccaccc gctgtgcgtc ccactccgtg tgccccattg 3540gccgaatgca aaggttctct gctagacgac agcgcaggca agagcactga agatactgct 3600gagtattccc ctttcaaggg aggttacacc aaagggctag aaggcgagag cctaggctgc 3660tctggcagcg ctgcagcagg gagctccggg acacttgaac tgccgtccac cctgtctctc 3720tacaagtccg gagcactgga cgaggcagct gcgtaccaga gtcgcgacta ctacaacttt 3780ccactggctc tggccgggcc gccgccccct ccaccgcctc cccatcccca cgctcgcatc 3840aagctggaga acccgctgga ctatggcagc gcctgggcgg ctgcggcggc gcagtgccgc 3900tatggggacc tggcgagcct gcatggcgcg ggtgcagcgg gacccggctc tgggtcaccc 3960tcagcggccg cttcctcatc ctggcacact ctcttcacag ccgaagaagg ccagttgtat 4020ggaccgtgtg gtggtggggg cggcggcggt ggcggcggcg gcggcggcgc aggcgaggcg 4080ggagctgtag ccccctacgg ctacactcgg ccacctcagg ggctggcggg ccaggaaggc 4140gacttcaccg cacctgatgt gtggtaccct ggcggcatgg tgagcagagt gccctatccc 4200agtcccactt gtgtcaaaag cgagatgggc ccctggatgg atagctactc cggaccttac 4260ggggacatgc ggtaagtttc tccttccaga aatgtcgcct ttcggcccag ggcacagagt 4320cgctctgcat tctggggtgt ctagtggctc ctacctgcgc gaacactcag actgcccctg 4380ggagagctca gcagggtaaa cctagagctc tccccgtgga ctcccggcct gccagaggtt 4440taacctgagc tctcctaatt tctgctgcgt gtcctgggtg ctgattcctg ccctcccaga 4500ttcttcaact cccccaacgg ccccaaattc tcgctacctc ctggtacccg agtcccaaac 4560ttaaatccta ttgtacgggc caccttcaga gacaaagctc ataagccctc cactcttcct 4620tttctcctgt cctcgaagtc tgagaacctc aatcagaaat ttgggcaatt tcttctcttc 4680gggtctgtta ggacttccct ttcagcctgt gcagattaga gtcaaaaaga ctggcccaag 4740agcttctcag cggatctcct ccaaagaggt aaaatgaaat tctcggttag ggaaagaaag 4800tggtctctgg gtgctgaggt ctgctatgtg aaggagtgaa cttctttccc ggaagcaact 4860ggggacttgc tccagggctg gaggtcagta gagataatct gaaccgtcat gtttagagta 4920ggcagagggg caactttctt ggtaaagact ccacaggatt tgcattcaca gtttctcaac 4980gttggttgac tatgttgaaa gtagttgctt gggtcggttt tctcttataa agtgtttatt 5040ttctctgtgg attttaacag atccacaacc ccctacttca ggtttgcatc agatctataa 5100agaggagaat attcttttaa tgtacaattt aattaggctt cagtctgact tacaaaagtg 5160ttggaaaaca tatttttgtg aaacatttcc tgctatttca gtgtgcccca aaatctccac 5220tggggaggga ggagtgaggt ttttcttatt atattccttc atttttagga catgttggca 5280ttttagaata catgctgtta gctctaacaa attgagtaag aactcttagt gacctatgag 5340ccataatctt accccagagt tttaattagc atatgagaaa agtggcaggc aattgcatcg 5400tgcttattaa aaattattcc tcaccgcaat tgttgagctt cttggagacc atgctgaaga 5460ttttctcccc cagcaaatta agatattagt ttatctagtg agggaggaca tactgaattg 5520gggaattcac tcctcaggta gaccaggtgc tgatgtccct gtggacttat gtcttattct 5580ttgtttctat ggctgttttc ttttatctgt gacttctccg aaatttcttt gttagcctta 5640acatcttcgt ttggggactt aaatccagca atttgccttc tttcactgat gctttccttg 5700ttacaaggta gagatagcac gctattagtg aagaaagaaa gaggagggta ggatttcata 5760ttattttgtg ggctgttgaa gaaacagctt cttaccaggc tttacattcc attaggtttt 5820taatgtttgg cttacaagat tttgaaaggg ttcatttgat atcgtcaaag tattttccag 5880ttaatttaga ctctttattt ttgtaatggg tttatcctat gggacaaaaa aagtattctt 5940cattttataa gaataaattt tcttggcagg gttaattttt tttctaagcc tgtcactaga 6000cggtggagcc cttcttctac tgtaaacttt tcttgtggga aaatgtctaa ggtgcatttt 6060gacctgccat gatactaaac ccagactctg gaaccttcca tcttctgcat gcctccccca 6120caacttactt acttagcagg gaaaaaactg atggttccac atatttctta aaaaatgtgt 6180gccttcaaag gcaaaaccaa aatttttagg gaataactat agagagcaaa agttactccc 6240atcaggtaga caatgagctt ggtgatttta tttcaggtct taatgaaaaa agcttcttta 6300tgaggaagat tatcatatct tggtgcctcc ttgacagtct gcttaaatta atgacataaa 6360ctaatgagaa tttagcagtt cctgcagaaa gtacaagatt tttttttctg gtttttgatt 6420gctgcactga ttatgaggag tctagttaaa aggaaaactg gtgttcctgt ctcgtaagtt 6480gacgaagact ttccatttct aggatagaga aaatccttaa gtcagtttat tgaaaattaa 6540tcaatttaat cagaatgcaa tcaattccaa tccaaaagtt gatattttct tactttctct 6600ttttttcccc tcactttgta ggggtgcaat ttggtgaaag gcaagagatt tcttaagcca 6660aatcaagagt gtcttccctt tctgtattgc atgcattatg tgccattttt tagctaaaaa 6720tctcaaaatt gtgcaggctt ccagtgacct gttgggttcc tctcttttcc attcatgtgt 6780gtgtttatgc acattagtta attttgtgaa gggatttttt taaaccttag taacatctgc 6840actcactctg tgttcttaca catttacaat gtttctgctg agaggatggg agatgcaaag 6900gtggtctctt ttacttaatt tagcatgtga tttaaacaga aggaaaaata aaaagtgatg 6960ggacttgtgt gcaaccctga tgatattttg tggagttgtc tgtcttctct ctgagatcaa 7020acaggactac aactttgtta attgaccact ggctcccttg gcagaggtag ggcttcttag 7080attccagcag gcagcacaat aatatgacaa aaatttattc ttgggagttg ggttctaaga 7140gagtctgcat gccagaatta gagtttgggg tttagagaaa ttatccagat gcaaaaagaa 7200cattttaatt tttctcttgg taatttgttc tggtctccat agtaggtagt actttagcag 7260tgctttgata ttgacaagtc ttgttccctt tttctattag attttacaaa ataaggcatt 7320ttattaattc ctctttcctt ctcctctctc ctctcagtta ccaagcattt ttatgactat 7380cttacaaggg acagtttgtc ttgtaaagca gaattttcct ttgaaaccaa gacagactat 7440ttctccccat aggcttcaag aaccaatatt ttggcaagaa gcatcttttc cttgtggtca 7500gcaaataggt agtgagttct gtctggattc caacaatcaa cacctgagga ccaaatagcc 7560acactgggtg gcaccccatc tggaagtata cacaggatgt agccctcttt cttgtccaca 7620gctcaagtca gccaaagatt aacactggtg agagatattt tcgaagaagt ttgcaggctt 7680ccaattgcag ggtcgttttg gggtgctttc ttgcctgtgc taattttatc tcatcaggct 7740tccattcttt gagctgtaaa ctttgaaata atatattaga ttcgctggta cgtttaattt 7800tctttgtcaa gtgtttttca ttccaatagt aatttttcat ctggtgtaca tatatgcatt 7860taaaacaaaa aattctttgg tctcctttcg cgtacatgca ctgtggcttg tacgtgtgca 7920agccacttgg tgggattatg tgaattgggg ttagaaatgt ggacaatttt attatgatta 7980tttttaatgg tgatatcaag atcaccagtt tcattcagaa ccttgcataa gcagggagca 8040gaatgtggac tgggtgtggc

aaagcaaggg cttattttat agccaaacct gaaatcacaa 8100ctctgaaata taaaaaaaaa agcaaacaaa aaaatcaagt tttgtgagct tggtcagaga 8160aggaaaagaa aatctctccc caccccccac ctccaccatt ttctctttgt ctgcagcttc 8220ctcaagtgct gcctgtcccc gattttcttt tattccactc ctttcatgtt tttgacattg 8280aaatacagac tcttctttcc acttctcagg gcatttttct cattacacct gtggcatgct 8340cctaaataat ttcttaaaaa aaaaaaatct gtaaagtagc cgattagatc aaccccagca 8400tctctccctt aagacctaga tgacatgagg ggattgcaaa atgaatagct gggttttttt 8460taccttgagg ttaaagcctg gttcaacagt tgctgaggga gttaactaga tggcttgagg 8520acttggcaat ttcataaagt attttgtctt atgctgtcgc tgtctctgtc tctgtcttga 8580tctctgtctc tctctgtgta ctgtaatgtt ggccaccttc tctcagaacc tgagagagag 8640ctctgagacc cttcccaggt cggttcggtt cagacctcgg tagcctggtc acaagcagta 8700cctaatatgc atatgtgggt gcatgctgta agtgtcctgc tgggctaatc tgcttaagct 8760acataaaaat taatcatatg aaaacaaaga aagatattaa agaaattatt ctacctccga 8820cttctcatat cagcattcca tcaagttctg ggatgttaaa ttcagagaaa gttaacctca 8880tcttaaacac aaagttgact tttaaacaaa attgcttata aagttccgta cagttaccag 8940cattggttgc cctttgtcat acggaagaga attatgaaat ctcatattta catagcattc 9000ttaaaaaaaa aaaaaagaca cagtgttttc cagtttattc actgcattca tgttagtttg 9060agtaggccag gaggggtgct tagtgattac ccttttgcta ggtaaagaag tagaaagata 9120gattttctat gatgtttgtt taccatgtag gggaatctct ttagagcaac actcccaggc 9180tttttcttct tgaaatttcc cacctgacaa atactttaga ttgttactcc taaggacttc 9240tctcagtagc tgctacatag agacgatagt ctatgaatta ttgcttgcac actcatgggt 9300gatgccacac gctctctctc ctggcagttc ttgctgccaa cctgcaggcc acaccaggac 9360tgaaggcagc tcatctagat aagtttatag cattaaagtg ctgggtcact tgagaatgtt 9420gtcaatttag gttacttagt acctaagtgt tattttttaa ataatagctt tattgagacg 9480taatttacaa tccatacaat tcactcttct aaagtgtaca gttccatgct tttcagtata 9540ttcagagttg tgcaaccatt attgcaatca attttagaac attttaatca cccccaaagg 9600aaacgctatg cacctttttg ttcaatgcct tatgttccct cagtccttag caaccaataa 9660tctacttcta tctatggatg tgcttattct aatattttgt atgaatgaaa tcatgtaata 9720tgtggtcttt tgtgactagc ttctttcaca cagaatatgt tttcaaggtc atccatgctg 9780aagcacgtat cagtacttcg ctatttttta tagcctaata atgttccact gtatgactat 9840acaacatttt atctatccgt ttatcaggag atgagcatta gggttgtttc caccttttga 9900ctattatgaa taatactgct gtgaacattc atgtacaagt ttattgtgga catattcagt 9960ccacatattg tggacatttt caattctttt ggatacatac ataggattga aatctctgag 10020tcatatggta cctctatgtt tatcctttga agaactgtca aactgttttc gaaagtgtct 10080gcactgtttt acaatcccat cagcaacgta tgaggggtcc atttcttcca catccttgca 10140aacacttgta attctctttt ttattacagc tatattagtg ggtgtgaagt ggtacctcat 10200tgtggttttt atttctattt ccctaataac gaataatgtt cagtatctat tcatgttctt 10260attggccatt tgtatatctt cttttttgag aaatatctat ttggattctt tgcccatttt 10320ttagttgggt tttttattat tgagttttaa gagttttaaa aaatatattc tggatgcatg 10380tcctttaata gattgtgatt tgtggatatt ttttcacatt ctgtgggttg tcttttttac 10440tttccttttt tttctttttg tgttcttaat ggtatctaga ttgaagcaca aaaaaagttt 10500ttaagtttga tgaagtccaa ttcatctgtt tttttttttc tgttttggcg tatgattttg 10560gcatcatatc taagaaggct ttgcctaatc caagattaca aagatttaca catatgtttc 10620cttctaagag ttttatagtt ttcgctgttt acacttaggt ctttcatcag ttttgatgta 10680atgtttatat atgattgagg taggggtccg acttcattct tttacacata gatactcatt 10740tcttacaata ttcttgttga atttttcctc acttaactgt cttggcaccc tttgtgtaaa 10800atcagttgac tgtaaatgtg agggtttatt tgtggactct caactgtatt cagttgatct 10860atatgtttat tcctatgcca gtaccacatt atcttgatta ttgtaggttt ttagtgagtt 10920ttgaaattag gaattttgtg ctctttgact ttggtcttgt ttttcaaggt tgttttggct 10980cttgtgggtc ccttgagttt tcatatgaat tgggataagt ttgtcaattt ctacaaagaa 11040gtcagctggg attctcacag gaactatatt acatctgtaa atcaatttgg ggagcattgc 11100catctcaaca acgttaagtt ttttcatcca taaatatgag atgtcttccc atttatttag 11160atcttccttt tgtcaacaat tttttattgt tttcagatga taagttttgc agttcttttt 11220aaaatttagt cttaagtgat ttattttttg atactattat aaattgaact gttttgttga 11280ttttcttttc agattattca ctgccaatgt atgaaaacat aattgttttg tgtattgatc 11340ttgcatcctg caaccttgct gaaaatacct gagttttgaa tacttctggg acttatgggg 11400aagagggctt ctgctgtttc actgaacgtt aaagcttatt tcatttcatc ctgtatgaag 11460gctgcataca agccttctgt atgaagggga cactgttgtc atttttactc agctataaat 11520ttgaactggt aatcccatcc cctttcagga tgaataggag agtgttttta aatgttcatc 11580tctttagaga acagcgggaa agaagcctaa taaggtttgg gtcgtttata atcccttttt 11640cagaatttgg atttgggaac tattagcaag ggagtgagta ataataataa tttctacata 11700gaaaactaac atgtagaggt gacaaatgaa atcactagct atatttggct tatgtttagg 11760tttttataag cagctaaaat cataattttg tgtttttatc tcttgtcctt tggacagagt 11820aaattccaat actccttctg atgtgcattt ctagatgggg aaaggattcc tttactctca 11880tataatttaa gcttcttttt agagatgtac tccatagcca tgaagcaaag ataaaattca 11940tctatgtaga gattgaactt tgtcttcatt aacactctag gctaaaggtc atagctaatc 12000agctacaact gtcatgtcct gataattgtg agttaactgc aggccaccca gcaaaaggtt 12060tagttataat ctgatagctg tctgtagaga ttaccctaat aaagggaatt ttttaaaaaa 12120gaatctggca ggggatagta gctcactcct gtaatcccag cactttggga ggccgaggtg 12180ggcggatcat ctgaggtcag gagttcaaga ccagcctggc caacatggtg aaaccccatg 12240tctactaaaa atacaaaaat tatccaggcg ttttggtggg cacccataat cccagctact 12300tgggaggctg aggcaggagg atcacttgag cctaggaggc agatgttgca gcgagccgag 12360atcatgccac tgcactccag gatccgtcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 12420aaaagactct atcaatcaac cacttttcat taagcacctg ctatgtgtcc agcatgtact 12480aggaagagat aagataaaag gggacacaat tcagacagaa tcttcttgag gtaattgctt 12540acaaggagct tatagccact gaaaacaaaa acaaacaaaa acaaataacc aaaacccaaa 12600cagaaatgca gcaccatcat gccataatgc ctgtatgaga tcctggattg tacggtgtgg 12660atctttttaa atgtagatat ttaaaaaaaa aaaaaaagag agagagagag agagaaatga 12720atcaatagag gctgaagtgg tcaacaatgt tacctgtggc tgcttttaat cctttgtggc 12780agtaagtagg agcatgtcta aactcaagca atagattaaa gatcctgatg tatattttaa 12840ataacagaag ttggtacctc tggaaagaat taactggagg catgggttga aatctatttc 12900tgcttattaa atagtgcacc ccagtcaagt tagttgccaa ttttttttca gtttctttgg 12960ctatatcatc gcacttgttg ggtacatgtt tttgatgtat ttatctgaac aagtccgcaa 13020taatatgagt aataaattag aatagaaggt gattaatagc tctgaatttg atataagatg 13080cccagtgtgg tggtcagatc aagagttgtt tttcggccgg gcgcggtggc tcaagcctgt 13140aatcccagca ctttgggagg ccgaggcggg tggatcacga ggtcaggaga tcgagaccat 13200cctggctaac atggtgaaac cccgtctcta ctaaaaatac aaaaaactag ccgggcgtgg 13260tggcgggcgc ctgtagtccc agctactcgg aggctgaggc gggagaatgg cgtgaacccg 13320ggaggcggag cttgcagtga gccgagatcg cgccactgca ctccagcctg ggcgacacag 13380cgagactccg tctcaaaaaa aaaaaaaaaa gagttgtttt tctgccttct aagtttccat 13440tgatcctgat ggattgcaca aatagaacaa ttcggggagt atgggggcac atgacgatct 13500tataagagct ttgctgtaat agacaacgta acattctgaa acggcctacc acctaacatg 13560ggctctggtt ctctgcaggt tgagtgagtt ccttgcttgt ggaactgtag tcccgctatc 13620tggccgctag ggggactgca agtgccccgt ggcaggattt ccctgggaat ggtgagcctc 13680cattgacggt ttcaacacac agccaaggcc ctatcgcagg ataacttcaa ccagaactgc 13740ttagcaccag acaataaata agctactatg gtacttactg tttcatttgg gatgttcttt 13800ctcgaagtgt caagcatttt aaagtaatat tttgactttt taatacctct ctttgcatat 13860ggagcaggac acagcaaata tattcaagta gcactgtcca gtttatagag aagtttcata 13920ttccattatt gcatttcatt cttgtttcta ccctgtacaa gtaactagag tttggagtat 13980tataatagta ttcatactat tacaatactt ttattcccat tataaaaatt atgctaagag 14040tggttaagtt acatgtttac aatcaaacag catcaaagtg acagatctgg gatttcagtc 14100tcattctttc ttctccagat catgtgttcc ctgcttttat ctcacagctc tttttacctt 14160atagatagga aacatgagag tcagagaggc aaaagaacca caagtggtgt caatactaga 14220aatttatgaa gttcttaagg cttctaggtt tgttacccat ccaccagact gatggatttg 14280gttgtgtgag agttctgggt gtcaataacc ttgccattct actttacaga ctgcatacat 14340tcaataaatg cctattaagc atctactatg tgccaaattc tgtactaggc accaatgatg 14400tagcagcgaa cagaacacac aaaaatatct gaatggagct gacagtttaa tgagaggaga 14460catgtagtat acatctgagc atgaatagtg tcatgcagaa taacttcaga gtatagggta 14520tagagattca tggtgagagg gaatatttta tatctgctgg ccagggaaaa ccttactgga 14580aaggtaaatt ttgagcagtg acctgaagga aattaggaaa tgagctgcta tttggacatc 14640tggagttaga atattccagg cccagggaac cacaggcaca aagggcctga ggcaggagag 14700catgcttgct ttgatggagg acaaaaaggc tcatatggct ggtttaaata agtgaaggat 14760ggtagacaat gagatcagag ttaatgaggt tgcatggtag gtcttcttta agactttgga 14820ttttactcct aagcagggtg tattggaagg ttttgagcaa agtaacatga cctgacttac 14880actttaacag gctccctcct cttcataaca tctgtcactc tgatatatta tacgtttgtt 14940tgtttactta ctgtatgtgt ggagaagaga ctgtgggagc aaggagggaa gcagggagac 15000aaggccactg cagtgatctg ggtgagaggt aaccatgtct cagactaagg tagtattggt 15060ggagaagata ggaagtggct gaattctaga tgagttttga tggtagagcc aacagcattt 15120actgacaggt tggatattca ctgtgaaaaa aatagaggag atgaggatga ttgccaaatt 15180tttggtctga gtaactggaa aaatgagatt gccatttact aaaattgtga agactgtatg 15240tagagcaggt gcatgggcag gatagaaatc aagagtttga ttttttactt ataaagtttg 15300agttatctga tgagcatcct gatggcttct cagttttcat tcagtgccct cagctttgct 15360gttcttcaag aagattaaaa aggaccttag agatcaccta ggctgtaggt accctctccc 15420ttctttcctt ttactttata gaggtctata gaagggtagg gacttatcca aggtaaaaca 15480gtgagctggt gacagaacta gggcacaaac ccagttctct tcgattctga ttcagtagat 15540ttttgtgtgt gtgtgtgtga ttctgaggac tcatttgggc aagagtgagt tttttgtttg 15600tttgtttgtt tgcgcaaacc taaaaccagg tgattaaact aaatagtgac taaaactgga 15660aaactataca aattggttgc tctccccaat caaactgaaa tattattatt aggtttttac 15720tgaactacat accaaaatat ttttttcctg taaaaacaca gtaagtgggc ttttaaaggc 15780aattgagctt ttatcaaagc tagaatctac agggcacctg gacaaaaatg gcctaaaatc 15840ctaagaaatt agagttcatg gaacctggaa gaccatcttg tccagctagc tcattttatt 15900ggtagagtgc ctgaggcacc gagatggaaa gggacttggc taagctcata cagcaagcta 15960gtgcctgacc tagtcagagc ctgttctaag tattagttgt atgttgtttt cttgaaaaaa 16020gtctatattg gaaaaatgaa aattctttgt tccatactga gaacaaagaa ttatatataa 16080tcatatataa taataatgat agcacttact gaatgtttgc tgtgtaaact tccgcacctt 16140gcatgaactg attcatttaa ttctcatgtc aactttagga agcaggccta gagacgttaa 16200ataacttgtc caagggtcac acagctagga agtagcagaa cttgtgtgca ctcccaggaa 16260gtctggcttc taaccacaag gttctaacta ctgtgcaata tcagcagctt ctcagattac 16320tcttcacctt caccatccca aaagactggc gacataggtg acttcattat gcactgcccc 16380tattatagtc cactgatcct caccaaatag ctgggtggcc tagaggttaa agtaggggca 16440cagtgatgga aaggggtggt tagaagaggt tgataactta tgatagggat tggaaaacag 16500aactctagga attattgaaa agggcctaga gatcccaagg aggttgatct cagactgcta 16560caaaccaggg caattcgatg cctgcttaaa taggagagtt aagataagaa aaataaaatt 16620gccagttttt acagtcaggc attgttttat ttcttttaca tgtattaatt cgtttaatcc 16680tcaaaataat ccatgaggta gctacaatta tcatttctat gttatagatg aagaaacagg 16740cacagagcaa ttaagtaacc tgcccaagat tagagaacaa gtaagtgaaa gtgccaatat 16800tagaatctag gtgattcagc tccacaactt atgttatttt ccaatacatt tatggaacga 16860ggtaattttc atataacaga aagtgtttaa agtgcaaaaa cattgtgcct gaacttcaaa 16920cattgaacaa ctcatatcct taatatacac cagctgcttt taaggactct tagaagtaag 16980gatacttacc taaagtcata tgttgaacaa gtagcagaac cggaacttga atttgagact 17040ccagactgcc agacctcttt ccactctatc acttgggctc ccttctaacg ttgatttgtc 17100tctctccatt cttcctccgt attgctctgc ccttcacctt ttaattacct gtctccatca 17160acaagattgg acagagaatt gggggagtga gcagagtcca tttccttcca gagactggac 17220aaaaggaaca aaatgttggg aaaaaagtca gcatgtggat tttgtgggat ttacactaaa 17280taagaacgga cacttgccag gactgacaag atgctacctc aatccctcta ggccccaatg 17340tgttatgcag gatcccataa gaagtcatga atgtagttgt cagataatct ttttgttact 17400gtggaaatgg aagcaggata ctgcaaaaat ctgtctctcc aggttttctt ttaaagaagg 17460tacagtcttg ctaaatgata actgtttgga catttatttg aaaatgggca gtgcaggaga 17520gaaagaattt ttccaagctt gtcacattgg gccatctctc tgaagcattg tccaacctct 17580aattagatga ggagactgca ttaaccaaga gttgagagta aagatggaaa cacttgatgt 17640ttggtgtttg ggtgcagaaa ggattccaaa acatgttctg agtttcttta ctctgcccat 17700ccctccttcc ctttcatctt tgtttaaaaa ccatggttag caaatgtgtg tagtctgttt 17760gcaattgttc atctgaaaaa tttgtttgat cagccttttg aaaaaaagat caaaatagac 17820tgagatattt tagtcaccaa ctatctaata atagaccaaa aatttaaacc atgctcatac 17880tttcatatgg tatgtggttt gttttagacg ctttctgggc ttcgctgagg tgctagattg 17940actcaaagta tggcaggtca gatgtggaat tgagtagggt ggactcttct ctatgcctcc 18000agattcagaa ttccccatca gagatgatct catagtgttt ggaaaaacca agctgaaggc 18060tttgggaatt agggtggtga agggatatgt tgtttcccaa agccttctca gtcattcctt 18120ctcccccaat tcagattctt aacacctctt gccgggatta gtgcagtgat cccacatcct 18180ttctctctag ctctctctgc tactctctaa ttcctattgt atttgtgcca ccagatcttt 18240ccaaagttta gctccaaccg tttctgtata ctgctttaaa tgtctattag tctttaagct 18300ccataagggc aggagtcctg tcttattttt tccctattct tcatgcttaa tacaaaggaa 18360gctttgtatg attaaaattt cagcttctcg ccattggctt atgggtaagt ccaaattatt 18420taaatctggt gttcaagtcc ttttatgatc tgcttatttt tccagcctga attcctggag 18480ttcccttaca aaactcttaa aacccagcca aatggatcta gtcaccgtca ctttaaacca 18540tcctcactct cttgtttttt gaacatgtta cttttattat tatccctttg accttgaagg 18600ctatcccaat ttcaatacta tccattcttc tataacagtc ccctacaaaa tgaatattat 18660caacccccca acccaaggag aagtgatcta tatgacacaa catggttgaa agaatgttgg 18720tttcactact ttatctgtaa accaggggct agaaatctct agtttataag attttgtgga 18780gaggggatca catgtgatta tggatgttag gctcgagtca agagtgcata agactttttg 18840gatttatccc tttcttcttt ctccatcaat atggtactta gtcccttaag tactcgtggt 18900acttgtgtta atgactgata gcatccttct aaatatactt ctaaacatct gtctcttttt 18960agggcaaagg ttggatatat ctgcaaagat tctctttgga tataagatat ccacagcaca 19020taacttaaca gtgttgtaca tagtagatat tccataagta tttctttatt aaatgattca 19080gagtcaatag tagtaagtga ctgccgaaga caactgatag attgtaagtt ccattaacag 19140aaatacagtt agccctccac atccataggt tccatatcca cagatttaag caacagcaga 19200tggaaaatat attttagaga cacagtaaaa ataacaattc aacagtaaaa aaaaaagtta 19260tgtaaaacaa ctatttacat aacacattgt attggctatt acaagtaatc tagatataaa 19320tgaaatatat gggggatgtg tataggttaa atacaaatgt gacaccattt tatatgtttt 19380aggtaaggaa catgaatatt tttggatttt ggtattcctg ggagtggggg aatggaacca 19440agccccttca aataccaagg gactattata tgggatacag aataaaggaa ttgattgtct 19500tgctctgtta aattctggtc agacacattt gcaatgtgtt gttcagcccc aatattcatg 19560gagcatctcc ttttgtaaag catggaggag ctatgagaga gacatggagc agtgaacata 19620actattgttt caatgaacct gaaggattat catggaataa agaagttaga tgtttttctg 19680tagcacccca aagggcaaac gcaatgagga cagattacaa ttcagtaaaa gaaagagttt 19740tttttttttt gtttggtttg ttttgttttt gggttttttt gggttttttt tgtttgtttg 19800tttgtttttg tttttttttt tttagatgga gtcttcactc ttgttgccca ggctggagtg 19860caatggcgca atcttggctt actgcaacct ctgcctccct ggttcaagtg attctcctgc 19920ctcaccctct ggagtagctg ggattacagg tgcacaccac caatcctggg caattttttt 19980tttttttttt ttttagtaga gatggggatt tcaccatgtt ggccaagctg gtctcaaact 20040cctgactgca ggtgatccgc ctgcctcggc ctcccaaagt gttgggatta caggcgtgaa 20100tcaacgagac cagcctgaaa gatattttct tagaagggct tctttcatcc ttcatcagaa 20160gttgttaaca tggaccatat gagttttgtt tggtctatat ggggtgtgtg tgtgtgtttg 20220tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtattgaat tacttgctaa cattttactt 20280caaaattcag atttccaccg tagggaatga agatctgaca atacagaact ttcattctta 20340catggtaatg accagctgca ggtgaaaagc agctgatcct ctggatgggc catgcacttt 20400gcagtttgcc caggcaccag tgacccactt tattcattta agttacctgc ttgactcttc 20460tagtcattcg agtatgtcat ccctgtcaga tcagagacct aagcaaatct tgagtccctt 20520gcttactcca agggctttca ctcctcgtat aggaggggct aaagaaatgt acaagcagca 20580ccacaatagg atcagacctg actttcaatt ctagcacagc catgtaacat agttggatga 20640cctcaggtca gtaatataac ccctctgagc ctctagatct tcattatctg tagaacactc 20700tccttacaga gttattgtaa gaatgaaata aaacaactag gataaagggc attacactta 20760gtaggtgctg aaatattggt tcccttcttc ttattcatca caccatttct gtctgtctat 20820tggctgaatt acataaatag taaattcaca ttcactgaag acatttaaga agagtctgga 20880ccctttggga accatgtata ggacaaagat ttggactcat agattatttt tacagtcact 20940ttctaacaat ttaaaagcct atggatgact ccaaaatgcc catttggatg atttgaggca 21000tactttgtgt agttaaggat tttaaataca taacagagag actgaagggc ctttgggaaa 21060caagctgggg taagagtcaa aatgtaatat gttgactgat gttcaggaat aggctttggc 21120atctgataga ttttgttttc agtactgccc ctgggtctta ctagcttcca gttctgggcc 21180acttcacctc tcttgagttt tagtttcttt atttctaaaa tgaagatact aatgcttcct 21240ttgttgggtt tttgtgaaga taagtgagat aataaatgta aaacatgtag cccagggcct 21300ggtgcatagt aaaagcttca taaattgtac ctattattat tagtagtagt agtagtccag 21360acaaacagag cttgggaaaa tgctagactc tggctgacat acatggactt ttccccaggc 21420cactgctgcc tggcttcccc ttccacaaag ctttgagtct ccaaaatgct ttggctggaa 21480tgtaagcgtg aggtcattgc agataacagg ggagcatgat ttgcttcggt aatgcaagtt 21540attaagttac ttccctcagc ccagctaaaa tctcttattg gttgatgttt gcttcaaagt 21600gtgagactga gctagtttga ggagagaggg agagtaagaa gattcctctt cttggccaga 21660ggtcatggtc ttccacaagg aacagaatga ctcaacgcaa attatgggac ctctttgagt 21720ttggggcccc tacatttaaa ccagtcactc cattgcacaa attggtaccc ttcccccaac 21780aaaattactg ggcaggaatt ttcttgactc cttccatggc ctggaatgat ctcccttctc 21840atccttgtga tccacacagc tggcaaatgg caggcagcag aacaaaaaca agcctcttag 21900catagagaga gagagaaaga gtcacagcag tactgaattt gcttgggaac ctaatgttaa 21960caaaggatct tcctctcaac accccaaaca gattaaaaca ttttttttta acagcaagtt 22020gtgtctcaga gcagctcttt gcttgggtat atttaaagat ctgctgagtc atttaagagc 22080aggctggcag atcgtaagag gcaaggacta taccccagtc tatgggggag taagttgaga 22140ggtgaaatct gtttggcttt ctcccatgtg aaacaaacaa ggtgatccac ttccatctcc 22200cacaactctg gagagcatct actaaggctt cttattctat caactttgaa ctcctcagag 22260tataatagag taagggtgag agggaaggag cagttgtacc agtgtgtctg ctgtctgaaa 22320ttgtaatgcc cctgcattgg tagctgagag tagcatggaa gtgtcaggtt gatgggttca 22380tttcattctt ttcttttcag tttctggtca catgcattgt taccatggca tatgacagtt 22440gctagaaagt gaaataattt tttctacttt attcttaatt gcacttctaa atttattaaa 22500ggagaaatta gcagttagca actgttaact ataggtacac attggggttt ccttagagcc 22560aattttcccc ctagttttca acttgtaaat ctgatagatt ttgtcctaaa agttggcaaa 22620acctggagct tctctttggt cctggccttt ttgaaccctg ttccacagag cccaatcttc 22680tttcttgttt gagacaacta tccttctctt tgcccactgc cattttcctt catctacttt 22740tcccatctct agcacctcag actgtcttcc cacagtggca cagactccca ctccactttc 22800actgtgccat cttcttgcta tcaaaaccat cctcacagac ccttactttg ctgaaaccac 22860ttctaggaag ggaaatcaca gtggatccat gaaggatgct ttctggatga ctttaaaaga 22920ttggtattaa gatattttat tagtggtggc aacactgact tactcaggca gccatgccca 22980ggatctataa gaaatcagat aagctaaaag ttgcttgagc tggcaggaga cctagttctc 23040tgttttcctt tccctcatgc attttgttta tcaatggttt tcagagggct tagaggctgg 23100ctttgttata gttagttggt

aagagaaatg gtggaggact ggaaaatggg agtggaacca 23160ttgagcatgt tattacaatt cctaggatgt ataaatcgct tgaaagtcta ccaagtactt 23220tcagacacat tatctttttt actcttcaaa atcaacttgg aggtaggcac aacagggatc 23280aaatccttag ttcacagatg agtaaaacga gactggagga aattaaagga cattccaagg 23340taactcagac aataagcaac agaactagga tttgattagt tttttggggg gtggggagga 23400cagagtctca ctcaggctgg agtgcagtgg caaggtctcg tctcactgca acctctgcct 23460cctgagttca agtgattctc atgcctcagc ctcctgagta gctgggatta cagacatacg 23520ccacaatgcc tggcaaattt ttgtcttttt agtagagatg gggttttgtc atgttgccca 23580ggctggtcct gaattcttgg tctcaagtga tccaccccca ttggccttcc aaagtgcgtg 23640gaaccactgc tcccggcccc ggaccattaa tttttgatgg taggtccacg ttttttcaag 23700ttcacagctc ggatttgcta tataatgaat gaatgagtat atatgtcatt tgggaacatt 23760attccaactt tcggttgaag atttgtttta tcagttgtgg aacttttttt catttttagc 23820attatcagtt tagttaaatg aacatttcgt tcatgaattc actaattaat tattttattc 23880atcaatacat ttcctgagta ccaaactttc tatcaaatgc tgtgctggat tctgaggcta 23940caaaaagaaa tacgacacca tctcatgact ctaaaatatc acagactggg gactgacatc 24000tcagtagtaa acatatgaat agcaacttat gaaatgccat tagaaaaatc tcaagttata 24060ttcctcagtg agtatggcca tcctaaaaat gagaagtctt ttattttggg tacatgaaaa 24120tgaagcgttg tgagaaattg cattttaatc taatcttgtc ttactaagaa cagaagtgaa 24180atgtttcagc ctctgtgtgt gtatttgtgt gagtgaaggt tgagtgtgtg atgatggatg 24240gggctgcgag attgctaagt aggatctatg gggggcctta gatggtcctg gtgagtccca 24300actttctggt tatgtatttg ggtgcagtat gggagtgaca aagattgttg tttaagagtt 24360gattttagat tttttccaag taaatagtca gcagacttgg agcatcatca ttccacttgc 24420tttgaaaacc taccacttaa ggctccttct tgtcataggt taactctttc tggtcaagta 24480ttactctttt tgagcatttg cctgtcagtg acaggtgcaa tgttagatgt tgtctctctg 24540ttttcttgtt taatctttac tttgatccta ggtagctctt attagttcca ctttataggt 24600aagaaactga atttcagaga ctttaatgac ttgttcaaga tcacatagta agtaacttgg 24660tagtttggga cttgaatttt gattgttcaa ttttttttcg tttcctggcc tcactgctgt 24720tttcactatt ccacaccact tcagctttat ttttcacaga ggccgttaaa tgtaccctcc 24780atcagccaaa gcctcttgcc tcccttcaac gtaactcttc tctagcgtgt tcctaataat 24840cttctgaaaa ggttttacag cctttctggg tactgggacc cagagtctta atccaggctc 24900ttaagtgcct tagttaactg taatatggat aatcaaagtc acagctaatt caggaaaaat 24960gagtttggga tgtgaatttc ctgggcaaca tgtcatctct tttttactcc cttagcttca 25020taaacttacc cacaatgttc cctgaggact aacagtaatg gagggtgatg aggaaaggct 25080ttcctccctt cctggtttcc aagagtcctt tagccaaatg ccacacctcc tcctgtttcc 25140ctagtctctg tgcagagatg gaggtgggag atagacatgg gttcttttca gccctgagtt 25200catgccagag tttttttttt ccctctagct ggagtgaagt aggaagagag gttcaatgtc 25260caccaagaag accatgagtg aagaagacta aagtacttga aagaacatca gacctatgcg 25320taaaatacca gggtttgtgt ccagactttg tgggttacta tctgtataat tttgggcaag 25380tcaacagttc tgagtcagag tttccttatc agcagattgg aagataaatt ctaattatat 25440ggatgaaaca ttaagtctag aagtattttg taaattcaga aagggcttat agatttaaag 25500tgtagctgtt ttatcacata ctaaatccta tacttcaggg ataaaacctt ctcctgtttt 25560ttctaaaagc ctgtgcatgt gtggtgtaag ggatgggttt tgcccctgta ccagccactt 25620agcaattgta gtaactgggg gctgagggca gtggcctgct tctgcactga gcaagtgtga 25680aaagagggta atgcattcag gggtcagcag atgacaggca gagtagcccc tccaaatctc 25740cctcccatac cgcaaagccc cttatttatt caaacttaac attggaaact catttcaagt 25800aggtacgtct gtgtctgggc gtctattttc tttctttgta tatagcaggc atttgtcaac 25860ttggtgaaaa gcattaccct tctttccatt tctgaggact aattgtgctt attcgctaga 25920catgagttca aaacagtggg ttgaaagagg gcaagtttat gccaaagaat cagaagtagt 25980cataatttag agagaattct agaggtcagt tccctttcgt gtggattggg caactgaaac 26040ccagatagaa aagcggatta gaccaagttc acaagcacaa acacgttact ggcacattca 26100gattggaagt tgagggcttc tgctcccagg tcagaactaa atgccctttc cagctagggc 26160gttctttgat ctcagtgatt tggactcttt ctactacact ctggggacag tgggttctga 26220gataccaact ccaattaaag taggaatatg taccagctcc tccccttggt ttttttctag 26280aggcctggca ttcagaggca gtgtgatctc tatatgtaat attttcacac tattgttctt 26340atttaaatca catttgaatt ttggcaatta acaaggcagt aattggcatc aggaaggtat 26400gttagtttgc ttatctgccc catcccccct cttcccgacc cactgtgcat tgcagaatgt 26460tttatcagct ctgatttgcc aagttgctct cttctccagt aggtgctgca agcagagagg 26520gattcctcgg aggtcatctg ctccatcttc ttgcctatgc aaatgcctgc ctgaagctgc 26580tggaggctgg ctttgtacca gactttgtac agggaaccag ggaaatgaat gcagagtgct 26640cctgacattg cctatcactt tttcccatga tactctggct tcacacgtgg gaggttcttc 26700agctgaaaac ttagaactca ttttctaggg tagtgagtgt tgtaaggttt ggactgtgac 26760ctaatattat gcagccatga cattatctat taggcatcta gaccagcttg cttgaatatc 26820ttagcatgtt gactaatttg gggcagacta cagtgtgggt ggaggattgt gtgtgtgtgt 26880gtgtgtgtgt gtgtgtgtgt gtgtatgggg ttgagcaatt cattattatt aatatgcaaa 26940aagcacttat ttcgctatga caaggttgcc tttttcatgc atattggcct acctgcaaga 27000cccctagaga cagtaagcaa catacatggt gtcttccagt tttcagcctt tgtgcaagga 27060acaactgtgg gtttttgcat gtgtgttgtg gtttgatgtt tgtgtgtgat tgtgtaccag 27120ggtatgtgtg tctgttactg tgagttcact tctgagcagt tgtgacacac agagatccag 27180aaacagtgtc ttactctgtg tgctctgcta gtgggaacgt gtcttctctt ttgtgctcgt 27240atctctgtgt aatcaagtgt cttgctaagt cagtgtgcct ctgtctcttt ttaccagttc 27300ttccgtcttt gtgtctctat gccttcttgc gtttctttcc cctgagtttg cacatgtctc 27360tgtctatgtg gatatctctc actccaggcc actgtgtcac tgtgtctgta tttacagctg 27420tttctttctg tcggtgtgtg gattctttct gtcggtgtgt ggatttctat gtctgttttc 27480atcttaattt gtgtgtctaa gcaagaagac tgttttgggg tcactatttc cgtttatgtc 27540atagccccga ttgtccccat ctccatgtct ctctgtgtgt atatgttcta atgtatctgc 27600ctacttatct ttattcgtat ttctctgggc atatatccct ctcttgcagt tcttggcctt 27660tgcagttttt ggcttatgtt tttgtatata tcgactagaa ttggcctcct tatgtttttt 27720gtgcatgttt tagttttttg tatatatcca ctagaattga cctccttatc atttttgtgc 27780atgtatgagt gagcatatcc aactctgtct ttgagaagca gaactgtcta tgtttgcagt 27840caattgtgtt ggctgtccct gtgtttgtcc ctgtgtgtgc atttcattgt atgtgcaccc 27900attcatgtat ctttctgctt ctgtatgacc atatacttct gtgtagctgt ctatgtatat 27960tggcttctat ctgtgtctgt gttgttggct acatgtctgt gcatatgcac ccactgagtt 28020cataaaaagc tcacctgctc tctaaggaat ctaccagatt gttttgtgaa ataactcaca 28080tctcgttttt tacttgctta gttatcttct ggcttgccag atgctttggt acttaaaagt 28140gtgttggtac gtaggggtgc ataatttatt catgtaggat gtcaaaagag tcagttaaaa 28200attatacaca gtgtgtcttt attaacagga cagttgtgtg tagagaatcc ttgagaaatg 28260agcggttaga tgataaatct tttcatatta atttcatgat ttgagtgaag taaatttgaa 28320aggtacaggc tgcataagag ctatgtgctt tttaaaactc attgtattga tggtggagaa 28380agcatttatt tgtactgcaa agtcttattt gtgatgttca ttactgggtt agaaggtgtt 28440acttttctga ttttgtttgg ctttttgaag agttactaca aatgacatct tagagacaaa 28500gagctctgaa ggtgacttag aacacatgga gtacagacaa aaaggagaat ggaaaataac 28560agagagatgg gcatattcct catttgaatg gagtcagcca ggggctcagg atggggtgca 28620caggaaatgg agaggtgacg gtcatagaga gaagcttagc aggaccagat ctttccttgt 28680cctgggctgc tgtgaccata taaggaaggc agtaagggga ggggtaggga tgaggaagag 28740accagctctc cctttctttc tgatggaagg ttaccacctc tatttaaaac ttctgttctt 28800ttggttctct ttctttgttt gattatatta ttttctggtc ttgttctgcc atagcaagaa 28860ggaaattcca catgtggctc actcatttat tatacttgtt tctttgcatg atattataga 28920gagcttgtta agtgtcactg cgaacatcac acacactgat ccactgatat gggcagggtg 28980gtctttatgc cagctctgct cccttcccag tgtatctgtg gtgcttaatg gggacaacca 29040tgatttttct gatgtcagtc tgtgatgtca gttgtccagt gtgtatgcag actgcttaaa 29100agtacataca gttcctttgt aattatggta gtccctgaga aggaagtgct cactaataaa 29160agactaggtt cagtagaaac atgtaagttg tctaggtgtt ggaaattaat atagtactct 29220gctaagggaa tatatatcta gaagttaact ggattatgct caataaaaag attacaaaag 29280tttcataaat atttttaact aattctataa gattaggaga gggatatttc agatattcaa 29340ataatttttt taattgacaa acaccttaga catattattt acatacaatt gacataataa 29400ttaaatcatt atgtctgttt tatgataaaa caggatcttt tggcttagtt tgaattattg 29460aatgtaaaat aatgaaaatt taaaaaaaac agaggaggaa tctatcctat tttataattc 29520agaccgttga attgaatttt tcttttgttg tattgatttc aatgtagaga agtctgtggt 29580gctggattcc agtcaaaaga taaacatttg tatgtgggct ctacattgca gccaatcttg 29640ataatttcaa accttgattt tctcatctgt ataatggtaa taataaagac tgtctcagct 29700accaaatgat tgcatatgac aaacctctca cttatgtaag ggaaaaaaga aaaagaagga 29760caatggggtg gatttttcgt atagtaaaat ttattcagtt agggtaatat tctgagcttg 29820tcttctgaag caaaccctgc aaactctggc cattctgttt tgtttaggaa agagttaatc 29880agttctgatt ctgcgttttc tggggaagga ggctgagtat ggattgaaga ggagtcacta 29940cttttctgag atgatatatc tgtgctaaaa attagtaatg ctttgcacat gcaacataca 30000gtgttcaatt ttgttagtca acagatattt aagtggcagc tgttatgacc tcaggggtgt 30060agtgacttcc ttatataatg tcctttaatt attgaaaaag aaatctacat cagaatatca 30120ggtaaaatct tattacatca aatattataa caaagatact ttttatattc tctaaaaaaa 30180gtggagatct cagatgttgg ttcatttatc aatataatat tggatttgaa aattccagta 30240tacaaaggga aaaagacagc ttcttaaagt ttatagtgat tttctatgaa ctttcaattc 30300aggatttttt ctgttttact ggtatgatag agctaaattt cgaattgtaa gtagtagatc 30360attagactgc agggtaagcc ttgagattgc ttcttttcag gtaggaaact ctactgtgta 30420tttggctagt tcaacatatc atgggtagtc aaaaatagtt acatatccaa gtcagcattt 30480tttaagttgt tcagttgtgc ttaaagattg gtcctttcca ggaccaatcc agctttatca 30540aaaagttatt atgtacatct aaagtgttct gacattttaa tgctcacagt agccgaatga 30600tgtgagtagg aatctttgtc ttcattttat agatgaagag acacagagaa ataaactaac 30660tgggccaggg tcctaccact agaatgtgac agatgacaat ttgagcccag catatagttg 30720tttccctata atattcgttt tatgattgta tagatatctg ctgaccaacc ttaatctctg 30780ctccctgaga ttaaccgttc tacaaagcag aaactggagg tcgttcaaat gaaaactcta 30840cacttttaga gggccattaa caatgctcaa gttaaagaaa agcaatcaaa gacaactgaa 30900atactggtac cttcagacag tacatatgga tttttttttt tttttttgta ttatacttta 30960agttctaggg tacatgtgca caacatgcag gtttgttaca tatgccatgt tggtgtgctg 31020cacccattaa ctcgtcattt acaataggta tgtctcctaa tgctatccct cccccttccc 31080cctgccccaa aacaggccct ggtgtgtcat gtttcccttc ctgtgtccaa gtgttctcat 31140tgttcaattc ccacctgtga gtgagaacag gcggtgtttg gtttttttgt ccttgcgata 31200ttttgctgag aatgatggtt tccagctgca tccatgtccc tacaaaggac atgaactcag 31260ccttttttat ggctgcatag tattccatgg tgtatatgtg ccacattttc ttaatccagt 31320ctatcattga tgtacatttg ggttggttcc aagtcttggc tattgtgaat actgccgcag 31380taaacatacg tgtgcatgtg tctttatagc agcatgattt ataatccttt gggtatatac 31440ccagtaatgg gatggctggg tcaaacggga tttctagttc tagatccttg aggaattgcc 31500acactatctt ccacaatggt tgaactagtt tacactctga ccaacagtgt aaaagtgttc 31560ctatttctcc acatcctctc cagcacctgt tgtttcctga ctttttaatg attgccattc 31620taactggtgt gagatggtat ctcattgtgg ttttgatttg catttctctg atggccagtg 31680atgatgagca tgttttcatg tatctgttgg ctgcataaat gtcttatttt gagaagtgtc 31740tgttcatatc ctttgcccat tttttgatgg ggttgtttgt ttttttcttg taaatttgtt 31800tgagttcttt gtagattctt gatattagcc ctttgtcaga tgagcagatt gcaaaaattt 31860tctcccattc tgtaggttgc ctgttcactc tgatggtagt ttcttttgct atacagaagc 31920tctttagttt aattagatcc catttgccag ttttggcttt tgttaccatt gcttttggtg 31980ttttagacat gaagtccttg cccatgccta tgtcctgaat ggtattgcct aggttttctt 32040ctcgggtttt tatggtttta ggtcttacat ttaagtctct aatccatctt gaattaattt 32100ttgtataagg tgtaaggaag ggatccagtt tcagctttct acatatggct agccagtttt 32160cccagcacca tttattaaat aggaaatcct ttcccaattt cttgtttttg tcaggtttgt 32220caaagatcgg atggttgtag atatgtggta ctgtttctga gggctctgtt ctgttccatt 32280ggtctatatc tctgttttgg taccagtacc atgctgtttt ggttactgta gccttgtagt 32340atagtttgaa gtcaggtagc acgatgcctc cagctttgtt cttttggctt aggattgtct 32400tggcaatgcg ggctcttgtt tggttccata tgaactttaa agcaattttt tccaattctg 32460tgaagaaact cattggtagc ttgatgggga tggcattgaa tctataaatt accttgggca 32520gtatggccgt tctcattata ttgatacttc ctatccatga gcatggaatg ttcttgtttg 32580tttgtgtcct cttttatttt gttgagcagt ggtttgtagt tctccttgaa gaggtccttc 32640acatccattg taggttggat tcctaggtat tttattctct ttgaagcaat tgtgaatggg 32700cgttcactca tgatttggct ctctgtttgt ctcttactgg tgtataagaa tgcttgtggg 32760ttttgcacat tcattttgta tcctgagact ttgctgaagt ttcttatcag cttaaggaga 32820ttttgggctg agacaatggg gttttctaaa tatacaatca tgtcatctgc aaacagggac 32880aatttgactt catcttttcc taactgaata ccctttaatg aattatttaa ccttagataa 32940tttggctttg agctagaaag gtagagaaag atggaggaac caattcttcc ctgggttggt 33000acttatttat cttgctcttt tgaagtctag gtcaatcgtc ctatttgttc tgaatggccc 33060attcatgttt atccatttag ggacagcagg tttggcacaa atggattggt tttctgaggt 33120ctcatgtaga gggctgcact gactgacttc tgaaagtccc ctctaaccct tcaaatctcg 33180ggatcatttg atctcaagcc ttcattcatg catacatttc tatttccttt ttgagtacca 33240gcacaacact gcaggctgac ccactggatg gatagaatgg ggctcttgcc ctaccaccct 33300ttggcaaaca atttgagggt ggcattgtca ctatctcatt gatatagggt ctcttgaggc 33360ccagaatgac aaagtaattt tcccactctc acacagctag ttattgtcag agtaaatagc 33420aattttgaat ttgtagaaca cgtggtttta cctctatcat ttctgtttat tatgaaaatt 33480ttagaagtaa taattaatta gaagtagaaa tgatgattaa aataaatgcg taactactaa 33540aaagtagttc attgcagcac cacctaaatt catctcacca ttctaccagt agtacacatt 33600tcgccattgg gttaacattg ttttggatct tatagctgtt gaagaagaca aaattctttc 33660cattctctag attatatttt ccccatttgt aaaacataat ggaagtgtat ggaaaatagg 33720agttgataat ttttaaggcc cctgtcagca tattggcaca taggattctt gtaagtggtg 33780gtttacttca cttcagctat ggaaggccta tgcgacacca cccatagagg atagtttgaa 33840agaaactgct agtgactgcg tgtgtttcct tcctgacata tttgctagaa ggtgatgagt 33900tccagctttt tttcagactt ggatctggct ttcattcccc ttctcctccc accctcttaa 33960acaacagagg cagcaaccat ttatacactt tccagaagta agtaagactc tattccagaa 34020acaccctatt tcaaaatgga aatatactca gtgccccaat gacccattgg gcgagtttga 34080acgtgtgcat tctctgtgct ccccgtttta gcttaggcct actccctaac ctgtcatatg 34140tcacccagcg atggagccta gggcaatgag tgccatcata tctgactttg tggcctctca 34200gctttcaatg actagctttg tagcagaagt ttagcctctc atccccagac ctttggaagt 34260agtgttgaga taaagagagg ttgaattgaa ggttgtgttt tctagatttc tttcaattgc 34320tccttaggct ttagaagaca aattctccta aaagacaggt gctacaatta atccaagcaa 34380agggaaagat gtcaatagag ctgccccttt tcgtagaggt gtggcaactg ctgggaagga 34440agaaattagc tggaggccgt gtgatcacta ataaaactca aagcggtgtt tttttacttc 34500tcaatatgag gttgaaacta taagcttaaa ttgctgactt tctggcagca ccaaacagta 34560aggaaaccac aaagataaac ccaaataata gagccaattt tctttttttg tgggggtggg 34620ggatgacttc taactggtga tatgaggaag gataagaaaa tgtttatttt aatctaaaaa 34680aaatggatag cacatatgat ctttgctaag tgcactgaat gtatgtagag gagacaagtc 34740tgctaaaggt atgagaattg ggccgagatt taacacattt tcaaagctcc atgaagaaac 34800ctactgaaca gtgggagtgg agcaggttgg ggatagtgaa gtatttgtaa tttattttta 34860aaaaggagag ggagagagag aaaaggaaaa actgggccac ccatcctttg aaaagaaacc 34920ttgaaagagg tccaaatatc cttagaaatc cttgacttct taaaagtgat aagagtttgt 34980tttttccccc tgacaattat agaggtcaga gagttttctt ttctattgca aaacattgag 35040agtgtgtaga aataattgta ggtagcttag ccttggctgt agtcagaact tttgtactgt 35100gactttagga tctgtataga attgtatgat atgaggatac accaaaaact ctatgggcta 35160tcaaaatggg atagcattaa aagaaatagt gcttttgttt agaagaagaa atgaaatgct 35220tgtgtccagg tgcttaaagg aaggcagtgc agactttcag aaactagact ttaagagcta 35280tactcagata ctgagaaggt ctgatggctg aaggaggaac aatttaaaag aatagccatc 35340tctcccttcc ctgtaaatta gacataaaag aatatcccat tcatctcaga aatgtaatac 35400aacattttag cttgctagta actttacatg ctatttcctt tacctcttat atttgaggtg 35460tctatttgga gtgggctgtg tttctagcta ttctgtttat ctggtttgtt tttgtttgca 35520taggaaactg gtgtacattt tatttgggta aatatcacct caattttcaa ataaagcttt 35580atttaagttt cacatgaaaa agacaaatga gacaaagaag agaataattg cattgtcaga 35640attataagaa aaaaatcaaa taaacatatt tgaaatgtcc agaaaaccta gagttttatg 35700tatattatac aggagagata ttctgtcatc tggttgccaa actatggagg gtgggagact 35760tagaattttt gtccaaaagt attgcttcat tagaaagata catgggtgtg cttccacatc 35820agcaacatga ctgcagaccg ggaagtcctc acggagagct ggaatatggg tattttggac 35880tctctggtaa gatgcggctt ttacttcact tcctcagtgg tactactgta aattttcatt 35940ttcctatgga ataccctatt tggttccatt gtatatagtt gacaactaga attcgttcgc 36000tgttgcttga actcaactgt aacttcttgg cactatacat atcttctgat gcgcctgtgg 36060aagagctacc ataatgactg tgtacatgga caaaaaaaaa aaaaagagag agagagagag 36120aattaaatca tgagtttgtg ccttgggagc tacagtttaa acatttgctg gttttctcaa 36180ttaatgaaaa atttatttga aaataacagc acagaaagga agaaagacag gccggcaagc 36240atcctcctcc taatatactt atccactttt ggataccttg atctcagtct cagaggtcat 36300atttttagta aaatggccac cagaagtaaa ggattttatt ttccagactt tggtgtttgg 36360agctggtgtg ctgagagctg gtagagaaag cgctactcag gtagatgtac caaaggagga 36420tggttgctgg tggatatggc agagtacctt ttatgtggtt atctcttcct tgtaactctt 36480ggctgcataa ctcttatttt cttttctatt tttgttctct ctcttggaaa aaatttggtg 36540gtaaattttc atatgagcca tattgtcttt ttaaatagtt ttattaatat aaaatgtaca 36600taccataaag catacccatt taaactgtaa aattcaatgg gtctctctct ctctctctct 36660ctcttttttt tttgtatact cagagttgtg caacaattat caaaatcaat tttgaaacat 36720tttcattgcc ccaaaaggaa accctctgcc cattagcagt tactccccat ttcccccacc 36780cccagtcccc ttcaacccta ggcaaccaca aatctacttt ctgtctctat agatttagct 36840gttctggaca tttcatgtaa acggaatcat gcagcatgtc accctttgta tctggcttct 36900ttcacttagc atgatgtttc caaggttcag ccgcattgta gcatctgcca atacttcatt 36960ccttatttat gactgaataa tattccattg tattaatgta tcatatttgt tttttccaat 37020catcagttga tggacacttg ggttgttttc atcctttgtt tttttcttgg ctattttaaa 37080taatgctgct atgaatgttc atgtacaaat tttttaatga acatctgttt ttatttctcc 37140ttggtataca cctaggagtg gaattgctgg gtaatatggt agcttaacat ttaacctttt 37200gaggaactgc cagatttttc caaagcagca caatcatttt acattttgac cagaagtata 37260tgggagtttt agtttctcca catcctcaac aacactcatt attgtcattg tccttttcag 37320ctcttttgat aatagtaatc tcaatgggtg tgaattggga ccccattatg gttttaattt 37380gcatttcctt gaagactaag gatattgatc atcttttcat gtgcttattg gccgtttgta 37440tattttttga tcttttgctc atttccaaat tgtgttgtct tttcattatt gagttgtaag 37500attttaaaat atattttgga tatgtttgtc attttaggga tgatacttca cagttacatg 37560atgttttcta gcaagcattt gtgttgttct actggtgtta catatcttag ctgcattagc 37620cacttcgttg ggtatgaatg ccagcagaat ctaaatgacc ttggcttcac tgctgagaat 37680gcaacccaag aacagaaatt tgtcagaaat ttaacactta agccccccac ttcccaaact 37740catctgggac aaggagaatc tacatttaaa gttctatatt ttgtgttgct gtggtttttt 37800tttttttttt tttttacttt agcttggttg ggtttaggat cttttctttt tgttttgcct 37860taggcatacc taagcagagg caagggagga aagggatatg aaactgatag aaaagtgagt 37920aagctttatt cagatcagca tattcatctt aatatggttc aattggctga agaaatatct 37980caactaaaac tctggaatac tttgaagtac caataaaatg tacctaatgt acattttatt 38040tatgtttggt ctctatgtac ttgtgtgtga aacaatgagc acaaataatt ccctcctttt 38100ttttaagcaa tttatattgg tgatttaaaa ataaaataaa tgcaagtggg aagtcatgaa 38160accccatgta aaacgaataa

gagcatatat taaaatccca cagactttag tttcaaatag 38220tggttttgct gtttcttagc tgtgtgtcac tgtgcaagtt actttgcttc tctgagtctt 38280tatttcttta ttggtgatgt atgtaaaaac ccaccttctc gaattattgt gaggacaaaa 38340tgaattaatt aacataaagt tcctggtgta taataagtgg tcatattttg tatttgagca 38400cagggcaact gagtttttga aactgcacat taatgttgca gtcaaatccg gcatgaaatt 38460agagagtgca tagacagagt gggctgggaa aatgaaagga ctttgaacat ttatattctg 38520ctttatttag gcatcagtgc ttaataatta ttgatagttt cttctggtta tctgacattt 38580tgaagagact attacctagc agaaatttct tgtaataata atctcttaca cttatatagt 38640gttttgtgcc tttagaagta cttaatgctc tttatttcac tatccataaa tattctctga 38700agcaagcata cagtcagtat caattccatt tttcagatga gactgcaaga catagagtta 38760cttgtttcaa ttcacatagt aaagtgacag tttgaaccag agcccaggtc ttctctctga 38820acatagctct ttttctcctt cattatatca ggcatagcgg caatgtatta ttttactagc 38880tttttatctt gaatatcctt ttagtgacct gcctttggtg ttagtgtgcc tataacattg 38940tcgttgaata tcttaataca tttagtggtc ttagcaagca gttttgtctt cagaaggaca 39000ctgaaatctg tggaaaggac tgcagaagat tgggtgggca gatacctatc actttctggg 39060ctggtagact ttctgttgaa gctatttgca aggctagttt gtattatcga aaagcactac 39120ttcagaagag ggttgtgatg tcaaagtagg cactttgagt gaagaaaggg ctgtaagcat 39180gggtggaaaa tgtggtagat gattgtcttg agttattttc tttaatgtca agcaggcagt 39240ccttggaatg ctatttcaaa aagtgttgta taatgttgaa gacacagtta cagatttcca 39300acacgaagct cataaatctg caattccctg tcctcctagg cacatgaagg aaaatttatg 39360agcttcaggt ttctatgcag ctattaaagc atatttaatc tgctttgagc tcaagctccc 39420tctcatttgc tctcttcgtt tgttcctctt acatgagcaa actgcctttc tttttcttta 39480aaagtagtaa gtagatttgt tttcctccag gtgtcatgaa tgcaaacatt gtaatacctc 39540atctgttagt tcagtctttt gcaaaacaaa atggcagcac ccaggaggtt gaaagagtta 39600aattgtttcc ttctctgagt ggtaccataa gttgttagtc tgctactctt tctcccagtt 39660ggcacatgac gctaacatcc aatcgctagt gatgtggcca ttttttgcct tattttggcc 39720tttcctcagc caccagtcat cagttttcat gcatatttgt cagaccctgc ttcctcaact 39780ccacagttct tagttcatct taagcaaatc gctgtctttt ctctaaagat cctcaaggaa 39840aataaaaagc atctccaggg ggaatttact gcctcatagc cctgacagag atttctgacc 39900aaaccctaac caaaaaattt cttccctcca tttgtctttt attgttttta caggggagat 39960atgtaacata ataacaatta tattgtacat aataattact tttacaaata ataatatctg 40020tcatcaaaaa tatacagagc tttggatttc cttagtatgg cacttcatta agttgtggtt 40080taagaatagc tatgattatt acttttgtga taattacgtt ccataatatg gaaacttata 40140aaattacctt taaaatgtta ctcttattct ggccacagga tggaaagatg ttcgctagtt 40200actcatttat aacctgaatg tactttttac tgaatctaaa ggtatcatct ttgcttggca 40260attcccatga cttgtctttc tgactcttca gatctcagct taaaagctca ctcttcaaag 40320aagccttccc ctgaccactc tggttttgtc ttcttnnnnn nnnnnnnnnn nnnnnnnnnn 40380nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 40440nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnngagtt tatattttaa ctcttagttg 40500aataatctaa gccaagaatt atcaaccttg ggttgcacat gagaatcacc aatgaagctt 40560taaaacagtg acaaggctat cccaatctat tcattaatta tctccaggtc taaactttag 40620catgtatata catttttaaa agctcataag tgattcttat gtatagccag tgctatctgt 40680ctcttctcct gttctttccc ctcctctcct tactcctttc tcatagtttt aagataagca 40740tggccccaca acaagccttt aattcgcatg gcagtttcta gggtttatca tggaaaatga 40800gccaaattgc cttcaagaag tttttacgta cctcttatat agagtgtgac attttatatg 40860tacctcttat aaaatgtgag cttttaagag tcatatctta ttgcaagaaa tttcaatgtc 40920gaaaaaagta ttgaatattt ataaagtcac aaatacaaac ttttatatga ttctcaaacc 40980tgtgaagtta tgtcatgttc aggccttctt taaagcatgt ggctctcagc cctggtactg 41040tccttaacca taaacctcat ctttgccctc tatagggaga ggattgtgat tataattact 41100cattttaaat aatgtatatt agtaatgtac cttattcata tatttgttga gcacctccta 41160tgtgccaacc actatgctag aaatttttta atattcttca aaatcttcaa gatattaaca 41220tatccccatt ttacaaatga ggaaactgct ctcaaagagc ttagtttaca cagccagtaa 41280gctgctaagc ctagattgga tggagggtgt gtgagaaaaa aagcagcatc cataaggttt 41340tcattctcct accctgtatg atagaggtac tagaaattat taaagaaaca atagaatttt 41400acaagacttt aggaagggag aatgtgaagg gtacagttcc cagttgctgg aatgagtact 41460ggagtaccaa tacatggctt gccatggggt ttggactacc tatcttaact cctttgctcc 41520tcccaatctt gatctcattt gtttgaaaga tcatctgccc aacataaaaa tgcatttcta 41580attctgtaat ttaagtcagt ggcaagatca gattcagtta aagtttactt tcctgacaac 41640tatttaggat gatatctatt ttgcaaaact ctagtgataa atgtatgcac acttacacat 41700catacagcgt ctcttctgat tctgactaag atgtgatgga gctgtgcaga tgtgatgggc 41760tctttggaag aaaggtttga tatactacta atctaaggac tgaattttct ctctcatctt 41820tgtttttgtc ccttttgaat gatgatgaga gcagcagcac ataacattct tttgtgctaa 41880cagtatctct gcatcacatt gatcaggaga attggccctg gaatggtatc ttctcagttg 41940attttcagga aagattaggt gattattttc tccataggaa gaggatgttt gatgtgtctt 42000ggctttggca aaaggaagct tgtcgactca actgtaagta gatagaattg cctttgactt 42060catctgtttc agtcgttgtt catactcagg tcctccagaa ggcctttaag catttttatt 42120gactttgtgg tctattacac aaaactaaag atactgattc tcagtcgtga gtctgcttca 42180aaattgccta gagaatcaaa aataattgta ccagttcctg ttcctggaca ttgtgattca 42240tttggtctgg tatgaaggcc aggaatctgt atttttaaaa ttcactcaag taatttttgt 42300atatagctat agttatgaaa ttataacaat aatgaaataa taataatgaa taatgaaata 42360ataatgaaaa tctgtggctg aacttgtcca ctcccctatc ccctgcaata cttccccaag 42420gtggcattta agatgggcct agaaggttat ataagatttg aatattaaaa catggattga 42480cagtgaggac tttttgagag gtgacaatgt gctagcagcc ctggcttgct cttggcacct 42540cctcgacctt ggcgtccact ctggccacac ttgaggagcc cttcagccta ccgctgcact 42600gtgggagccc ctctctgggc tggctgaggc cagagccagc tccctctgct tgcagggagg 42660tgtggaggga gaggcatgcg tgggaaccgg ggcacggggc tcatgggcca gctcgagttc 42720ctggtgggca caggctccac cggccctgca ctcggagcag ctgactggcg ccgtgggccc 42780tgggcagtga ggggcttagc acccgggcca ataactgcgg agggtgcacc aggtccccca 42840gcagtgctgg cacaccaatg ccacgcttga attcttgcag ggcctcagct gccttcccgc 42900ggggcagggc tcaggacctg cagcccgcta tgcccaagcc atccccctgt gggatcctgt 42960gtgtgccaag cctccccaac gggcaccatc ccctgctcca cagtgcctgg tcccatctac 43020tgcccaaggg ctgaggagtg tgggcacgta gtgcgggact ggtgggcagc tccacccaca 43080gccgcagtgc cagatccact aggtgaagcc agctgagctc ctgagtaggg tggggacttg 43140gagaactttt atgtctagct ggaggattgt aaatgtacca atcagcactc tgtgtctagc 43200tccgggttcg tggatgcacc aatcagcact ctgtatctag ctaatctggt ggggacttgg 43260agaactttta tgtctagctg gagaattgta aatgcaccaa tcagcacttt gtgtctagct 43320caagtttgta aatgcaccaa taagcactct gtgtctagct caaggtttgt aaatgcacca 43380atcagtgctc tgtgtctagc taatctatgg gaacttggag aacttttgtg tctagctaaa 43440ggattgtaaa tgcaccaatc agcactctgt gtctggctca aggtttgtaa atgcaccaat 43500cagcaccctg tcaaaacaga ccaatcagtt ctctgtaaaa tggaccaatc agcaggatgt 43560gggcagggtc agataaggta ataaaagcag gctgcctgag ccagcagctg caaccactct 43620ggtccacttc cacacagtgg aaggtctgtt ctttggctct ttgcagtaaa tcttgctgcc 43680gctcactctt tgggtccaca atgccttcat gagctgtaac actcaccgtg aagatctgca 43740acctcactcc tgaaatcagt gagaccacga acccactggg agggatgaac aactccaaac 43800gcgccacctt aagagctgta acactcactg caaaggtctg cagcttccct cctgaagcca 43860gtgagaccac aaactcacca gaaggaagaa actctggaca tgtatgaaca tctgaaggaa 43920caaactctgg agataccatc gttaagaact gtaacaccta ccacaagcgt ctgcagcttt 43980attcttgaag tcagtgagac caagaaccca ccaattccgg acacgttttc acatggagat 44040aatttggaag aaaaacttgt aaaaatgtga gaacattgag aacttttatt ttccaaggaa 44100agaagtggca gcttcatttt tggtcattgc aaacagcagt gccatacatg aaaggaaagt 44160ggtggtgctc atcaacttag aacacttgag actcttttct gcttataaag aaaaagtgtc 44220aactgtaaag ttgatttatt tatgaaccat aggctactat gaaatctctg ttcacagcta 44280gaggcctggg agagtaagat aactacttgt ttattccatg aagccactta ctgtttcttt 44340tctattgcac atacctcaaa tgaagcattt caatagaaga accacattct attcacttgc 44400ttcattttat tctgatttct gtaaaaactc aaaaattcct caagcagtgt ttctttgcaa 44460ggcaacaatc ttcagttctg ttgcaaaggt caggagtgat agaatgaaaa tggtactaga 44520ttcaacagaa ctttggtatt tgcatggcta taacattgcc atggggctgc aagacttgtg 44580agagcttgat attttgcttg ttgatgaatg agtctgtgtt ggtgctggtg gagtgatttg 44640agaggtagtt ttccactgtc aatcaagagg ttggttttga aagctgattg ccagtagtca 44700ttctgctaac cactctggtt ctcctttaga tagagaccta ctcagattca agtctcatgt 44760actttgtggc ataaacattg tacacaccag atgtattgaa caaccacaaa gaaaactatt 44820aggactcaag tagtatgtca gagagtagtc actgatgatg tataattctc cacttccaag 44880aagatgtaag cgcactgttg agtggctaca tcctacatat gttggccaga atttaggaat 44940acacatgtgc tctatacatt ttgaggtact gcctgacccc tagagaatcc tggtgaagtt 45000tttctggtgt cagtttggtc ttaatgttta ggaaatgccc acagacgact cctgctttct 45060gcttactcat gtagtaaaca caaagcacag gactagtttg tcttctggat caaggagaaa 45120tgagttagca gatataaaac aaatcagaaa ggaagtagtt ctcacatatt taaccataaa 45180tagttgctgg atgttcatta actctatagc aatatttact acttattggg gatcctggaa 45240agaaaatata ctgtccatgt ccactgttca ctgagggccc cccgccaccg agaaactccc 45300tgtcttcatc actcactctc cacattcatt gacctagagg aacagttcat ggatgagtga 45360gagcttgagc tatatcttaa aggatggagt tggatttcaa ggcaagaggt ataagagaaa 45420attcagagac aatattgacc atggtctttg cgaagaaaag tactttggga gataaggttg 45480aggaaaagta cgtttgaatc ttcatccaga ggtagcccct aaatatgttg actctgttga 45540aagagtactt gacttggatt cagacagatc tgcatttgac tcctgttttg ccatttataa 45600gaacttgagt aattattgtt tctgaataag agtttattta gccaagcact cagtaaatgc 45660ttgaatgtga aaatttactg ccctgttttt ctattgtcag atggtcccct tccttggata 45720actttgtaat cgttgataac cttttctcag gaatcagaag gtagaaggat tgggaaaata 45780taagaaacaa aaaggcatat tcttattttt attttcatat tgtcttccaa ctctccaagg 45840catcttcgtt tgcaaggctg acttatctaa tacttgttgg gtagagcagg tctttctttg 45900gttttcccct gtttggggtt aaactctgag taacgttatt ttctaggtct cagccaactt 45960tgaagcgcat gaactcacag tagcctcacg agggtcactt cagcagtgag aagttacctt 46020tcccatataa aagtgtaaga gtcgatggcg gccaggcgca atggctcatg cctgtaatcc 46080cagcatttta ggaggccgag acgggtggat catctgaggt caggagttca agaccagcct 46140gaccaacatg gtgaaactct gtgtctacta aaaatactaa aattagttgg gcgtggtggc 46200acacacctgt aatcccagct actcagaagg ctgagacagg agaattgctt gaacccggaa 46260ggcagaagtt ggaggttgca gtgagccgag actgcaccac tgcactccag cctgggtgac 46320agaatgagac tctgtcaaaa aataataata ataataagag ttgatagcaa aataactatc 46380tgtagcgtaa acctcagtat tctttatcat tcagtatcaa cattattacc aaaaaaacga 46440taagcaatag ggactgagtt tctgtggggt ggaaatgtga agtggatctt ggcatgatat 46500aacttgtgat ttggcttcct ttataaacat tatcaactac ctcagctcta tcaatcactt 46560ggcagtccat agtgaacatt ataactcaaa tgactagtcg agtctgttca ttgtccatgt 46620aaaggcgtat acctgaagtg agaagtctga ggtaacttag caataagttt gcagtacagt 46680gtttagtgaa gtctgaaaat tcaaggcttc gagtcatgcc agattgctcc ataaccatag 46740cctatctctg tcacaagtaa gaaggtttaa aaatcacata ccattattgg tcacaatgtt 46800tggagatggg gaagagtttg tggatggatc atggcagtgc atggacagtg attagcccac 46860agcacagcca gtgagcactg ttgtacccaa agcacgtaaa tcaccacata tactatcaat 46920atatttatgg atgacaacag acactatagt tttatgtcag tgctttctgc tgctgaaaac 46980aaagttagtt aagggtacct tttgtatatt tgcaacatat ctccacacct gttcctttgt 47040ctccttcttg caagttcttt ctttcagctg actatccgct gttcctacta tggctcccag 47100tggcttttca agagggtgat tgttttttaa gagaagatcc ttgaaggaca gagaaagcct 47160gaatcgttca aaataatgaa ttactcagga tgaaatttca ataatttgca agtttgtgga 47220gacagatatt ttggggaagc ataattttct atgtacccct caaatcatgg ctggagatga 47280cagcctcttc cacctccata taagaccatt tcatttcttt ctactttttt ctccctcctt 47340ccccccaaaa cacaaacata cacatatcct gtgcttcagc cacccagaac ttcttactat 47400gtcttttcaa ttctctgtgg ctttgcatgt tctgctcctt ctgcctagaa tgctcctttc 47460cttttcttac ctggaaacac cccaattcaa atgtcacctt ccttatttat accaactttg 47520tccataactc ctttatcaca cttcttcttg tgattagtct attcacttgt ctgctgttac 47580acctgtatga gagatgaaaa ttccttcttc atctctggaa ctcacgccct tagcatatag 47640tagacaatct gtaaatgttt gaaggttgag tgaattaatg aatgaccttc aacctttcag 47700gcttccaatt ttctctctga aaaggacagc taaatgaaaa ctcataattt tagaagatga 47760ggttagacgg ttggtaggtg catgcagaga ccaattatta tttaggcatt atagaagtgt 47820atagttcttg tatgttgagt gcagtgtaag agtggcccca aatatagtta atgcccactc 47880cagacccagt tattatagag ttggccccag ctgtattgct tctatttaag actgagataa 47940gaaatgacac tttcctattt ttttacctta ttgaaagggt aggggctggc tgttatcaat 48000ctcagttcac ttgttgattg cattggcttg ccaagtgaga atattagcac ccctgcacat 48060ttctatagtt ctgccactta tgagatcctt ccttcccatt gtcatattta ataatcagga 48120tagccctata aaatatgcat tcttatttcc cagatgagga tactaaggct caagtaggag 48180aacttacttg tttagtaaga tcgtacaact aggaagtggg agaggcaaga gttgaaccca 48240gatcttccta gctcccggta catcgctctg tctactgagt cacactggag cagccaggag 48300gcaggaaaat catctgggga atgtggtgcc aacgtgtgat gtttgcctaa atgtgtgcat 48360ccttgctgga agccagccat gattccatgc tgcataagta ttcattaatg ttcatttcat 48420ttatttggct atccatatgc tttccagggc gaaggcaagc taggacaagg gcagacaagc 48480agccttaaag tttgggtgct ttccttcaaa gctgggctgc ctgtttgaaa atcaaacatt 48540tttggtgata gaagatggtt ccagtacaga ttttattcat tactgcatct acatggacag 48600acattttcca aagcatagct gaaaatatgt gtaagtccca gaatatttcc tgatttagac 48660acagactttg agcatgataa ccacatttag catgttagga aattctgtca gaatgcttct 48720ggaaaggcta cctttccaga atgaaatgaa aaaaaaaaaa aaaaaaagga tggactttga 48780aactgattag atttgggtta tactccctca cagtgtgacc ctggcaaatg atttaactta 48840tccgagtttc acttttctta ttctttgaag tgaaatttta aaatgtcatc ttgcctgatt 48900tttgtgagaa tgaaaatgag atcccacacc aggaatttag aagctactca gtaaatattg 48960cttctctcct ttccccttcc cgagtcctgt cccccaagtc attcattagt tattcagagg 49020catgcattct gaaatctgcc tactgctcca cgttgaaatg cactgctctt gcaaagactg 49080attatctatt tttttgtctt ccaaggcccc ctgtgttcca ctccaccctc ccaattctgg 49140gggcttccaa agtgggcagg tacagaatgt tctgtggagc atcggaggct gttactcaat 49200atcctggcca gcactctcaa ctgctctttg cacatactcc atatgaaggc aaactccaga 49260acttggagtc catgtttgtg tcatgcattg cactgcttct tttacccaaa tccatctcaa 49320gggtgagtag accaagctca gacttgtctt tggagcagat ttctcaagct gcccatgtcc 49380ccacactgct tgattaaaag gaggtgcttc aaactctttg gctttatata gactagaagc 49440agaatgattg gtggtgcctc tgttctcaag gtatcccaaa gcactttgta aggaaatatg 49500acaagcgctg aggccacgca ggctagtaca acagccgcca cccagcactt cacaattagt 49560catgcccagc ctgggatcat caagcctgtt tttgttggaa gagcaagaga gggagggaat 49620gctagctggc aatttccccc ggtacccttt atgaaagtgc ccttggctct tccaatttca 49680cctgaataac cagctcaggc aaattttcct ctatcaaaaa gcagaacgtt atagtgacaa 49740gctgatgcct ggctgatgcc ccaggacatt gaccaaatag gcttggcctc acaattggtt 49800tttattcccc atatcctttc ttcccttttg ttctttttct atgtttcttt cccccatcgc 49860catctgcaga gtgtcctcag tcagaagtca gctgtggggt ggacagtttg tcatttaaaa 49920tcatccctat tctgtctacc cttcttatcc ctcacataat tgcttttaga gcaaggacaa 49980ttctggaagt gaaactacaa taacaccctg ggctcctttc cctctagtag tactcagcac 50040acttgcaatt acatgttcaa atttgtcttt cttatttctg tttaggttca tgaaggcaag 50100ggacatgcct gtgttgctta ctttctcttg gcaggcacat atagcaagtc ttcaaaaaat 50160gcttgttaac tataaattaa gtgtttaaga agcccatcgt tagtatcttt gcccctgcct 50220tatttgtaaa caaccggccc cttctatttg taagttacct tgttttgatt tccatatccc 50280ccaaagcaaa ctttagctca tggccttaca gagtgtgtat attagtatgt taaaatgaaa 50340tcaactctcc tcccccaagc cttctaattg acatgaattt gggagttgac ttgcattggc 50400ctttgtcctg acagccaaca gagtcctctt ctggtgtatt cactgttggc ttccatgaag 50460atgctatgga gaaagtttgc cattgacata cattttgagg gcagactcaa cctgagtaga 50520ccggattgag ctttccccat ctgcctgcca gagatcacta cctgtgtgtt gctaaaaaga 50580gaattatagg agtcctctca aggcagaaag acctaaaatt agacatggca gccatgcctt 50640tggtgtgtat gggggtggga tacaggcagc cagtttcccc tctgttttct cccttgctta 50700cacagccaag gagtggagcc aagcctcaaa gggaagagct gtatactgga gcatgccagt 50760atacaggttc ctggccctgg ctgagttact attttatata ttccaataga gaagcataga 50820agacttctag gttgccactg tcatttgaaa ttgggtattt ttaaaagaga aacttgaaga 50880ctcaaagaaa gctttctttt gcctcccctt acagttgatt tttgagcttc ataaagctac 50940ctagtccaaa gtacccacac tcttattatt tttgtctttc ctaccggttt tttttttttt 51000tttttttttc atcttcccag gtgtttgatg atcactaaga gcttcaacat tgctcacctt 51060gaccaggtat gaaaccaaga gttttgttta aggcataaaa gaatgtagga actcaaggat 51120taggttgaga tggggaaggg ggatgaaggc ttcttttttc ttgggttaaa cagaaatgac 51180ttagatctca gagtgaaagc cttgaattgt cacatatatc actggcaaag actagttctt 51240tgctatgata agaattgttc atcatctcgc ccctgaggat ttagggtcaa ggcctggcta 51300caccttttga tgatctcagt catatgactt aacctcttta aagttaacct ttggtgagca 51360ctgtgccccc tgcaacccca gtaaggccca acagggctct ccaaggaggc aaaattctga 51420tgatacattt ctgtttagtg aaaatgggta gggaaaatta tgtcttagaa tcaattaacc 51480aaacataaaa tcctccaagg ggcttggtag gatgcctagg gaagagcaac gagataaaaa 51540ctccaggctg gaagggcatt gttgcagcac tgtcattctc cagtttctct tggagttgtc 51600actaccctct cctttgttct cactgctgac atcatttgta aaataatttc ttcccataaa 51660taaacaaaac gtacaatcct ctaaatgact aaagaacagt tatctagaag aacagtggaa 51720agtattttct tcacctaagg gatgattctc tttacagagg tggagtaaag gatgtgcgag 51780gaggcataat caagctaaga gatgcatgct gacttaaaag gcatgacatg tgtgaaacta 51840agataatgtg ttcaagagtg atgctttgtt gatgcagaac ccactgaatt ccttactgtt 51900atgtttgact gactatcagc ttattaataa agaaattgtg gtttgagtgt tcattgaaat 51960tagccatgtt aggtttatgt ggggatgtga ggatctatgt ctaccaattg cagcttctga 52020tgcagattgg aggcagaaat ctggcctgaa caataagtaa gagtgtcagc tctacagata 52080tctcacatgc taagcaagca caatataggg caatccaggt ttacacaaag gattaatttg 52140ggaacaatta tcctcatttt cactttctta aacgattttg aataaggtct tttaagtaag 52200aagctccctg aatgcattta aaatatggtt tgattatgta catttaagat ttttctacct 52260ttgtaggagt atctctgttg tataaaaaca caaaattccg gaacttttga aaggaagatg 52320tgcctctctt catacatttg tcattcttga aagattgtaa aatgaagtga ctgcatatca 52380tgtcgtgttc cctattgatt tcttttctca ttttaggaat attcccagaa taaaaaaaaa 52440ttttttttaa tctactaagc atgctaggta agactgaaga tgaatctatt taagttatgt 52500caatatctat ttataaagat ttttgtgata ttctttttac tgtagaactt gaagcatatc 52560ctaaagggaa tggttagcta tgtctgcaaa ctgtggcaat gacttactga gtaattgcta 52620gcaactgatt tttggtgctt cttgttttga tagtatagca gtgcgagtag gttttagaaa 52680agcaaaacta agaaaatcca gggaaatgcc atttgagaat ttctaacttt aaaaaacaaa 52740taaaatagtg tcaagaaaaa atattatcca actaacccca aagtctacaa tgtaactctt 52800ttattttgat aatgctgttc taactctatc tacttcagtc cattgccatc cagctggttt 52860aggaatcaaa ttcccaatgt ttcatcactg ttaacattac tgttttactc ttcagtttag 52920ttcttaaatg gcatagtgtc ttaaattccc tcagcctctt tcacgtttga tttctttgga 52980aactttttac cttttcattg aagcccatat gatcttttct gaaacagacc cttatcttta 53040ccttcttctt tggagtcttt ctcctacttg aatttctgaa cttcttaaaa tggccgcttt 53100ggattggtgt aataaatttt cttttctttc tttctttcct tttttttttt tttttttttt 53160tttttttgag aaggagtctt gctttgtcac caggctgcag cctgtagtgc tgtggagcaa 53220tcttggctca ctgcaacctc

cacttcccag gttcaagcga ttctcctgcc tcagcctccc 53280aagtagctgg tactacagga gtgcagcacc atgcccagct aatgtttgta tttttagtag 53340agttggggtt ttaccatgtt ggccaggatg gtctcgatct cttgacctca tgatctgcca 53400ggctcgccct cccaaagtgc tgggattaca ggcgcgtgcc actatgcctg gccagtaata 53460agttttctta agtgctttct taatgttctg atattttaaa aaagatctgg actattttgt 53520catacaggca acagaatgtt aaaccatttc ataaagcaat gacaaatata catgattttt 53580catcagttat aaatgctttt cctttataac attgaacatg tttttgcaac tgaaataagt 53640gtgattttca tttttagaag gtacatgata aagttaaggc agtggttaat taattttttc 53700agattaattt ttcagaaaag tgactgtttc tgtctgttca cttaacccca ggcatcaaac 53760gactttaatc agaaagaact gaagagtaat ttggttattt tagtgccctt ttttgaggca 53820aagtcttatt ctgtcaccca ggctggattg cagtagtgtg ctcatggttc actatagcct 53880cgatctcctg ggttcaagtg atcctccaac ttcagtttcc cagataactg ggaccacagg 53940tgggccccac actctctgct attttttttt ttttaatttt tcatagaaat ggggtctcac 54000tatgttgcct tggctggtct caaaatccta ggttcaagca atccttccac ctcagcctcc 54060taaattgctg tgattacagg cgtaagccac tacacttgcc ctattttaga gatttgtcaa 54120gctttggaaa gagaaccatt tacaatataa taggtaaatt atggatattt gaggcagttt 54180ttatcatagt atttgtagta aactacagcc ccccctttat aatatttgta tttaataaaa 54240atgaaaatat tacttttatc ttgaacaaca aacataagtt ttaacaaagc aagcatattt 54300agattagcac taataaccaa acgaaaacct ttataatgat agctgttttt aacatgatta 54360caaaaaattc gctacacaaa tttttatcct aatcagtgtg aaaaacggaa aatattagct 54420tatagggcca acttagtctt cagagtcctc ttcctaccta ctactgctaa taagccaatg 54480aaaaactccc tgatgtgtgt ggtggctcag gcctgtaatc ccagcacttt gggaggccaa 54540ggtgggtgga ttgcttgcac tcaggagttt aagaccaacc tgggcaacat ggtgaaactt 54600tgtctctact aaaaatacaa aaaattagct aggtgttgtg gttcacacct gtagtctcag 54660ctactcagga ggttgaggtg gggggatcgt ttgagcccag gtggtcgagg ttgcagtgag 54720ccgagatcac aggactgcac tccagcctaa gctacaaagt gaaaccttgt caaaaagaaa 54780gaaagagaga gagaaaaaga gagagagaaa gagagagagg caggcttctc cgctttttca 54840gttcctgaat aattttccaa tctagaatgc aaaagattct gaaggaagac agttaccatt 54900tcagattggc agaagttgtg actttaatct ggacttgaat atgttttaca tcaaagggtt 54960gcctcaacag tgctcaaacc tgcctctctg aaaacatgct gagcgcaaag gttacttgaa 55020gtcttagctt gagtacttaa gagaatgcta tggagggatt gttgaagaga gctgtgtcac 55080agctaattct tctttagtaa ttaaaggttt agaaaactct tacactgcat attgacaaat 55140ttagcaacaa aatgagcttg agaaaaaaat caaggcctgc tgtggaatct tttttttttt 55200tctctaaaac aaacaaacaa acaaacgaaa cctttttaga aagattatgc aactgtatta 55260tctgtaacta ctgcaatagt gtaaattctg atagtataat ttgcttttta aagctatctt 55320tacttcagtg caacttagat taaatttatt ttaaatttaa acgatatttt tctctttgtt 55380tattatttta tagtaagttt cccatagaat tcacaaaatt cattagaaag attttctttt 55440ttttacttcc ttaggtcatt aagtttctga tttgtcagtg gatttcacag aaaccctgtc 55500tttccaaaaa tatacaaaaa aaaaaaaaaa aaaaaaagcc aggtgtgatg gtgtgtgcct 55560gtagtcccag ctactcagaa agccgagttg ggaggactgc ttgagcccag aagttgtggc 55620tgcagtgagc tatggtcaca ccacttcact ccagcctggg caacaaagcg agaccccatc 55680tccaataaat aaataaacaa ataagtaaaa agtttttcac cttgaaaagc ttataaacat 55740atgaaacacc attagggtct ctgatatagt ttggatgtgt gtccccgccc aaatttggtt 55800ttgaattgta atccccagtg ttggaggtgg ggcctgcggg gaagtaattg gatcatgagg 55860gcagtttttt catgaatggt ttagcaccat ccccttggta ctgttgtcgt gatagtgagt 55920aagttctcat gagatctggt tgtatagcac ctctcccctt gctctcttgt tcctgctttc 55980accatgtgac atgcctgctc ccccttcacc ttctgccata attttaagtt gcctgaggcc 56040tccccagaag ccgagcagat gccagcacca tgctttttgt acagcttgca taaccatgag 56100ccaattaaac ctcattttta atataaatta cacagtctca ggtattcttt atagcaaggc 56160aagaatggac ttacacagtc tcttttgtat cagggagaag gtctcctggg tgactccact 56220tcttttcttg tttatgtatc cttccagatg atgtatttat ttcctttgtt tttcaattga 56280tatttactct taaattaaac taatttatta ataaaaagca ttttaaagtc tcattttaga 56340ttattttgac tatctgattt tttaaatgga gtaaaaaaaa tctaccttgg cctccatatg 56400caatcaagca agaaacacat tttaagcata ttatttgcct tgtggattct gccttcctcg 56460atgtgttcag tctgtatata ttcatttctc ccacactgta agaagctagt cagatgtata 56520attggattat catgctacat gatcttagca cactcatttt aagcttacat agactagtga 56580gcaccactca ttacatgtca tttctctaga gaaactagtt gggccgtggc tgcaggactc 56640tcacttgaag agacacatgt ggtgatgttt tctcaggcag ttaagcaata aagtgtaccc 56700tgatttgcac tgaaaataaa gattccttta aagggagcag ttctagttat ctctctcttt 56760agataccata tgctaaacgt ttttctatgc actaaaacaa taactaggtt ttatactctg 56820ccttacagcc tacttcacac ccatttcaca gggagaggaa cagagaggta agtgatttgc 56880cccaacttac ataactagga agttatttac tcagtgtgga aacttgttca gacggtcatt 56940tcattgaaat gtaggaagag tttctggcac ttctcttgag caggagtcaa aaacttcttt 57000tttgcactag cccagatagt aaatatttta ggctttctgg gccatatggt ctctgtcaaa 57060actcctctac tttgttgttg tagtgcataa gcagctatac acaatcctga aatgaatggg 57120tgtggccgtg ttccagtaca accttacaga aaaggcaata ggctggattt ggctctgaga 57180ctgtagtttg ctgacctcag ctcttgaact gagctcttta actgacctca gctctcgaac 57240tatggtccaa gatcccgtgg tcctgtttgg tacctccatt tgccctcctt ttcactctct 57300gggagcatag ctaagttcaa aattgaatta ggtacttgta gtaagagtac acttataatc 57360ctgggatctt catgttgcca gatattaacc tcttgaagtt tatcaccaca gcctgggcac 57420ttttctgatt tgctcacttc tagccccacg tttgggcccc ttcacaagca aacatgcaga 57480ttttccagag agctgtatgc tactgaatgt agaaaatttg gctcatactg gcctatggac 57540tatctgctca ctgccctgat aactattttc caagggagtg ggtgccctac ctttcctaca 57600cagagttttt ttgctagtct cgccctaaaa attctaggta tcccttgctt ttaggataaa 57660tatgtttcac taggaccagc cgaaaaatga aaaatagagt tatccaacta ccactttaaa 57720actggacaag gatttttgtt gctgttgttg gagggggtgg taaacatcat tttggcagac 57780caaatatact tttggtgtaa ggcagccttt tgcaaagaca gaacacttgg acaagatttt 57840gaagtcctgg ttgcctttac tactgattta actacagtat ttgtggactt gggcaagtca 57900cttcccttct gtgagcctca ggttattcat ctttgaaatg agtataatac ctgtgattat 57960aattacttct ctggattctg cagagaactg aaggagataa tggatgtaaa agtactttag 58020tgcccagcac tgctccttat gaaaatgagg aaataattga gatgagtgag ccattgagac 58080aaccgtacaa aaagtgctga aaactcactg cttaaataag cacctcttac tgcttttgtg 58140gcactttgta gcaatgtgtt tttattctga ttagaaagta atgtttggtt ttgtttggct 58200ctttgctcag taaacccata ataaggatac ctatttgccc ttggaccatc agttcaaata 58260ttattttact aatatggaat tatttggctc cagaagccac agttttctta gctgctcccc 58320atccccactc tcacctcaaa tttttttttc actttatttt ttttttcttc tcagggaaag 58380gtttgaggca aaaaaatgcc ttcttatgat ccaaaaccaa gcatggtggt gatttattca 58440ccaagcgatt cctgagtacc tgtgtgatgg acatggtaga atctttgtcc tgatccatgc 58500cttctgatat gcagccagta gccacttgtg gtaatggagc aacagaaaca tcactagttc 58560aagtggaaat gtgagatgag aagtaggagg tggagagaac taaccagaag agggtaccca 58620aataaaccag aaataggtat ttgttagaga aggggcctat tgagtgggtg gcagtggtat 58680gtgtggcatt acttgctcct gtattctctg ctttttactt agttgtggct ttggtggtat 58740agtctcagat ctctaagtta tgcaggtaat attgttatgt atcatgtttt ggcaatgtag 58800actgaatact tgctcataag agtacaggac aatgaagata gtttggtttt atttactgca 58860tggaaagtac aggatgttta gtaaacagat ccatggcata gtgagttcac cactaaaatc 58920agactctgag aatgggtttg atttagatgg ctagtttaga atactggatt caggccactt 58980gattaagaaa ggccattttg gctaattata agccaccaac attgtgtttt caatgttaaa 59040gcttatattt gtcttccagt taccagaatg taagcttctt gaggaagaaa agaggagttt 59100tcttaatctc tgaacctata cctgtctttc ttctgtgtct agcccagtgc ctggcaccaa 59160acaggtgctc aatcaatgtt gattctatgc taccaacaaa aatgagttca tgatgtttac 59220tattcgataa atgaatgcaa ttttagagtc aatttttact acttacacta catgtagatt 59280ttctttttag agatttcaca atgctgattt ttttcaaaat aagcttgaag ctaagtgaca 59340aagctgaatg atgatttgtt ttttattttt aattctaaac ttacaatttt ccatgtcatt 59400gccagaaaaa tcattaaata aattatgata tactcatatg gaatactttg caaccattaa 59460atcaaccatt aaatactatg caaccattaa atcagccatt aacgtattta atggctgatt 59520taatggttgc atagtattta atggttgatt tgcacatttg catataccaa catattatat 59580agttgagtga gaaaagttag tttcaaatga ctatgttaat atcccctgac tcttgcaaaa 59640agaaaaccat acatttgaat gtacgtatac gcgtatgttt atacgtgcat agaaaaagct 59700atggggggat atacctcaag ttgctaaaag tggctccacc tggagaggga catggaaagg 59760agctggctaa aaactgaggt ttgttacgtt atacacccct gcacagtttg atttcttaaa 59820agcgatgatt ataaattcct tttgttattt ataaaaatat tatttaaaac tttggtacta 59880aaaacagagc tccatcaaca gatcaatgga taaagaaaat gtggtacgta tatacagtgg 59940agtactattc ggccataaaa aatgagatcc tgtcattttt acaacaaaat ggatggaact 60000ggaaattatt atattaagtg aaataaggca ggcacagaaa ggcagacatt gcatgttctc 60060atttaatctg tggaatctaa aaatcaaaac aattgaactc atggatatag agagtagaat 60120gatggtaacc aaaggctagg aaggatagtt ggtggggcag gggagggtga ggtgaggatg 60180ttaaatgggc acaaaaaaat agaaagaatg ccattctaac tggtgtgaga tcaggaaaca 60240acaggtgctg gagagaatgt ggagaaatag gaacactgtt tacactgttg gagggattgt 60300aaactagttc aaccattatg gaaaacagta tggcaattcc tcaacgattt agaactagat 60360gtaccatatg acccagccat cccattattg gggatatacc caaaggatta taagtcatgc 60420tgctataaag acacatgcac acatatgttt attgtggcac tattcataat agcaaagact 60480tggaatcaag ccaaatgtcc atcagtgaca gactggatta agaaaatgtg gcacatatac 60540accatggaat actatgcagc cataaaaaag gatgagtttg tgtcctttgt agggacatgg 60600atgcagctgg aaaccatcat tctcagcaaa ctatcactag aacagaaaac caaacaccgc 60660atgttctcac tcataggtgg gaactgaaca atgagatcac ttggactcgg gaaggggaac 60720atcatacact ggggcctatc acggggagag gggagagggg agggattgca ttgggagtta 60780tacctgatgt aaatgacgag ttgatgggtg ctgacgagtt gatgggtgca gcacgccaac 60840atgacacaag tatacatatg taacaaacct gcacgttatc cacatgtacc ctagaactta 60900aagtataata ataaaaaaaa attaaaaaaa tagaaagaat gaataagacc tactatgtga 60960taacacaata aggtgactat agttataatg atttaattgt acattttaaa ataactaaag 61020gggtacaata ggattgattg taacacaaag aataaatgct tgagggatgt atacctcatt 61080ctctataatg tgattagtac acattgcatg cttctatcaa aacatttcat ataccccata 61140aatatataca cctattgtgt actcacaaaa atttaaaaaa aaactgtaca ttaaagaaaa 61200acaaaaataa aaactgtagt tcaagttata aacaaaataa aagtaatttg gaggaaaact 61260atcttcagtt atattggata tttgggggac atttttgtat gttagttagc aaaaatcact 61320tgaaaaaaag gattcttcct tccatgattc aaaggagcat agcaaaaaat aaatgaaata 61380aaataaaata ataaaaagag aaaaagaaaa ttattccata aattctactt acttatttct 61440ggcaaacttg ttgacagcac atgtgacctt tttggtaaaa agacatattt ttatattttt 61500agttaagttt caaatataaa ttgtttgtgt ttttaaaata aattaaatgg atgacttcag 61560ccaggtcatc atgaaaacac atgagatatt gggttatgca atgactaaca gtgtgtacgt 61620tttcttggta tttattcata aactggggaa taaaaatact ttttggctca tttactcccc 61680aaataatttt atgtctccca aggagaattg taagttgttt gatagtaaat gctatgtatt 61740ttgtatctta gtgtatgtat gggatttcag cgttagaaga gctcttaaat gccgtcttca 61800tagtccaacc tgtcttctga tgcttgaaag ccccttgcaa taggaaatgc aaagtagaga 61860gtagatactc aataatgtgg ttattgaatt atttagaaag aggcattttg agcccataat 61920gtacaatagg tacttctaga tttattgttt tattctttgc agagctgcag aaaactaaga 61980aaaaagttta tttcagattc atgtgtttat ttgattaatc tcttcataag tttcattttt 62040cagctcctgt cagaaaatac agattcttat aaggttcacc tttacccata agaataatag 62100tataaaaggg ttaatgtgaa atacaatcac ttcacagact gtttcaatta aataagagct 62160cgtagataat tcagtccacc ccaccccatt ttacagatgt tgaaattgaa gcccccacca 62220aaagtaaaag acttgctcaa agtcacacag caagtcagtg gtgagcctaa ttaggccccc 62280tgccttccat tttggtgaga ttcctgtgct gatagtcata cccgtgtcaa atcctcttcg 62340gcagttatgg cttgcccaca gtaatgtgtc ctgaaaaata tgacaataaa ttaagttgga 62400gacagaacca taacctcttt ataaaaatgt tctggaaagt ttacatgaca gtacgtaata 62460tataattaga aaggataatt cttatttcat atttatcttt ttgtttcaga ataataaact 62520aagctatctc tactcagtcc attttaatac aaaaatattt ttaaccagat tgagttttta 62580tgctttttag gaactttttg tctacctcac ttaattaaaa tactagctgc actaatcact 62640tactgtggta ggcagaattc tagaatgacc ctgattacct tgtccttgta tgattccttc 62700ctctttaagt aaggatagaa actgtgaata tgatatcact cccatgatta agctttgtta 62760catggcgcag ttaactttaa gaaaggacca gtcacacaag ccatttgaaa gcagagagtt 62820tgggattttt ttaactggtg acagaaagcc acgcagagat ttgaacattg agggtaattt 62880gaatttgata tgccagtact aacttgaaga tagaggaggc tgcacagaaa gtggccttta 62940ggaatgatcc ctggctgaca gccatctaga aaatgagggc ctcagaccta cggccataaa 63000gaattctgtc aacgaacttg aacttggaag tggattcttt ctccagaact tccatataag 63060agtccagcct gattgacact gtgattttgg ccttgtgcga ccctgagtag agaatccagt 63120tgacttctga cttaaaaaaa aagtaagata ataaatgagt attgttttaa actgctaatt 63180ttgtgataat ttgttacgca gcaataaaaa ctaatatatt taccatacaa gtcaaggcat 63240ttatcctttc atgattcagt ttctttttac ctgacataat ggaattaatt tatactgttg 63300tgaaattgta gttgagaaac acgacttcca aagtaataaa atacatgtat tattaatttt 63360aatagtatta atagtaatga tactgattct ccgaggccta tacaaatcct ttgatacaca 63420aatgaatagt aaaggaacat aagttgtctc taggtaggct ttcccacaat gcaattttac 63480gatacagaag tcatatgcct attattctac tatggcagag aaaataagga gcctggaaaa 63540ctgttcattt gcatcacata catcttaaga gctcactctg aacctggtac cttaataagc 63600tctgtagaca gtataaagaa gaaaggaatc agacatggtg tctgacctca ggtgtctcat 63660aatggagtag aagaggtaaa atatgggtca cactaactct actgctaaat aggaagtgct 63720cgttgccttg agattgacaa aatttgataa gagttcagag gacattttct gtgaactggg 63780ccttgaaaaa taggatatga gtaggagaag atgaagaagg aaggcattcc agctagagag 63840aagagcacaa gcaaaagaat agataacctt gaaagtcatc atatgggata attcaagagt 63900tcagtataat ggaagtataa gatgcataaa aataagtgta gtaggaaacg agtttgaaag 63960tacagattgg ggtttgtcat agaaggcctt gaatttcagg ctgaggagtt ttaatattaa 64020catttgtttt tgaacaaagg ggttaactga tcacatctgt gatttagaaa gaaaattcta 64080gcaatagtgt agataagggt tgatggtaaa gtttggaggg tggtgaggca gagactggag 64140acagggaggg catttaggat agaaagatga tgaagagatg atttagaaga gttgttttgg 64200aaaaggagga gagagaaaat gttttagatg tgtcacagag ataaaatggg catggcatgg 64260tgcaaggagg taaagcccaa tagctttgta aggtgctgag atagattgaa atcacagagt 64320taagaagttt tagaatcagg attagtacca agacagcttg gctctagatc tcatacttaa 64380ccattatggt ataatcctga gagggtgggt aacagcaata gtcagaggaa agaacccttt 64440tatacatgat ggtacaggaa cagcactgtc ttccaacccc acagctgctc tttaacagaa 64500ggtcagaaac tggggagaaa ttgtgtgtgt gtgtgtgtgt gtgtgtgtgt ctgtgtgtgt 64560gtgtgtgtgc catttctgga actaaggatg ggaagtagat tagatgaggc cactgcagtg 64620gagtctgcaa gttactagca ctcacccgtt ccaagaggcc ttaagggtgt tgacctgttc 64680cctgggcatc accacattct acaaatttat gttcctctga gagaataggg tgattcaatt 64740tcactgtgct tgaaggttac ttttggggtt catgtttgtt tgttctaact ctatgctaat 64800gatctgccaa ctgtttgtca ctttctctaa cccttaggat gtctaaactg atctgttggg 64860aaatgtgtag catttacagg atggtaggat ttgtaacatg cgatcacagg gctgtctata 64920tagagtcctt gggaagggga gagaagagta tttctgttac aaatgcagat tcctagggcc 64980ctcctcaaac ttactgaggt tcaaggattg atatttataa taagcacata tccattttca 65040ataagcatga aagtttcata ccctctttta atgtttgaaa tcctcaaata aattagtcat 65100tgatgccaga gtattacata attatggtac agaatgtgtt tctctgaatg acactttctc 65160ccagagattc tgatatatat tcctctgcac tcaccctgtt tgataattac cagtatatgg 65220accatttacc tgaagaataa gagtagggtt ttctactatt gttgaaaatg ttctcgactc 65280ttaacaactt gtgtgtgact gtaacaagat cacacagggt aaacagtatt agcttattca 65340accactggct gaagaaattt aggaaagtga acacattttt ctttacattt ctctttgttc 65400tgtgagcctt ttatgctgga atagttttca ctgcaggctg ttattgtctg cccccagagg 65460agggagttga cctagcgatg gtaactggag agtgtttttt gaaacctctt tcctaggttg 65520gttgccaatg gcatctttgg aacagtgtcc ttcactttag tccctcaggg accagtgtga 65580gaatgggaac tttatgatct ggagctggtt aagtgaagtc caaaaataat taggaaagtg 65640tttccttccc tgggaatgag ttcagtagga atctcaatat attgtagagc acgaaggact 65700cagcatcagg catttgcaaa ggattcttcc agttgcctgt gttacagagg acacagttgg 65760aatttccttt tagtgttgag gggagatgtg tacatgattg tgagatgact cacccttttt 65820gcttagatgg ttccactttc attgtggaca gactctttgg agggccagtt tggcatgcac 65880gtgtgtgttc attccatcct ggagcattct ttatgagaaa gccatttgtt gagtggtttg 65940ccattttgtt ttacagccac tctgtgggct atgaaatggt catctggccg ctttatttgt 66000ccctaaaaaa gcagtttttt cctttcttat cttcaaggct gccaagcagc agaaagagta 66060actcagggaa gccatgtgat agccttttat ctgtctgttc agaaactgat gatgtatcgg 66120atttgataat tcatgaaatg tgaggtttac tggtttgcat ttgcctcaaa atgggcatgc 66180aatattttgt caggtaacat aatagataat tggcattgct ttattgaagt gaattaattc 66240aataagccta taagtgcctg acatgtgcca ggcactgtgc taggcattct gttaatagat 66300gagacaaatc tctgtctttt aggtgttttt agtcaaccag gggagacaaa acacctttaa 66360aaagacaaaa acacttttta aattgctatt ttaaaaaaaa ttcatagtgt acgtgaatat 66420aaggtgctga atatgtgatt gattctgagg gaaaagagtg ataagggaaa attctcagag 66480aaactcaagc tgagggaaga aaaggacccc agacagaggg actaggctag agctatgcta 66540ctacattgca ttaaggggaa tggcacatac ttcactgttg cttcagcaga gagcaggcct 66600gtgttaggtt acaaagggcc ttggatgaca tcctgtgggg ttttaaaatt ttatttaatt 66660tttaattgac aaaatataat tatatatttc agtggggtac aatgtgatgt tatgatgtag 66720gtatgcaatg tagaatgatt aaatcaagct aatttgcata tttatcactt cacatactta 66780tggtttggtt acaacattta aaatttattc ttaacaattt tgaaatagac aacacattat 66840tatcaactat agtcaccatg ttgtgcagat ttcaaaaact tctaacaaaa actttttgcc 66900cttcgaagat attgaacttt gtcttatgaa catagtctta gaaggattta aaaaataatt 66960tgctattcac tgagtacttc ttatgtacac tgtgcatgaa atgagtatta ctttttctaa 67020tattagtttt cttgattgag gcttggcaat tattagtttg tatgcctgta gaaggattat 67080aaacagaggt gtatcccagt aggatttgca ttttagaatg atgactgcga gtaaaataca 67140gagaagtaaa accaaagata gtgggatcat tcaggagtct gtttcctaca ctgaacagta 67200gttgagcaaa aaaaggatgg gcagaatgtg ttgcttctgg gtactgcaaa ttcatggcac 67260ttgaatgaac aagtttaagc cttttattgg ctctttgtgc atatcttcaa catgtatgac 67320tacaaagaga ccacacggtt ttgttgttgt tgttgttgtt gttgttgttg ttgttttatc 67380tgaggtggag tttcactctt cttgcccagg ctggagtgca atggctcgaa tttggctcac 67440tgcaacctcc gcctcctggg ttcaagcgat tctcctgcct aagcctcccg agtagctgga 67500attagaatca tgtgccacca ctcccagcta attttgtatt tttagtagag acagggtttc 67560catgttggtc gggctggtct tgaactccca acttcaggtg atcctcccgc ctcagcctcc 67620caaagtactg ggattacagg tatgagccac cacggccggc ccacacggta tttttgaaag 67680aacagtgagc ttggaattag aacactagtg tctgggccct ggtgctactg cataagtaat 67740tatgaatcca tagccatctt gttgctcttc ttctctaagc cttggtttct ttagctataa 67800aatggaaagt tgaaactttc tagctacttc tttgagttat gagtaacaag ttaggtaata 67860cacttgaagg agaatgtgct atacaaatac tggttcttaa gacagctgtt gttaatgtac 67920tgagtattat gcttacctca cagggttgtt gtgagcatca aatgggataa tggatttgaa 67980agcattttgt ttaaagtgtg attcaaatgt taagaattag taaaaatagt aaaagagaac 68040aattcattct ccatccagat gttccgtccc cacttatgtg ctcattcaga gttgtacaga 68100aaaacctcca cgtaattttc acagactgga gttccacatg taacagaatc atatgggacc 68160aaaaaagctc tctattgact tctttcctgc catattttgg ctctgggacc aacaagacac 68220ctatttttca tgagctgcct gccaccaact ttgggctcac atctagttct gttgcccatg 68280tgcatgctga atttgggccc

atgtccccag atctaacatg aaactcaagt ttccttctgt 68340tcaaactgtc caggcataat agtcttgaag tgtgatgccc aggagagctg tagatttttc 68400actgtccaaa aatcaacatg aaaccagatg tatctgtaaa tctagtttca tgccactttg 68460tagtcaatgg aaatacacta gcaggcagac aagaccagag tttactattt ccagcggaat 68520taatagccac atggaaactt tgcctttggt atctgtgaga tggaagataa aggtgagaaa 68580tcaaagcagt tcccacctca tcctctaaat tccaacataa agaggccttg aatatccttc 68640tatcttattg tatatttcat taacagaagt atgttcctaa ttacttagtc attctatctc 68700cattctcctt tgttttaact tcagtggtgc caggttaaga tgctctggct ttcagctttc 68760atggagcatg gcatgttttt aaacttattt ttaaggacag gtatgttggg aagatcctag 68820ttcctcatct ctttgctcct ggcaaggaaa tttagaattg cctaaagaaa agctgtattg 68880gccaacataa taataaatca gtattagtga atctaaagcg tattggagaa ctttgtaaca 68940tgagttgaaa ttcagacctg caatgaagtt tttttaaaag atttaaaatt gaaataataa 69000aaaaaaagtt aaaaacaagt aaaacatatc agtagttaat cattctacca aaatttggtt 69060ttacgtttgc atatttaacc atttttattt tctgtatttg tccatgaaca tgtgtttttg 69120tatattgttt atattaaaca tggttttaat catggcttat ttcttttatg ttttacttct 69180tttcctttga cataaaatat tgtattttta aaattttaac tgcttcttgg tataccattc 69240caatataggt ggctacatag attgaagtta aaactaatta caatcagaga aaattaacaa 69300ttcatccctt cagtctcatt agtcacaagt taaatactca atagccacat gtatctagtt 69360gctaccgttt tgaatagaac agatataaga cattttcatc aacacagaaa attcagttgg 69420aaagtattgc cctggagtaa atgtgccata ctgtactaaa tcatttttct cttgttggac 69480atctaagtta tttcttattt ttttaatatt ttatataact tgacggtgaa tatacatacg 69540tacatagcta tttgctttgc tgaattattt cttagaatca atttcaaaag tggagttatc 69600aggtcaaaga gcctgagaag attttttgga acctgtagtg tattgccata gtcctttcac 69660aaaagtttat gtcaacttaa agtacttcta gcagcaaatg attgtactaa tttcgctgca 69720atctcaacaa cactggacat tataagtttt tattctaccc tattttccat taaaagataa 69780cttatgcttg attgactttg cattttattt tattattaat aatgttgtgg tttccttttt 69840ctgattttat ttttagttaa ggtatccttt aattttaacc tgatattttt ctctaaaaat 69900tattctaaga aaagacaaag gtgatgtcaa atatatcctg agttttcatt ttttcttgca 69960tggaatttgt atatttgcac ctttgcccat ttatattatg atttcttagt gtcttcccta 70020tcaattttaa tgaagatttc atatatatca atttttccac aaatataatc tttttaaaaa 70080tatatttttt ccacgatata attctaatgt attctccgaa atgttggaaa aacttaagta 70140gtcatcaaag catttgaaga ttttttaaag gttgttttta taccagtctt aaatgttaat 70200ttaagggtcg taaaaagagg tgaaaattaa atcatttttc agtaaggggt aagaccattt 70260aactcttgga aaatacagga aacatgtaga tttctagagg ccaagaagga ggtagggatt 70320aattattttg taactgcccc caaccttcta acctataatg aaagaaccac tgaaggccct 70380taaatatttt taggcttaat tggctgtcct tgtacttagg gcacatctaa aaatcctgag 70440gcaaccactt aagagaacat gcttttgtta attcacaggg agctgtccta agagtgtcca 70500gaatcctctg tagtcttggg cctggtgctt gagagaccca aaggaaaggt caatggaatt 70560gcagcttagt gttagagttt tcatggatca cactaattag ttaatgtcat aaaggtctct 70620ctcctgttat gggaaaaagc agcaaatagg aacttctggt agggtgctta aagttggttt 70680gatatttttc ttagtaattt taactaataa aagtaataca tgcttatggt agaatgataa 70740acctgaacga aaaggtatga aaatgtagaa gttctcctac ttatgacctc accccttctt 70800tgcactccca gtttcactcc tcagagggta accatagtga ctagtttctt gtgtttggtt 70860cctgagattt tctgtgcata tatattgtta gatatatgca tattatattt tcaaaattcc 70920tatcacatga caactactgt tctgtaactt aatttcttca cttaattaat agaccttata 70980tatgcttttc catatcaata tatatagatc tatataagtt ttcctaaagg ttgcacaatt 71040ttcaactgta tggctgtctt gtaatttact ttttgtttcg cctactaatg gatatttcat 71100gttttcataa ctcttttgat attaaaagta gtgctgcaat taacatcctt gagaggcagt 71160atatatggtg tttaaggtga atggctctgg agccagacta ctttggactg aatattgatg 71220ccactaattc cttgctgtat gaccttaggc aagttgctta atttctttgc ctcagtgtcc 71280ttgtgtgaaa aaatggaggc aataatggtc actatccagt agagttttta tgaggattta 71340ataagttaat aatgcacatt aagaacttag ttatttttag attaagtagt gaaggactat 71400ataattgtta gtataattgt atacctttat tagcatactt ttgcatgtat agcaataaga 71460caaattctta gatgtttaac agttggacat aaggagtgta cacattttca gtactggtag 71520atgttacctt ttccctgcca aaaattgcaa atatttgata ttaactttta aaatcttagt 71580aaatctgata agtataaata acaatttatg atcattttaa gttgcctttc ttaattttgt 71640gtgaaaatga gtatcttttc acatgttttt tggccattta tgtttctttc catgtgaact 71700aactgttctt ggccgttgcc tattttttgt tcctgttact atatggcttt tcatctgttt 71760ctcgttgggt tatggagctc tttgtatata aaaggattta gcctcttgtt atatgtgtga 71820caaatacttt ttccaattta tatttcaact ttgcttatgt tttcctattc atcagtctaa 71880aattatgtag ttaaattcat cattgttttt tcttacggct ttggagtttg gagatcatgc 71940ttcaaaggtc tttctaggtg gggttgattt aaatcaagta ctggaagtat ttttgccaaa 72000aagactcatg aattatagat gttagagcta aaagggacct tagagatttg ctagttcaac 72060ctccttttct tcataccttt ttaatttttc tctgcagatg aaaagaagtt tagtcccaaa 72120gaaagaaagg actctaaagg ttctccagta agctaatggc aaaaatgtag actggaactt 72180ctagctcctg atgggtattt cagtgatcat tcaatttaac cagatggttt cacaaaagga 72240gctttctact aaaaaataaa atacatattt aagcaactca gataaatatt ttttatttat 72300cagattaatt tttacttaga gattcatcag catatgtact atatatgtac aaatcaccta 72360tgtgttttgg atatttagtt gaacaaatgt gcaaatattt taaccaaagg agcatatcta 72420ttttcatttt actttcttaa tggttttagt tatgaatgtg aaatgtgtac ttaccttaac 72480agaaattaag tagatttttg gtctgacata tatgagaact gaaaagcatt ggcttggctg 72540ctaactgcat tctcatcttt ctttccctgc tttggcaaag tctgggatta aatctaatac 72600cttttaaact gtttgggact tcagccagag tgacctgtct tgaattcaga actgtgcaga 72660tcattcccca ttctaaggtc ctctcatggc tcctcattgc ctgtaggatg agatccaagt 72720accttagcat agcttacgca ctgcagtcac ttgacctcta gcacctatgc agtcttccag 72780tcttatttcc acattccttt gcacatgctg tttccccatg tggggcaact tttttcttgc 72840ctgtctgcct gcctaagcca acttaaataa acatgatttc tgtaacttct gtgaagcctt 72900ttccaatctc tccattccaa gacgaaggtg tttctatagg catgacttct ggaatggcag 72960atcaaggatc tggtggaccc tctactcagt gaaacaacca tttaactggt aaaaatgatt 73020taactggtaa aaatgatcaa tcaaccattt aaaatcttca gaaaatatcc taagggcaca 73080tagcaaaaag agaaatgttt attcaagaaa agctattaag cctcagtaaa aacagcaaga 73140gtctatggca tttgagtcat gacctgttcc tattccttcc cttagctcca ttctacaggc 73200aagtgcaacc aagaagacgt aggcttcctc tctttcaaaa tcttactcca tagttataat 73260ttcaccctac aatggggcag gccacaagca tctctttccc cccccacccc agccctatat 73320tacagaagca ctgttctagg aaggcatagc tgagaggatt ggagattcct tcctcaccca 73380ctttctacat atgagggctt tgccccaggg atggtaaacc aagaatacag gggtcctgct 73440tgtgcctgcc tcagctcatc tataaggtaa aacttccaca ctaggaaagg ctaattaaga 73500ggactaggga acataccatt atccccaggg tccacttgta gaacagggga gttattctgg 73560gagaagcagg tcactgcccc acttgtggaa caggggagtc actctgggag aagcagatca 73620ccgtccctgc tcccaattct attgcagtga cagaagttct gtcccaggga aaggcattag 73680gatggagaac tctatagttc tccctgaggt gactgacttt atttggaaca gagcatgaag 73740aagcttatgc ctaagggcac tgtcaaaaat aatgcagatc ttggtggtaa gcaattaaga 73800gtggattggt agctccatga taactagtag caacaagcaa aacagcagac caacatggag 73860gataccagag aaccagacaa aggaatcact aagaagcgcc cttgtggaac tacactcact 73920gctgggtgtg tggaaagtta tgcatgtgtg ctttactgta ccctctcaaa agcaacctaa 73980acaggatgtg gcgtaggctc taaagcattc ctcaagccac acatggatcc atcagtaaaa 74040tatggagggc ttaaggttaa aaaggcttaa gtacaatgtc tggccctaca ttttctacat 74100gttatgccac cctgaccaag gggcaactcc tacaaagcca ggcataataa taaaatcata 74160tttgtctctt ttggaatgga tgactgtgcc taaaactgtg ccctttgaaa agcaactaga 74220gagataattt ctgaagtgtt tgtccctacc tgaatgcggg caaaattcta aactccctga 74280agtgtgaaag tgttttccaa gtcacatgca catccagtag tggtaaaggg taaaaatcta 74340actgactaag agggcttcac agcaacatta accaaaaagt ggtttatgta atctttgcct 74400acctcataat tccctaggca ttctatgcta ttctgtactc agaaggctta aaagtcaggt 74460tagggaaagg aggcctttga ggttactgtg cagaggcagt gctgggaaag gaatgaagtt 74520caataaattt aggccatcat ggtttaaaga atggattatg tagataggaa ggataaagga 74580aacccagagt caagaaaagt aaagcttttc attggtgcta tgccaaccca tatctgagcc 74640tgaggcaaaa ggaaaaatgt gctccccaat atacatttat acaaaatatc aactaatttt 74700atttgttgaa ctgaatttaa aaagtcaaca aaaattaaaa ataaaaaaat cgtgactata 74760ttcttaataa gtggtttatg taaacccaga gttgaccaat gggatgccag tctcaaccat 74820aaaaacaaac aaataatgtg agtagcaaca ccagaagttt caaagtgtca gggaaaccag 74880tttcacagaa gtggttcagc caagtcacta aacaaagaaa tgactaagca aaaaacaaaa 74940tgagtctcag agagggtcag gtcaatatcc agagttgtta caatatagta actaaaatat 75000tgttttgaac taaaaatttt gaggcatgca aagaatgagg aaagtgtaac tcatacatgg 75060tattatatga aaaaatcaac aaaaaactat ccatgaggaa acaaggatgt tgaacttaac 75120taggcaaaaa ctttaaaaat cagctattta aacatattca aagaactgaa ggaactatgt 75180ctaaaatact aaaataaagc gtaataacaa tttctcatca agtagagaat gctaataaag 75240agatagaagt tatagaaaaa gaagaaaatg gaaaatctgg agttgaaaag tataactgaa 75300atgaaaaata cactagaaaa ggtcacaaga agatataact tggcagaaga aacaatcagc 75360aatttagaac atagatcaat atagattatt catttttaaa gatagaagga aaaaaagaat 75420gaaccaaact gaagattccc aaagaaatgt aggacatctt aaaggcacat cattaggaga 75480agaaaagaag aaaaagaaaa gagcagaaag aatatttttt aaaaatggat aaaatcttcc 75540caaatttaat gaaaaacatc aatctacaca tcaaagaaga ttttttttta atttcaagga 75600ggaaaatgta aagatattga tacttagata catcatagtc aaaatattgg agccaaatat 75660aaagagaaaa ttttgaaatt agcaagagaa aaatgaaacg gaaccacaat aagattaaca 75720actgattctc atcagaaata gcagagagca gaaggcagtg caatgccata ttctaaacat 75780tgaaagaatg aaaaaactgt cagccaagaa tcatatattc aacaaaagta tctttaaagg 75840taaaaatgaa atgaagacat tcctaggtaa acaaaggctg agaaaatttt ttgttagctg 75900acatgccttg aaagaaatac taaaagcttc ctagacagta gcttgaatct gcatgaaaaa 75960agcaattcca ataaagggaa atttgtaaat aataaaaagg tatcattata tattattttc 76020cacttaactt acttaaaatc aatttcttaa agcactatct gtaaaaatgt attgttattt 76080gataataaaa tgtaaaagag gggagtggga attaagctaa attggagtaa ggaaatggta 76140tcatatggta aattgaattt acagaaagaa atgaaaaaaa ttaagtggca aatatgaaga 76200ttaacaaaaa cttctataaa ttaattgtgt tctctttccc ttagcttctg taaaagacat 76260aagactattc aaaatgacaa tagcttaaac gcattgtttt attggtaaca aatatagaca 76320aattatgtac aacaattatt attatacaag gagagagaat ggagctatag aggattaaag 76380tttttataac ctattggaac taagtcagta taaatctgat gtggattctg ttaatttaag 76440atatatgtta gaagccccaa agtaatcact gagaaaatga tgcaaaaata cagttttaaa 76500aagttaaaaa catagtttag cttatgtatg cctagtattc cattattttt ttttttatac 76560tttaagttct ggggtacatg tgcagaacgt gcaggtttgt tacataagta tacaagtgcc 76620atggtagttt gcagatccca tcaacacgtc atctacatta ggtatttctc ctaatgctat 76680ccctcccaca gtcccccacc cccctcgaca ggccctagtg tgtgatattc ccctccctgt 76740gtccatgtgt tctcattgtt caactcccac ttacgagtga gaacatgcgg tattccgttt 76800tctgttctgt gttagtttgc tgagaatgat ggtttccagc ttcatccatg tccctgcaga 76860ggacatgaac tcatcctttt ttatggctgc atagtattcc atggtgtata tgtgccacat 76920tttctttctg cttgttccta ggagaaagtg gctgaagctt ccagagagaa gctgagagta 76980gtttaattct ttttgccata aacacggcaa cccagttttc tgcaagctgt gttagtttgc 77040tctctccttg gttcatccat tcatttattc atagcttcca taaatgttta acaaacatta 77100attaggggcc aagccatgtg ctaggcgcag gggataaaac tgtggacaaa acaagcccca 77160gctactctta aggaactgat agacaaatgg accagcaaac aggctggtcc tgttttgaag 77220gcaaagtgcc tggtgctcct gatctcatga gcacaaagca tttagcctaa atctcatcct 77280cctaaggcct cagaaacaag gccttatttt aataactgca agtcagtcat ttgaagacta 77340aatcatagaa tcctagaaaa ctagtactgg gagcaaaaca aaagaatggg atgagcatga 77400aacatatatt cagaagttgt ggtgtgtagg tgtataagcc aagctctttt cttcacttgc 77460ttgctaagtc acttagcttt tctgcctttt tctttgctct gtctggaaat tgagttaatg 77520aaatatatct acatgataga gatattgaga tgattaaata agatgctgct gtcacccagt 77580atgcccttac ctgctgtact tagaagtatc tgtaattcat tttctaaact ttttgtatga 77640gtgcttcatg catgcccacc accatggaag ctaccttaag acagtgaggg cctttgttta 77700acttgtttgt actgtatcct cagtctaatg gtgtctggct tatagtaggc accgaataca 77760attttattga cagaatggat tataatgaat gtgaaggcat ttttaaattt atgaagtgtt 77820gtgcatattg ttgttaattt taagctgttc agttaaagaa cccctaatcc aactctcttg 77880agttttatag atatcataga agatatatct tcccttgaca cagaagcttt ccttgaagct 77940tcccttgact catctatttg cctcacagag tgattgtgca gatcccacaa gataaattta 78000tgtgaatgtg ctttatgtgt ttgaagcgct ccacaaatac gggttttata agttgagaaa 78060atagagtcag ggagaaaggt gactgatcca aggtcatgca gcgagttagt atcagaattt 78120atgatggaat ttcaggctcc caatttccag tccagtatac taaggcagat tccagagaag 78180aaacagtgga gagcaggcac tgacgaggga cgaagaaaag caggctccgt ctggctgcaa 78240cttgtctctt catggcaaag agaaactagg acagtactat gccagagacc acatgataac 78300tttgcagaat ggaaagagct tgtttaccaa attgaacact ttatctgtgt ttatctaaca 78360atgacagttc caccagctcc ttaccagctc tcttttgcct agtttaacaa tataccaact 78420atgacacatt ttccttctca gtttttattc tagattacat tttgttcaac ttcatcttaa 78480tgtgtagtat agaaagagta aggtaagagt ataacaagtg gttattttcc atttctactg 78540aggacagaga aataatctaa gggatttgta ttagatatga agaagttcat ggccgggaca 78600tgagagatac tgtgatagaa tggatattgt taagtctttg gtagtttttg aggggaaaaa 78660agagaaattt tttatttgtc tgataatagt ttagcaatgt cttaatttag gattcaaaag 78720ttgttcaggg tccatcttgg ccttcaaatt aagatgcctg ttgagagata acgttgttgt 78780tttcaaactc cattctgtga cttaagaatg agagaaggag gaagaaaaga ggagaaaatt 78840ggagggaaaa gtgcccaggc agtgtcaagg ctagacactg gaaatttatc aatgaaagcc 78900acatggtgga tgggaatcag atatgtgcat caattatttg tgttctaatc catagagaag 78960taccgtataa tgcaccaaga tatgagatgc tttgaaagaa gaccatataa gtggagatgt 79020gttcctattc tatctaggga tagagtcaga aagggcttca ttgaataagt ggcagcctct 79080tgggctgaga cctgagttat gagatgatgt ggcaaaggag acagatgatt gggggcaagg 79140tggggtcatt gaagttggag gcagtgacaa tataagcaaa gctacagggg catgaaacag 79200caaggttaga ttagggaatt gcaacagggt ggtactgctg gaaggtcaca tggaaaagat 79260tatgagagta ttgagataag aagctagaaa taagctttga atgccatcct agtgctttga 79320atttgtatcc tgcaagccaa gtggttttca cttggtcatt taataaaatt gcagattctc 79380aggtctcacc tgtaacttca gattcagaag agtctgtgct aactgaaggt ggaatcagtt 79440tccatattgc taattagctc ctcagaggat tctaatatat cagtgagtta caaccactgc 79500tgtaagccat aggtagttat tgaaagctgc tagggagagg agccacagaa gcagatgttt 79560tagataggat ccctctgggg ttctgtgtaa tttatggact ggactggaga ggatcagaca 79620ggaaacagaa agacttgaat aaggcagttg cagttagttt ggaggcaaag attctctctc 79680tctctctctc tctctctctc tctctctctc tctctgtgtg tgtgtgtgtg tgtgtgtgtg 79740tgtgtgtaat tgtaggaact atttaggcag taaaattaac agatattagt cactgattga 79800ctgattggat ggcagtgata ggtggggtgc attgagggaa ttgtattaca ttaagtccag 79860gatgactcat ggttttctaa gttgagtcat tggggattgc cagccaatgt gagaaactat 79920atcgtctaat agttgatctt ggagttagac ttgaattaaa atcttgaagc catcaattgc 79980tgtatgtggt cttgggcaga acacttaagg tttctagacc tcagctcttt cttctataaa 80040ataaggataa taatgcatac ctcatgcatt tgttgtaaag actaaatgag gttaaattat 80100gtagagtgta gtatagtaac tagcacatac agtggcccag taaacgtcag ctgttattat 80160tgtgctatat gttgtgatgt gtactggagt gagatggggt aggggatttt ttagtctctg 80220acaatgactc ctctccccat gatcaaaatc agaaaatcag tctcttatgt gctgagaaga 80280gagacacttc tcccaagtgt ttaaggctaa taccttgcct tgttttgcct tgggccagac 80340ctcactacac atctgtttaa gagataaggg taagctctgt tcttggtgag tatctcagtg 80400gggctgtttt tctagttctt gtagtttctt tgggccaaca tgaaatgtct aaccttggct 80460tcttggttgt ggattctcgt caacatttca ctgctaccca agttgtgtct gctcacatga 80520tgctatcttc cttcttttgg gtttccgaag ccctcagaca cttggctgaa cacttttttc 80580acatttctta agctatatca tctgtgtttt ccctgccaca gacaaagtca caaaaggact 80640ttaagatagg gtctttttcc ccccagggtt tttatacatt ttgagtaagg gcaagtggta 80700aatgctgctt ttctgcctta accagtagtg tctgacagag gaggcagcat gatgattgca 80760gagctcactg aactgaaagt cagatgcctt acccacctgg actctagtac caaggggaag 80820atggagtggg atggggaaaa tggggataaa ttatcattta ttttgagtgt gccaggccct 80880ttcccatgta ttgtctgatg catttgtcac aattctcttt gggtttgaaa tgtgattttc 80940ttcattttat agataaggaa acttatggga agggagatta ggttcatctc gtgcccaact 81000ttacatggct agtgatcaat aatagtgaga ttcaaactca ggtttctctg ttccaaaacc 81060tttgcttttt catcttttga cactgtaact tattagaaga tgtctttgac tctgagtctc 81120atttgcctca actgtaaaat ggagctctgt aacccttgct ctgtatgaca gtaaatctcc 81180tgagaccaga tttatgatag gggacaagga tatttgtatc tttgggcccc taatgtattg 81240aaagtgcctc tcagtgcctg gcacagagaa gggcactcaa taaatattta ctaatcattt 81300tccagaaaga gggtagctcc ataatgagcg agattcattt tgatggctgc tgtagtgttt 81360aatgttttta ccacctgtta aaatgatttt ggagtataga tggataactg atgatggttg 81420ttatatagat tttttcatag gttgcctgtt ccaaattcta tgccctggaa gaagctaaat 81480atccagaatt tgacaggaaa tattattcta caacagatcc ctggcataag aacagtaaca 81540cctctgttct attctcagac ttgcctctga ataactgttt ctcctggtca attctctgtc 81600tctatctggg attgaaactt ccccctggac aatgagggag ttgaactagt ttagtggggt 81660tcagccttga gtggccatta caattatttg gggattgttg aaaaaaattg gatgcccaga 81720tttttgtcgt tgttgttgtt gtttgttttt taattatact ttaagttctg ggatacatat 81780gcagaatgtg caggttggct acataggtat acacgtgcca tggtggtttg ctgcacccat 81840caacccgtca tctatattag gtatttctcc tgatgctatc cctccctagc cccctagccc 81900cagacaggcc atagtgtgtg atgttcccct ccctgagtct atctgttctc attgttcaac 81960tcccacttat gagtgagaac atgtggtgtt tggttttctg ttcctgtgtt agtttgctga 82020gaatgatggt ttccagcttc atctgtgttc ctgcaaagga catgaactca tccttttata 82080tggttgccta atatttcatg gtgtattgaa ctgcttaccc cagttcaatc aaataagaat 82140acagaatgtt gagaggagca tcagtatttt aagaaggcca cctagtgagt tcaatgtgca 82200accaaggatg agaaacactg aactagatga ttggtaaggg ccatccaact ttgatagtcg 82260acaagagaca atgctataga gtatggtgga cagagcatgg gctttagagt tagccaggca 82320tgcattcaga ccctggctct gttacttact agttgtgtga tcttgaagaa atcaaaatgg 82380agatacactt tgtccctggc agtaatagtt gtggggatta agcacctttg ccagtgctta 82440ggacataata aacccccagt aaatagcttc tttagtatca gaagttcaga tggaagatgt 82500gagaaaaata ttggttcagt aagatttaac atgtagatta aaatcaagta tttaaaaaaa 82560ttttcctgtt tctttagcaa tggattccag aaacataatg tggaaatagc tctgagtcct 82620aagatttgat gacattgcag aaagaaatct ggctagttgt cccatggctg attggctatg 82680atggctaaga agccattgga aaaaaaaatt ggctcacaga agacagcaga tgtggcttgg 82740gaaatgcaag gacatgactc taataaggat ttgtcccatt tatgagagtg attccaggag 82800aaaaggacag atttgtattg tcagtgggat atgctgttaa aaaacacttt tgctaccacc 82860actccagctg tcttggcatg tttgttggtg atgtaagcta cagaaaatgg aaatcaccaa 82920aagggctata gcagcctgat gcatagtgac aagtaattgt tctattcatg gttatgtgtt 82980gtacagagca cttgctgcat gtcaggtttg aggtttgagt atgcattagg gccatggata 83040cccccatctt ctctctaagt agatttcaaa gtaaatattt gatgagtatg taaaatattt 83100agtttggtca gtcataggac tgagaacgtg gtgggggtta cctcctagta tctgcaggca 83160aaaaaacttt tttcttccta tagcaattgc catctcagcc ccttttgcag cgtttctctt 83220gctacacttt gcattaacca tctgtgcact tgtcttagcc tcaaacaggc catgaaagct 83280ccttgaggat aggggctatg tctttttcat ctttatatat gcatcattta gcagagctgc 83340tcctttataa tgtactaatt

actgaatgaa gggatccata gatgaataaa tgaatgcaaa 83400gtaggagtga cctctcttct gtctttcttc atgatgggga ttagtgtgtg tgtataaggg 83460aataatcgtg tcacataaaa tataacctta cttagaaggc aagacttcca gaatggtgga 83520atgagaacca acccccgccc ccataaattc accctttcat gaaagcaatg aaaacactag 83580gaaacgttgt gaaaattaac ttttccagaa ctctgggaag gaaacaaagg tttccaacaa 83640tctgagaaga atgtattcaa gaaaaacttc ggtaagttct ctgatcacag tggaaataat 83700aaacaattag taatagaagg atatttggga aattcaccat ttgtagaaca taaacagtgg 83760atcaaagaag aaatcataag ggaaatgaga aaatactttg agattaatga aaatgaaaat 83820acattatacc gaaacttaca ggatacagcc aagctaaagc agtacttaaa gggtaattta 83880taactgtgaa tgcctacatc aacaaagaca aatgatctca aatcaagaac ctaactttcc 83940accttaggaa actaggaaag gaacagcaaa ctacaaagaa agaaggaaga aagattaata 84000aagactagaa gggaaataaa tgaaatatag aatagaaaaa cactagaatc aatgaaatta 84060aaaattgttt ctttgaagag atcaacaaaa ttgaaaaaac tttagtcaga ttgaataaga 84120aaaaaaagag agaagattca aattatcaaa atgagcagtg aaactggggc catcactacg 84180taccttaaaa agaattctca aaggattaaa aggaaatacc attgcattag tttattctca 84240tacagctata aaaacaacta cctgagactg ggtgtttatg aagaaaagcg ctttaattga 84300ctcatagttc cacaggctgt acaggaggca tggatggtga agcctcaaga aacttacaat 84360caggtggaag gctaaggggc atgaaagaca tgtcttcaca caatggcagg agagagagag 84420agagcaaagg gggaagtgcc acaaactttt aaaccatcag atcttatgac aactcactca 84480ctacaatgag aacagcaagg agaaaatctg cccacgtgat ccagttacct cctacgaggt 84540cccttcccca acactggaaa ttacaattca acgtgagatt tgggtgggga cacagagcaa 84600aaccatatca accatactgt atgccaaaaa cttagatgat ctagatgaaa tggacaaata 84660ctcagagaaa cacaaactat ctgaagtgtc tgaagtgacc agtgaagaaa cagaaaatct 84720gagtagtcct gtaacaagtc ttgtaacaaa actggattaa taattaagaa acttcccaca 84780aataaaaacc caggttcaga tgtcttcact ggtgaatatt atcaaatatt taaggaaaat 84840ttaatccttc acaaattctt tcaaaaattg gaagaggctg gaacccttcc cttcccaact 84900aattctgcac agtcagcatt accctgatgc caaaaccaaa gatatgacac aaaaataaaa 84960ctgcaggcta atatcacatt tgaatataga taactttcta aaaatcttaa caaaatgcta 85020gcaaactgaa ttcaacaaca aataaaaagg tttataaagg gtgaccaggt aggatttatc 85080tctgcaatgt aaattaatat tcaaaaagct aagaatagga ggaaactttc ttaactttgt 85140aatggacatc tctgaaaaac acacagctaa catcatactt agtagtgaaa gactgaaatt 85200tttccttgta agatcaggaa caagacaagg atgactgctg tcaccatttc aatttaccat 85260tgtattgtag gtttattgta ggctcaagtc aagcaaaaaa aaaaaaaaaa gtaaaagaca 85320cccatattgg aaaggaagag gtgaaattat ctatattcac agatgacatg atcttataca 85380aagaaaaccc ctaaagaatc catgacaaac tattaaaatg agtaaacgag ttcagcaagg 85440tttcagaata caagattaat gtgcaaaaat caattgtatt tctgtgcact agcaatgaac 85500aatctgaaaa tgaaattaag agaacagttc actcacaata tcatcaaaat accagaatac 85560ttaaaaataa atttaacaaa agaagtgtaa gacttgtatg ctacaaaccg taaaacactg 85620tggaaagtaa ttaaaaatct aaataaatag aaaaacattc cttgttcatg tgccagagga 85680ctcaatattg tcaagatgga aatactcccc aaaggttgaa ggaaatccct gtcaaaatcc 85740tggctgtttt cttagcagaa aatgaaaatc tgaccctaaa attaatattt aaatacatag 85800aatctaggat agccaaaata atattgagaa agaaaaacaa agtcagtgta cccacgcttc 85860ctgattccaa accttactac aaagcagtgg taatcaagag cgtatggtat tggcatacgt 85920acaaacagat caataaatgg aatactattg agaatccaaa aattaactct tacatttaag 85980ggcaattgat cttcaaaagt gttgttaaga caatttaatg aggaaagaat agtcttttca 86040ataaattgta ctggaaaaat tggatatcca catgaaaata aaagatgttg gaccacttca 86100aacctgcaaa aaaaaaaaaa aatgatctaa tggtgtatca tggatctaaa tgctatagag 86160ctaagatgat aaatctcaga agaaaatatc agagtaaatc tttatgacct tgaagtaggc 86220aatgtttttt tggctgtaac accagaagca caagtagtaa gagaaaaaaa aaatggactt 86280catcagattt gaaatttttg tgctgcaaat gatgccatca agaaagtgaa aatctcaccc 86340acagaatgag agaaagtatt tgcaaatcat atatctgata agggtattga atttagaata 86400tataaagaac tcttgcaact caatataaaa agacaaccca attttaaaat gggcaaagta 86460tttgaatata aatttcttga tagaagatat acaaatttaa aactgctcaa cttcattagt 86520cattagggaa atgcagatca aaaccaaatt gagataccgg tttacaccta ttaggatggc 86580tatagtgaaa aagaacaaat aacaagtatt ggctttaatg tggaggaacc ttatacattg 86640gtggtaaaat gtaaagtcgt gcagcccttt ggaaaacagt ctgaaagtct ttaaaaattt 86700actatttgtt atttggtttt tcttcacttt taatttaggt tcagaggtac atatgcaggt 86760ttgctatata gctaaattat gtgtcacagg ggtttagtgt acacattatt tcatcaccca 86820ggtaataagc atggtaccca ataggtagtt tttggatctt caccctcctc ctaacctcca 86880ccatcaagta ggccctggtg cctcttgctc tcttctttgt gttcatatgt actcaatatt 86940tagcttccac ttatcagtga gaatatgcgg tatttggttt tctgttcctg ctttagtttg 87000cttaggatat tggcctccag attcatccac gttgctgcaa aggacatgat ctcattcttt 87060ttgcatagtg tactatggtg tacatgtatc aaaaatgtta ctgtttgacc tagtaattct 87120attccaatat aactactcaa gagaaatgaa aacatgtcca cacaaaaact tgtacacaaa 87180tgttcattgc agcattattt ataatagcca aagagtggaa gacaaatgtc ttccaaatgt 87240gggctccaaa tgtccaccaa ctgataaatg gaaaaacaaa atgtggtata tccacgccat 87300ggtttatctg tcaataataa gaaatgaagt aatgatacat gctacaatga accttgaaaa 87360tattatgcta ggtgagagaa gcaactcaca aaagaccaca ctgtatgatt ttatttatat 87420taaatgtcca taaaagaaaa atatttagag atagaaagga aattagtgtt tccagggtct 87480gggaggagat ggtataagca atggctgcta atgggtacag gatttctttt tggggtgata 87540taattgctct aaaattagtt tgaggtaata gatgtgaata tgctaaaatg ggtgaatttt 87600ataatatgtg aaatataact cagtaagccc attaaaaaca acctaattaa attaaaagca 87660agctataaca gaaatattat atagccttgg cagtttagaa tagtgggaaa atatggagtt 87720ggggcaggga aatagtcgca agtataattc tggttttgtc actactagtg tatggacttg 87780gatgagtcat ttcctttctc taagtctcag tttgcatata tgcaaaatag aggtaatgat 87840acctacctca gtggtagctt ttcaaaacct tgttctccct catctctcct ctacaacttt 87900ctcgtaagat tattacagta ataaccattt attaagcact gtgtcagcaa tggtgtggga 87960ccacaacttc actgaatcct cattgcaatc ttgtggggtc tgtatttctt tgcctgtttt 88020acatgtaaag aaattgacgt caaaagagtt gttcaaggtc attctgttag caagtggcag 88080agatggacat gaaaactaga tgttctacct atatgtcttt ccacttcaac taaagaattt 88140attaaagaga attaaaaagc tatgaactac ttttaatagt aaacattgct gtcctcgtga 88200atgaacacac actaaatttc aaatctcacg atggcaggga ataaagatgc tacctgtctt 88260aagccattac ttcaccaact tctccaccaa aatattcctt gtaaccacaa ataagtaagt 88320acaatagatc tataaggaga gaataattga gaactctctg attttatctt aaaagtcatg 88380tagggatgtc atgttccaca atgtaattaa taaaatatat tttgttacta aacataagga 88440aaaattttat gttcaacata aagatgtttg gtggttgcct caacctcttt tagtttgaaa 88500agtaggtatg tatgagaaag atacgtgttt acatgtctac ccttgccctc tctgtctctt 88560cccctctctc tctctctctc cctccctccc caccccctct gccctacacc ccccaacccc 88620cacatgtatt tacctttctc taaaagctct gcataaccaa gaaaaatggt cttttttatt 88680tttaggatgt tagatatttc attttcttat ggtaagacaa aagattaagg caaccaagac 88740ttacaatgta tctaccgtgt ggcaggcacg gaggcaaggg cttttacatg tgttatttaa 88800tgtaattgta attctcacaa aagccgtcta gagttgaaaa tatttccagc tctaattgag 88860gcaaatggag cacagagagc cttaattatt tcacccaaag ttcagtggta gaggcaggat 88920tccaacccag gtctggtggg ctccaaagcc ttgttggttt gccattcctc tcgctaacaa 88980atgaaactgg tctgtgactt ttgcatttca ccccacttcc acagtcactg gtgggactta 89040tttaaattaa tcagatcctt caaagtatcc ccaagtcctc ctttaaaaag aaagttaggg 89100ggcaggggga ggagcagagg agaggagata aaaaggaaag gagtcagaga gagagagaga 89160gagagagaga gagagagaga gagagagaga cctggtggtc tcagctgggt gccaaggttt 89220cctaagccca agttccccat ggttgagcct gcattagcag gccgacagct tctagtaatt 89280cacttttatt taattaatag tgaaactgtt gaagaattgc aagtggtgtt ctagttcaga 89340aaccttccat tctatggggc attgcttttg cctcagactc ataaaaccaa atgccctgcc 89400tcaggataat aagtgaacat gtaacccacg agaggtaaga aaaaacacaa tgtcacgtgc 89460aaattctgca cttgttctca aagcaaacct ctcctgtgtt tgcaattagg atgttatcta 89520ggagcatatt caaaactttt gaggttttta ttttagtttt tcttttatta tgtgctgttt 89580tagtaatatc aaagaataca tgtaatatat gttatatggc ataacaataa aattaatgtt 89640tatgagccct gattaaagaa tcaacaacat taacatcatc attgcaacaa ccctattaga 89700atggaagctc tgtgaaggca aggatttttt tctgttttgt tcactgctat atccccagga 89760cctagaggag tgtcagccac ataataggag cttagtcaat attttttaaa taagagcata 89820aatctactta tatcctcttt cctcttatca tcactcccag cctcccctca gaggtagcca 89880ctatcctatt ttagggtttt aatattccct tgcattttgt taacttttca catgtgtatt 89940cccaaataat atattgtttg cttttgcttc tttttgaact ttatataatg gaatcatatt 90000gtatgtatcc aattgtgagt tatgactttt acgcaacatt agtatttgag attcaactat 90060gtgtagctcg attccattcc ttttcattgc tgaattgtat tttattggat atgtgtgcca 90120taaattattt ttctcctgtc agttgatgtt tatcttttat gcttttataa acaaaacggc 90180tatgactgtt cctgcatgtg cctcctggta catatgtgcc caactttctc taggatataa 90240gcctcagagg gggactgcac ttggaatttt catttccaga gcccaaagtt tagctcatga 90300gtcagagctg caatgtgccc tttgtccaca ctaggtcagg atcagtggga gtgctaccca 90360aaatattttc ctagtggggg aatcagggag aggcagagac tgacctagtg aggccaggag 90420ttactatctc aggtctctag tcaaaatggg ttgcaattag taaaagttca gattctgaat 90480ccccttcatt atttatcttc ttcttcctcc tttacagtta tttttgttca aggtgcactt 90540tattaaactc atacctaaca aacaaaactc taatgaatat tttgtctttc attgattgta 90600aattcaatta gattctttga aaaaatttta actgtatttt cactttagca tggatgaaaa 90660tttcgatttc tttaaaaaac atttttaata ataacacaat aaggtctacc ctcataacaa 90720aatttaaggg cacaacacca tattgttaac tataggcaca atgttgtaca gcagatgtct 90780agaatttttt tcttcatgct taactgaaac tttatagcca ttgaacggca acagtccatt 90840tctatttctt aaaagtcctt tacaaaatga gctttctaca tgtttccatt ttgtttatct 90900gataattttt tttcgttttt tattatactt taagttctgg gatacatgtg cagaatgtgc 90960aggtttgtta cataggtata cacgtgccag ggtggcttgc cacacccatc aacccgtcat 91020ctacattaga tattactcct aaagctattc cctccgcttg cccctcaccc atcactggcc 91080ccagtgtgtg atgttccctg tcctgtgtcc aagtgttctc attgttcaac tcccacttat 91140gagtgagaac atgtagtgtt tggttttctt ttcttgtgtc agtttgctga gaatgatggt 91200ttccagcttc atccatgccc ctgcaaagga catgaactca tctttttata tggctgcata 91260gtattccatg gtgtatatgt gccacatttt ctttatccag tctatcattg atgggcattt 91320gggttggttc caagtctttg ctattgtgaa tagtgcctct gtaaacatac gtgtgcatgt 91380gtctttatag caccatgatt tataatcctt tgggtatata cccagtattg ggatggctag 91440gtcaaatggt atttctagtt ctagatcctt gaggaattgc cacactgtct tccacaatgg 91500ttgaactaag ttacaacccc accaacaatg taaaagcatt cctatttctc cacatcctct 91560ccagcatctg ttgtattctg actttttaat gatcatgatt ctaactggca tgtgatagtc 91620tctcattatg gttttgattt gcatttctct aatgaccagt gttgatgacc ttttttttat 91680atgtttgttg gttgcataaa tgtcttcttt tgagaagtgc ctgttaattt ccttcaccca 91740ctttttgatg gggttgtttt tttcttgtaa atttgtttaa gttccttgta cattctggat 91800attagccttt tgtcagatgg atacattgca aaaattttct ctcattctgt aggttttctg 91860ttcactctga tgataattta ttttgccgtg cagaagctct ttagtttaat tagattccat 91920ttgtcaattt tggcttttgt tgccgttgct tttggtgttt tagtcatgaa gtctttgacc 91980atacttatgt cttgaatagt attacctagg ttttcttcta gggatttaat ggttttaggt 92040cttacgttta agactcatct tgatttaatt tttgtataag gtgtaaggaa ggggtccagg 92100ttcagttttc tgcatatggc tagccagttt tcccaacacc atttattaaa gagggaatcc 92160tttccccatt gcttgctttt gtcaggtttg tcaaagatca gatggttgta gatgtgtggt 92220gttatttatg agacctctgt tctgttccat tggtctgtat atctgttttg gtaccagtat 92280catgctgttt tggttactgt agccttgtag tatagtttga agtcaggtag cgtgatgcct 92340ccagttttgc tctttttgct tagaattgtc ttggctatgg gggctcttta ttggttccat 92400atgaaattta aagtagtttt ttctaattct gtgaggaaag tcattggtag cttgatggga 92460ttagcattga atctgtaaat tactttgggc agtatggcca ttttcatgat aatgattctt 92520cctagccttc agcatggaat ggttttccag ttatttttgt cctctcttat ttacttgagc 92580agtggtttgc aattctccat gaagaggtcc ttcacatccc ttgtaagttg tattcctaca 92640tattttattc tgtttgtagc aattgtgaat gggagttcac tcatgatttg gttctctgtt 92700tgtctgttat tggtgtatag gaatgcttgt gattttcaca cactgatttt gtatcctgag 92760actttgctga agttgctgat aagcttaagg tgattttgga ctgagacgat ggggttttct 92820gaatatacag tcatgtcatc tgcaaacaga gacaatttga cttcctgttt tcctatttga 92880atacccttta ttgatttctc ttgcctgatt gccctggctg gaacttccaa tgctatgttg 92940aataggagtg gtgagagacg gcatccttgt cttgtgctgg ttttcaaagg gaatgcttcc 93000agtttttgcc cattcagtat gatattgggt ctgagtttgt cataaatagc tcttattttg 93060agatatattt cattaatacc tagtttattg agagttttag catgaagggg tgttgaattt 93120tgtcaaaggc cttttctgca tctattgaga taatcatatg gtttttgtca ttggttctgt 93180tgatgtgatg gattatgttt actgatttgc gtatgttgaa ccagccttgc attccaggga 93240tgaaacccac ttgatcatgg tggataagct ttttgatgtg ctgctggatt cggtttgcca 93300gtattttatt gaggattttc gcattgatgt tcatcagggt tattgtcctg acattttctt 93360tttttgttgt gtctctgcca ggttttggtg tcaggatgat gctggcccat aaaatgagtt 93420agggaggatt ccttcttttt ctattgattg gaatagtttc agaaggaata gtaccagctc 93480ctctttgtac ctctggtaga attcggctgt gaatccatct ggtcctggac attttctggt 93540tggtaggcta ttaattactg cctcaatttc agaacttgtt attggtctat tcagggattt 93600ggaggtctat ttaggcttgg gagggtatat gtgttcagga atttttctat ttcttctaga 93660ttttctattt tatgtgcccc agaggtgttt atagtattct ctgatggtaa tttatatttc 93720tatgggatga gtggtgatat actctttatc attttttatt gcatctatga ttcttctctc 93780tcttcttttt tattagtctg gctagtggtc tatctacaaa atagatagac tgtttatctg 93840atatttattt tgtaattatc taataataat catcattatc atcagcatca tcattgtcat 93900ctcctttacc catacataca tttgtgtctt tcaaataata atcccatctt tgaagtacat 93960cctcatctgt agcagtcttc actctgcttt cttatatcat ttactatctt attttataat 94020tatttacttc ccgtctttct tctctaacag atagtatttt tttagggcca aggaaatatc 94080tcgatcacca ctatatcccc agcatctacc cctgtgcctg gtccataggg ctagatgcta 94140agagttgagt tgaaccaatc tacctaatct taaccttcag tagcacaaca tggtttgtca 94200gtggttaaga atctacactt tggagtcaga ctcacccagg atggaatcct ggcattacca 94260cttattatta atagatacat gaccttgaac aagttcactt aattgttctt agcatcagtt 94320tcctcttctg tgatataggg atgatacaga gctacctggt aggttgttgg aataattaaa 94380tgagatgata tgtatgaaat ggcctggcac atagagtgcc taaatacacg ttgttctgat 94440tttatttgga ctgtttgtgt tagtaacaga aatcaaaaag gtggagaaag gagaaaggta 94500cttgggaaaa ttttctattt cttctccatg tttcattcaa gactgaggaa gggggcacag 94560tttttaccca aggaaacgac atttttagcc aaaggaatta tgatcttagc atttagctga 94620attgtatatt ggaagtaagc tccttccttg tggaacttat ggccttgcta gccttggttt 94680gttggaagtg ctcttgctgg ctttctagtt agggtaggga aaggaaggct tgtggggagt 94740gaagataggc catgatatca agccactgag tgtgcaaatc agtagaactt ttcgattgct 94800ttctgttgta cttgggactt gaataaaggc tgatatttgt gtcttgctgg taaagtgctt 94860gtaaagtgag tgaaagtttt ctttgttctt gtcctgccag agctgttcac ttggggctga 94920ggggaggata acctttcatg tttttatttt tttttattct gatgactgtg ctgagcattt 94980gaacgaaatg gccattggtg gaaagtaaag gtgaatggtg agaagacaat aggataatgg 95040aaactgtgat ggacttggag tcaaattctt ctgaacttct cctctccaag tcttacttct 95100ttcatctgta caatgaatat taaaatgaga aaataagctt gtcttcacag agttattgtt 95160aggtgttgaa atcacccgac acagcaaaca ggctcccatt agggctcatt ttccttcatt 95220ccttagtaag gaagaagtac ttataaaata cagcagttgt gctcttgtga atgatagcat 95280gggcagttgt catctctctg aggcagatta acccagaatg ccacttgagt tttgtttaat 95340gcttaggcat aagacatagg aaagacaaaa gttgaccttt gggtagtaag aacaatgttc 95400cattttgttc aaacttgaat ttttttacta taggagactg agaattaacc ttccatgaag 95460gttttaggat ttgctttctg actcttctct ttcatatcca cctgaaagag cttgggcaca 95520gatgttcttg gagaaaggta gttaaacaag gtgacttctg aagctccatc cttgcccaaa 95580gaacttatga gtcccttagt ggccaagtat tttgatggta gtagcctaaa agatgtccag 95640gatcaccgtg catcattttt tcaacagaag cctcaggcat agggattatg cttggtactt 95700tatgttgtgg aatggaatcc ggcagatgtc catgtgatct agagaaacac ctaaggaaag 95760tgaagaaatg ggggaaaaaa taacaagact tgtatgataa tactaatcac tatccttgtg 95820tatttattcc aaggacattt tctccattat ctgatttata ttaccactca cagcagcagc 95880tcaataggat gggagatatt atccctattt tatagatgag atttgaggct cgaggagcta 95940aaacaagaaa catcaaattc ctttgatatt tggtctgatt ttgttatagt tctccctttg 96000gatgaggtaa agtcacaaaa ctgggttcat atcatttaat tagtctgaaa atgttgcctg 96060aacaccacct taagttagat atcttaacct caggtttcct actttcattg ctgcctctta 96120tagacataga ctatgagatt ggctaatccc agagaacttc cctaatccct tggcaagatc 96180caaaaaggct cagtcacacc ctactaccac catctttagg agaagtctca gaaaattcag 96240cttcacacta actcacttga gcatcaaata atagtagttt atgcatgcag gttaatcctg 96300aagacctcag acttcacttg cctatttctg ccattctatg acatgtgttg cattggtttt 96360ttgtgtcttt ccagtttgga gactgccagg gaccatgttt tgccaattga ctattacttt 96420ccaccccaga agacctgcct gatctgtgga gatgaagctt ctgggtgtca ctatggagct 96480ctcacatgtg gaagctgcaa ggtcttcttc aaaagagccg ctgaaggtaa agggacatgc 96540acatgcactt ctgtttccct ttctccttta ccttccagag agagacacta acctttcagg 96600gcccaggatt ttatcatctc agaaacagag tcattggcaa ggccctatca aataacttag 96660gagcctaagg aagcaaattt ttgcacttgc tagttccctg gtttcagcag ccttgtttgt 96720acaggcaatg taggcagtga aggtggtccc agctggggct tggggctcag tgggtcctag 96780aaatgaagga aaaattaatg atttgaaaag atttaatttc ctcccttctt gttttctact 96840ctgctggcta gtaaaggaaa aatttgtcct tattagagag gttagaagtg gagaaacccc 96900aactgagtcc ccagcctgtt ccttgggatg aatatgagac tgtttcttag caaaggcttc 96960ctggcctcgg ccccagaaag agagtgttct cactcttcag cagactatca gtctctgcac 97020ctgctccctc ctgttgctgc ctccttggga cctgtctttg cgttaatagt tcctaggtag 97080gtaagaactc agagtgaaga aacacattta ttctcctctc cagagacctg acctcaaagc 97140ctgtccatta gtccctaacc ttaatctaag gtagcatctt atatctggct aaattggttc 97200aagccctagc tccttagttt tatttagctt agaacaactc atgtctgctc aacccctaaa 97260ggtgctcagc ctacattctg cagtagaaac tcccattttc aggcctctta tatatgataa 97320tgtctcttcc tctaaccacc cagggcttaa gcttcctgct tatccacttc actctccacc 97380ctgtatcgag ggctttcttc tcaaaaggac attgatgagg agcccctaga gagagatttt 97440gtgctctggg accagacccg ttgttaaacg ccagtattca cctctgcccc gactttcccc 97500aaagaggtac ttcccgccaa ggcctttctc tttcctctca ctggctggaa gtgttgagtt 97560ccatgtcaga accagaatag agaacctttc cttctataag ggctataaac cttgagaaca 97620gtcttaaaga taggtatgta ggccacacca ttcaccacaa atgtactgat actcatcaga 97680ggatggaaga agcaccagag agtttgaagc atctagagaa aaggtagaaa gagaatgccc 97740tttaactgac ctcctcgatg atagtcaatc acaatgatga gtgttgattc atcattttgg 97800ctgggtggca gaaatatcta taaaacagaa gctgccgtgt tgtttacttc cagtcctcgg 97860ggcccacaag aaggcagcta tcatttggta ttactaaaaa catgccccat gttcagctca 97920tacccccaaa tgacccactg ctactgttta tgctgggcta gcatgaagcc cagggcccta 97980gtgtctaggt ctggtcagtg aggcctagag cagagcctaa agagcctgag agcagtgcct 98040tcctttcttc agagtactca tgaaaggatg gctgtcagaa aaggaagtga ggaggggctc 98100cagagacttc agaccacccc aacttcccca atgagaccct ggcacttccc cataacctct 98160cactcagcgg gccctgtcta tagagcagaa aatgaaacag agcagtcatc tagaggtagt 98220gtatcagcaa gcccaggcac cacagtaata gcaaccatat cagatgggaa aggagttcaa 98280gtgaacaaac aagcaaattc aatagtcaga taggttagat tatacttgat gctgtttctg 98340ggttttacaa atctgggtta ccaaattgtt attttcagaa aacagaggaa atgctctatc 98400acattgtgaa agggaagatt

ttactgtcgt atcatatatc ctacatggga gctttctgca 98460gaagttagag ctgaaggagg gagacaggca gaagggcagc tggcagggct gcctgggagg 98520agctctgcta taaggtggat cctgtgccat ttgagaacag ggaagaaagc aatgaagttg 98580tggggaggga atcactcaac tcacagaaca tacagaaatc cagcaaggtt tcaaaatgct 98640ctacacccta gagtctctta agttagggaa actctctgag ctcatggggc caaatgctct 98700tgcctgcttg aaatatgaaa aatcaacaat ggattccttg caaaaccagg aaaagggaac 98760cttctgagcc ccttggttat tttgaaatac ggaccataaa tttcagtcct gagccctttg 98820aaggtaggag aaggtggttt agaaaacaca gacacagaca catacacaca caccccccaa 98880aataaagcaa aaaaaaaaat actggtgttt tctttctccc cacatctgta aagttgttgg 98940attgatttta ctgccatcgt tatccctatt tgaaggcagg gggctgtctt attacccaaa 99000gaggacattt attgatttga ttatcttttt ccatttttac agtgcatcat ctttttcacc 99060catatggcct ttctggaggt ggttctcaat ctggcttgtt gaagcatcaa attacacctg 99120tcttagagag agtagaaaca caaatctttc tcttcctcat ttacttgttg tagtcagtta 99180actcagactg tgtattcaga ctcttgatta tcacttaatt catagtttca gaaatctctg 99240gaatgggcac aagtacagga cttaaaagcc tggaatctca gacagaaata tatttctagc 99300tttgatggtt tataacacat gggactttta ggctgtcatt gatgcagggc tcagcacaga 99360gtcagttgta atctggccag gttttgttgt tgaggaagag tgggaagggg gagtcctaca 99420ttttctcctt gtcagtaata ttggagaatt ggggtgagag tgaagctggg cagggaaagg 99480tctgcataga aaaaagggtc tggcgagaaa aaatcatgct actaagccat gagggtaaaa 99540tgaccaagtt atggttgaca gaaacttggt catagtgtgt ggggggaggg tagggggtga 99600gggcagagag aaagttggtc taagtctgtg ttgggggaca gtgcttggtg ggatgaactc 99660tgggttagaa acaggcatgt agggaaatag ttggtttatg gtgtgggtag gatgaatggg 99720gcggtgaaag ggaaggcatt ttgaatgcta agagaccagg aagtcaaagc aaagcaatac 99780ccataaacag aggtaagggc tcagagaggt tttagttgta tagtcttggg taagaaattt 99840ccccttttga acctcagttt tccttgactg taaaacaacg gacttgaact agatatttca 99900aaatgtgctt ccaacttaga cattttgtga tcgttctaca aattacaaac ataatcatca 99960tcatttcagc aaactcacgt gtatttatac ctgcatatgt ttttggtctt gctttcctag 100020aagatgacta atccaagatc ctaatcaatt aaagaagcaa tcttcagatg gggatagagc 100080cagctgagag agtgtactat gtatggagtg ggttaaaact caggactctg agatttttac 100140cttgtgatca ttgctgggta acttcctttc ttttctattt ctcatctgga aaatcaggat 100200atgaatcccc atctctacct cattatgttt caaagagggt taattaatcc atcatgtgca 100260ttatgtgctc aagaatttac tatttttcag atattttcta gtaaaacgtt ggagattata 100320tgtccatttg ttttgtacac atggagtgct gtttggtaca catcataaaa ttgaaactgt 100380agtttacatt ctgaactcaa agaattacac catcctcact gatgtttaca ataggtccca 100440atttagtttc tttggcaaat tttatgtaag tatggctttg attctctctc tcaccccagg 100500tttttgttag ggaagaaatg caagtgaacc ctcattgaac tctttctgtc ctttaaatcc 100560attctttccc acctcaactc atgtggaatt gaatgttacc tctagtttgg agtctagcag 100620agagtttttg gtgcatatca gtgtcccctt cactccctga ctttttgagt aacatttccc 100680agaggcaaat taactctgct aagaggatct gcttgcagct tcaacagagc cttcatcagg 100740tatctttggc caaggagttg actgatcctg actttgcgag tcctagagat cttttcacaa 100800aactcctctc atgtttctgt ctctggtttt cttaaaagtc gcagacagac tttagattta 100860ggggttggtt aactttttgt aaagggccat gtagtaaata ttttaggctt tgtagatcat 100920atggtctctg tgtcaactac tcagctctgc ctttgcagga tgaaagcagc catggataat 100980acttgaacta atgggagtag ctgtgttcca ataaaacttt atgggcactg aaatttgaat 101040ttcacttaat tttcacatat catttaatat tatttttctt tttaaccatt taaaaattta 101100gaaatcattc ttatctcgtt gggcctcaca aaaacagatg gtagagtaga tttggtttat 101160gggctgcagt ttgttgacct ctgctttaga taatcacttc tgtacttata aatctgcaaa 101220ggttttatgt tttcccatct cttggtattt tagtagctct ctagattatc taatttaaaa 101280attttttctc agtaggccaa agtttgcaca tcttgttagc acagaatgcc tggcctagtg 101340gcttcttggc cctgagcctt ttactaaaca ggagaaaaac taaatgtcta gaaatgctag 101400aagaggatac tattttgttt taatgatcta gtagatcact cctccttgca atacccagag 101460gagaaactga aaatatttca agcattttct agacttctgt gttgtaaatg tgtggataac 101520tatgaactat acatgaaagc acttttctgg atgacacata tattccagat ggcaaaaagg 101580aagcactttg gggactctct ggtaccaagt atcatggaaa aattgtgtgt ctcatagaaa 101640gtagatccca ggaagccagc tgagttgtgg atctgccata tattacctca tgattctgtc 101700ttcgcacact cactggctta attctgggcc tccccataac acgactagac cacaggcttg 101760cagaagaaat aatttagctc tgtaactcat tgcagttggt gcccacccaa gtctctgtca 101820gtgcccaatt cgggagccat gccaagaatt tgccattgct gcttcgtagt ggccctgtgc 101880ctgcttattt atagcctgtg cattttatga aacagagatt aataagaagt tgccatagta 101940cttgcaccat tatgtaaata tctgcaatgc ttacatagcc tttgtcactt gcaagatctt 102000ttgagtccac tgccttctgc taccatgcct taccaatttc ctagtccctt attattattt 102060tttaatttat tatatttaac ttttgtgata catgttcaga atgtgcaggt ttcttatata 102120ggtatacacg tgctgtggtg gtgtgctgaa accaacaacc cgtcatctgc attagttatt 102180tattctaatg ctatccctcc cctagcccag tgtgtgatgt tcccctccct gtgtccatgt 102240tttctcattg ttcaactccc acttatgagt gagaacatgc agtgtttggt tttctgttcc 102300tgtgtttgtt ttctgagaat gatggtttcc agcttcatct atgtccctgg aaaggacatg 102360aactcatcct ttttgatggc tgtatagtat tccatggtgt atatgtgcca cattttcttt 102420atccagtcta tcattgatgg gcatttcggt tgattccaag tctgtgctat tgtgaatagt 102480gctgcaataa acatacgtat gcatgtatct ttatagaaga atgatttata atcctttggg 102540tgtataccca gtaatgggat tgctgggtca aatgatattt caggttctag atccttaagg 102600aatctccaca ctgtctttca taatggttga actaatttac acccccacca ccaatgtaaa 102660agcattccta tttcttcaca tcctctccat catctgttgt ttcctgactt cttaatgatc 102720accattctaa ctggcatgac atggtatctc attgtggttt tgatttgcat ttctctaatg 102780accagtgatg atgagctttt tttcatatgt ttgctggccg cataaatgtc ttcttttgag 102840aagtgcctgt tcatatcctt cacccatttt ctgatgtggt tgtttttttc ttgtaaatat 102900gtttaagttc cttgtagatt ctggatatta gccctttgtc agatggatgg attgcaaaaa 102960tttctctcat tctgtagctt ggttgttcac tctgatgcta gtttcttttg ctatgtagaa 103020gctctttagt ttaattagat ttcatttgtc atttttggct tttgttgcca ttacttttgg 103080tattttagtc atgaagactt tgcccattca ctattgctac aaagagaaca aaatacctag 103140gaatacaact tacaagggat gtgaaggacc tcttcgagga gaactacaaa ccactgctca 103200aggcaataag agaggacaca aacaaatgga aaaacattcc atgctcatgg ataggaagaa 103260tcaatatcgt gacaattgcc atactgccca aagtaaatta tagattcggt gctatcccca 103320ttaagctacc attgactttc ttcacagaat tagaaaatac tactttaagt ttcatatgga 103380accaaaaaga gcccatatac cctagacaat tctaagcaaa aagaataaag ctagaggtat 103440caagttacct gacttcaaac tacagtacaa ggctacagta acccttatca attttgtatt 103500gcctgtccat tttctgcagc cagaagcttc ttcagtcctt taagggaatt tctgggtgac 103560tatcaaactc tggtagttca tttttgcagt tgactgctat tgtgaggata agtgtcagac 103620tcactctctc ttcagagata gaaattatgt attaattatc tggattctag acccacagca 103680aggagcaaac tgctcctcaa aataactgaa ttcttcgaga agtcatcatt gtaaaacaat 103740atcttcagtt atagtagcca tgtgtgcatg cttctggaaa ctgtttttca gattttcatc 103800ttccttccct gtctcttcat agcaaggcag ctgctttcag ccttgtacag atgctagtga 103860gctttgtacc tacaaacctg agaaaattga actgagattt ggaggtgaat gactcttgat 103920aaagggaaca aggtttagaa ttatcagtcc ctttgctccc aggctgtgtt gtgactactt 103980aggcactcca gtgaaatcac tattcctcct atctagacta atgcctgtcc ctgcagagca 104040cctcatgaga acaggcctgg tagtaatatc ctcatgcatt cagtcagtaa atatttacgg 104100agtgcttact acatgtagga tattgggctg acatactcaa ggtacagggc ttgcttccag 104160gaggttatag tttattaatc ataaaagtgg catttttttt gagacggagt cttgctctgc 104220ctgtcgccca gactggagtg cagtggcatg atctcggctc actgcaagct ccgcctccca 104280ggttcatgcg attctcctgc ctcaccctcc cgaacagctg ggactacagg ggtgcaccac 104340cacacctagc tattttttct tttatatata tatatatata tatatatata tatatatata 104400tatatttttt tttttttttt tttttcagta gagacagagt ttcaccatat aggccaggct 104460ggtctcgaac tcttgacttc gtgatccacc cacctcagcg tcccaaagtg ctgagattac 104520aggtgtgaaa atgtgacaat ctttaaagct cttcagtgga tgaaaggcca ccctatctac 104580tgtccatttg aactttgcaa ctatcttggt acagagtgag aagttattct cttggttttc 104640catatgagta aactgaggct ttgccagttc atcagcaggt aataaataat gtatctggaa 104700tttgaaccca ggtcttctgg ggtcaaaggc agcattcact ctgttccatc acagcagctc 104760ctcaaataag ccaacataga aaccaagtac tatgcctagg caacaagaaa ggcagcaatg 104820aagagcaaca gcagagtgaa atatgagaga aggaagttaa gaaagatgtt aagtactgtg 104880gggagtaacc aagaaaccac caagtatcgc taacatcaca gggagcttgt cttcctaaga 104940aaactccaag cacttaaaac agctggtagt tcatcagcaa ctctctttat tagatgtatg 105000agggacatgt gggccatagt ccttctacca acttatatgc ttcaggggga agttctgatt 105060ctgatgagac ccagcatggt cgcttttaat tcactgttgt cacacaacta tagaacagga 105120agcacaactt aacacctgtg ctcatgagaa ttttgctcct tatgaccaag ctaaagaaag 105180agcttagaca ggatgtgagg atataaatgt agattcatgg ttccttggct ctttggtttg 105240agccttctca gcagagcatg ccacagagtg ttttccatgg ggccagtagc aagagaaatc 105300catttccctc ctcctcgatg tcagaaaaca gagaatattg tctttcagga tagaattaaa 105360aagtcataga ggcagcaact tgttttccta tattagggtt ttaaaattct gtttttcctt 105420cctctcctga gtcacatcat tgtgtggatg gaccttgatt tcactgtggt atctggatgt 105480gggccctgaa ggccatggac ttctaacagt tccttaagtt acagaagcac attcctatag 105540gtcacaagct catttactta caggatggtt gattcagtca caggttattt catgaaaata 105600cttaaaagat ttgcagtgtt caaaactgca ggatctttaa acactaaaac ttgaaggaag 105660ggaatttgga aatcaaaaaa tctggtcaaa ccgtttcatg gaaaagtaaa gtgaggctca 105720gagagaggaa attactttcc tgggtttcta tagcatataa atggcagaag tgagagcctc 105780cctgccattt atagttttct gcctgagaga ccctcctgct tcacagctaa ttagcagagt 105840tacagaggtc attaccttgc aattctcaag aattatgtga ggcagtatag taagcattta 105900tggcccttgg ttcccagaag gagcttagtc cctgatagtc ctctctgcct ttgctgccat 105960tgtgtgagac catcttctgt aactgtatgt cttcccccct agtaagttaa tgagtaataa 106020aggtattccg tagtgagagg actctgtaag agaattcttg gtgtaaggat tgttgcaagg 106080ttgttttgtg tgtatgtgca tgtataaact tttttaggga gtgtattcat agcttttaca 106140tggatctcag aggctctgta acagaaaatt acagaatact ggtcttgtct ttggtaagga 106200ttttatagac ccataaggga gtattctgac tacagtgata tccaacatgg ctatttaatg 106260cctggcattt tccccacata acatacgttt attcaacagt cagtgcctac tgtgtacatg 106320agacctatac caggcactgg gataagagac atgaaataac agctaaaact gtttattgag 106380cagtcaatat gcattagatg ctttgtaggc attttcttat tcaatctgta taccctcaat 106440ttacaaatga gggaaccgag acacaaaaga gttgagtgat ttgcccaaag tcatacaaat 106500agtcagtggc tatgtggtga atagttacca acatgaaaga gtgagattac tgctgtacta 106560aaagtaggca cataattccc tgagcagata gtatgagaga atgatttatt ttacctggaa 106620agtttaggaa ggcttcacag aggagttaag ggttgatctg gatcttgagg gatggataag 106680aatttgccag atacaaaaag gtagaaagag aacttcagga ggagggaaca ggttgagcaa 106740agacaaggtg atatgaaagc gggaggcttg tttggggagc attatggaat ctcgaagtca 106800ttgtggggaa tctcatcaga tgcagcaagc tgcttgacag gccttcaatt ggctctttgt 106860accttgctcc ctccccatgc tgagctgtcc atagctgcct taggctggtg tctgggattt 106920tcggaaggtt actatccagg tagtgtaaca agatgcagtg taagagcacc agatcggggc 106980tctggctctg ctactgactt aacacctggc attaagcatg tctagttccc tctttgtaca 107040ttaaaatctc cattggagca gtaacatggt tgtattaaat gatcttgaag attttaaaaa 107100taaatatata acaatataaa tcgttaacaa taattttagt agtaaatctc taaaatttta 107160cagataatcc agattcatcc attggccaat ggttcacttt gtatgcataa ttttttggga 107220aacaggcaga ccgaatttca atccttagtt gtaagactta atacatatgt gacctcaagc 107280aaattatatt gaatgcctct ataaggataa taatatctta cagaactatt gtaagaacta 107340aatgatgtgt aataaagctc ctggtactca gtcagttttg gatccttttc ctagagtgag 107400tcttggtcat aggcacgcat atacttgcag gggtccctga gtaggcagaa agaacaaatg 107460agagatggta tctgtggtat tccccaggta aaggaggcct tgggttggtg taagatttca 107520cttcacttta gagttactta attagggacc agaaaggcca tcgcatctgt atgagaatat 107580aacaaaggtc aatttcttcc tctttacttt ttacgctgtg agtaacattc cccagccagc 107640ccagccggca cgtgttcttt gcctctcctg acttccagac tttggtcttg aaggtgtcag 107700agctctctgt gtatctttgc ccccaacagg ataagtctga cctccccagc aaattcaact 107760cctaagccac tgtccaggag aagagctagc aaggtcataa attattctcc atattttcca 107820gccattggtt tcccttgtcc agccagaggt gtgtcttaaa gtatgctgag gctagattca 107880atagaaacct gagccagcac ctgtgtaact aatttttaaa actccctttc ctgaagctgg 107940atgaatattt tttaaaacta agctggatta tcttttatct agcatgccgt ttcctacatt 108000cctagtgcta tggacctctt ggaggaatgt agtttggtta tagtggtatt gtcttgcttg 108060tctgttgtgg gggaggagga catttctttc aaaaacaagg taatacttcg gtctggacta 108120tgactatttt gtttaaaatg aaactatggc actgtactgg tactcattct gcttcctata 108180ggttagcttt acatccctct gtcttcaccc actctacagt tctgatcctt ttaaaaagca 108240gccaaccaaa accagcaagt acatactgct tatctctgac ttctacctga atcaacttca 108300gatcttgtcc aaagctccat ctgaagagag ggggataaca ccctgccaag agccctcagg 108360gcccatcagt aagtagacat cctgtccttg aggtctctta actctgctca gcttcagaat 108420acagaagggg ttggttcttc atttgtgttg tttataacta aaagcctcct acttcccgct 108480ttttttgcat agcttcttct gccatcccac ctgtgtagcc tcttcaactc ccctaaaact 108540cctctgtagc ccgtgtcact tggaaagagt tttctttgtc tcttttgcaa cttgacaatg 108600actagccagc aagtttaagt tcaaattatt gttccatggg aacagagata gatataggaa 108660acaaaaaaag ggatatggag gtatggagta atttcccacc tacctagtga gcactactga 108720gatattcaaa tgctctctac tcaagaattc tattgatata aacgtaaaaa acttgatctt 108780aggtctaata tccattagta gtgtgacctt gggaaaacga taccactccc aaaggcttag 108840tttttttaac tataaaatag gaataatgat gaccaccccc agaggattca taaggataac 108900atgagataag gcaacttgaa atttcctagc atggcgatag acttttgaaa ataaaatgaa 108960ccaaacactg ataacagtac ttcctagtgc acaaatgaga aatcagtccc tcatcaaatt 109020acagcacatt tccaatgctc cgattatgtc actgtagaaa tgctaatgtg gattaaataa 109080tttgtctgtt gctatttata tggataattt gatagtaatt atttttggac atggatagtt 109140ttgaagcctt acagatgagt ccatccccaa gtacccaaaa ttaaagaaag ttggctagag 109200tgatggcaag gtggcagcac agagctccct gggttctggg ccctgtcccc tagctaggga 109260gaactccagg ctataagcat ttgtattctc atagtccaat ggcagggaaa agggttgaag 109320gtgagtactt ttcactcatt tattttttca acaagcatgt atggtgtcag gccttgtatg 109380catccacaga caaatgtgag ctagccctga cctcaaggag atttcagttg cagctttagc 109440actgcaaaga gtatctacct gcggcagata caatgtgatg ggacatggcg gagaaaaaat 109500ctataaacag agcctcccca tccccaggca tggaaacaat cctaacccag gctggcatag 109560tacaatgggc ctgtctctat cagcaggttt ggaagcttta acaacaacaa aaaaaacaat 109620aataatgatg atgataatca tagtgcctaa tgttaccaaa cattttccgt gtgttaagta 109680ctatactaag tgcatactta atcctcacag caactctata aggtagtaga tactcttact 109740actaccctga ttttacaaat atggaaactg aggcacagaa gactgagaga acaggaatac 109800acctaattca cctcagttca acaaacacca agcatctgtt ttatgtcagg cctcgtgctg 109860ggtgccaggg agagagaaat gagtaaagca tagtttcagt ccagtgggag caaatgacag 109920cacacagtgg acacatatat tgcagccctt ctgctttatg ctaagaactc attgtcagtg 109980atgaatcaaa cacagtcctt ctctcaaaga tcttcaagct tagtaggaga tatctgtgtg 110040aaaacaaaaa ttaaagactg ctgtgataag tgtcataaga gataagtgga aaatgagaga 110100gagatcactg tagcagttga ttggtttaaa tcaaagcccc ccaaaaaaca gtgttattga 110160gaattataga acaactaatt gatttaaatc aaagcccaaa cagaacagtg tttgctaatt 110220ttatttcagg ttggttgata gattttcatt ttttattcca tcccgacaat ggaagattag 110280tgcttgtttc ccacccaagg ataccaggat atttcaggga ctgtattaca atatagttaa 110340attattcctt tatctcaaag cacacccaca ctttctccta tcctttcctt tactcaggct 110400atctcttctg cctcaggtgc tttttctcca catttccata ttcttaagtc ctaccttcct 110460tcaaggcctc actcgaatgc ctcctcctcc atgaagcatc caccccatcg aaaggtacct 110520cgccatctcc tgtactccca catcacttca tgggtgtctc tctgtggttc ttaccacttc 110580ctgctttatc tttcagtaat gcacttacag ttctctttcc tccactagac agagctcttc 110640agacaaagat tcacttggct gaaaccatga ttttacttta aacacattga aaacctctac 110700cggaatgcat tgtgtctggt gggcttcaac cttaattctt aagtatgtga aaatacatta 110760cctatctgga ggtttacact ttctgctaat gactttattt ttaagtccac caccctaaca 110820caacaaatgc ttaaaacatg tcttcatttc ctttaggtct ggccctcatg catgcatata 110880atttatagag tcactgtttt gctcggttgt cctcatgcct ctatattatt ggaggtttag 110940attgtttcca cacacttagg ttgtattcat gtacattttt ttttcttttt aaatttccct 111000agcatccatt cccaccattg gaaattcagg gtcaaaacag gggttgggaa ttggagcatg 111060tgtatcacag ataaccaatc atgtgttatg acttaagaat ttatgaaagg gccctctacc 111120tgaagatatc ttgctactga tgctgtctca cagtgtctga aactcccatc atatgtggaa 111180ttgttttgga agattttgcc tcctggggca cattcagcca taatcaggaa atagtattga 111240gcattagact gtcagtatgt ccattagcaa gactgtggaa gaatggaatc accaatatta 111300tattttatag gggatacaga attcaagaga agttctgaag agaaaatgct tatctagaat 111360aggaaggctt agatacagca tgaaagctgc aggctttgag gagccagagg tcaaatgaaa 111420gcactgagta tttgtttata tgaaagaaca gaaagggaaa agagaagcag aggaagggat 111480agtagagaga aatgaataag ttttatccat ttaacttgga attgtgtttg gctatgggca 111540caacagaagc agtgagatca ctttatttta ttttattctt catagacagg gtcttgctat 111600gttgcgcagg ctggagtgtg cagctcttca caggtgtgat catagtgtac tacaccctcg 111660aactcctgaa ctcaagcaat cctccaacct cagcctcctg agtagctggg acaagtgcac 111720accaccacac ccaatgagat cacttaaaaa ctagggagag atgtgtgagt tctgggcaac 111780cagtagttag aaaaccagga ggggtttgga aatcagaaaa ccagcagagg caggaaaact 111840cagggcagca tggcagattt agtatataca agtaggttca caccagtcat cagacagaat 111900tgtaactgct gatgtggagt agaggctagc tttgtctgct gtgtgatacc caaaccttta 111960agaatagtag gtgtatacgg ggaattggag ggagataggt ggctgtattt actaattggt 112020tgatttcact gagatggttt gggtattgtg gcttccagat gctcatattt tcttttttgg 112080gtagagactc caacatcatt acagaactat aaattacata tggaaaagaa aggcctccta 112140tgttagaata gaaaatagaa tgctgtgggg ttgagggaca gagggtctgt ctaggaagtc 112200agatagcatt ttcccgttct gtccctcaga gttccttgtc cccattgaga ctcaatttct 112260cttactttgg tttctagtgt taccacccac tgttcttttc catctcaacc ctgagtataa 112320gtacagatca cattccttgg gttcttagaa cataatagaa atgaactctc attcatcaaa 112380atgcccatta gtaaatactg agggagaaca aactagaaat ccagtataga aagtaaaaat 112440aggattatat tccttgcaat ctcagaaaaa acaatgaaga gctttcttcg ggcattagac 112500accttcccat aaggtggctg actctctttt agtcatgtca acttgaccaa atcttcactt 112560ggtagcactt ctttcttgtt cattaaccca tctgctatgc tcctatgggg tcctagagaa 112620atgccgctca tgtacacgca tatccaataa cacaaagatc actctcgact ggcaagccct 112680tttatgatgc tgtgagcatt tgataccctt gttgctagta atatcagtga gtgacctgac 112740ccatatttgg aacagaatat gatcagtata ttgcctcaaa gaggccctca ctgttctaaa 112800aaatataatt ccagagtttg ctgactcaca ccgtggaata tgtgcaaaaa tgaatcctgc 112860agataagcct ttctctgact agtttcagaa tttttttctg ggtaatttta aaattatttt 112920tttatttttg taggtacaaa gtaggtgcat atatgtatga ggtacctgag gcattttgat 112980acaagtatac agtgtgtaat aatcaccagc gtcaatgggg tatcccttac cacaagtatt 113040tatcctttct ttgtgataca aacaatccaa ttatattctt ttagttattt taagatggac 113100aatgttattg ttgactgcag tcaccttgtt gagctatcaa atactagatc tcattcattc 113160taactatatt tttgtaccca gtagccatcc cacttcctcc cctcccacta ccctttccag 113220cctctgataa ccatcattcc actctctatg tctatgagct caattgtttt aagttttagc 113280tcccacaaat atgtgagaaa atgccaagtt tgtctttctg tgcctggctt atttcacgta 113340atataatgtc ttctagtgcc atccatgtta ttgcaaatga caggatctct ttctttttta 113400tggctgaata gtactttatt gtacgtatgt accacatttt cttcatccat ttgcctgttg 113460atggacaaga gttgcttcca

aatattggct attgtgaata gtgctgcaat aaatgtggga 113520atgcagatat ctcttcaata tgctgatttt ctttctttag ggtgtatacc cagcagtggg 113580attgctgggt catatgatag ctctattttt agtattttgt ggaacctcaa atctattctc 113640cataatggtt ttactgactt acatatccac caacagtgta tgaggatact cttttctcca 113700catcctcacc agcattcatt acttcctgtt ctttggatga aagccatttt aaccgtggtg 113760aaatgagatc ccattgttgt tttgatgtgc acttctctga tgatcagtga ggttgaggac 113820cttgtcatat atctgtttgt catttgtatg ttttattttg agagatatct acccagatct 113880tttgcccatt ttgtaatcag attgttatat atttttttcc tatagagtta cttgagctcc 113940ttatataccc tagttattaa tacttggtca gatgggtagt ttgcaaatag tttctctcat 114000tctgtgcatt gtctcttcac tttgttgact gaatcctttg ctgtgcagaa gctttttaac 114060ttgatgtgac ctcatttgtc catttttagt tgcctgtgct ggtatggtat tatccaagaa 114120atttttggcc agattaatgt tttggagagt ttccccaatg ttttcttgaa gtcgtttcat 114180ggattgatgt cttagattta agtctttaat atgttttgat tattatattt gtatttgctg 114240agagataggg ctctagtttc cttctgcata tggatatcca gtttttccag caccatcttt 114300tgaagagact atccattctt taatatacat ccttggtacc tttgttgaaa ataagttcac 114360tgtagatgta tggacttgtt tctgggttct ctgttctgtt tcattcgtct atgtgtttgc 114420tttcatatga ataccatgtt gttttggtta caatagctct gtattataat ttgaagtcag 114480ataatgtgat tcttccagtt ttgcttggtt ctttttcctc aagatagctt tgcctatcct 114540gggtctcttg tggttctata tacattttag gattattttt tctatttatg tgaagaatgt 114600cattgatatt ttgatataaa ttgcattgaa tctgtagata gcttcaggta gtgtggacat 114660tttaacaata tcaattcttg aaattcacga gcatggaata tcattctatt atttggatgt 114720cttcaatttc ttatatatgt attatatata tattagtttt cattgtagag atatttaatt 114780tatttaacta aatttattgc taggtatttt attttatttt tacctattgt caatgggatt 114840gttgtcttga tttctttttt agattgttca ctgttggcat acagaaaagc tactgatttt 114900tatatgttga ttttgtatcc tgcaacttta ctgaatttgt ttatcagttc taataggctt 114960ttggtgcagt ctttaggttt ttccaaatat aagatcatat cgtctgcaaa caagaataat 115020ttgacttctt tcttttcaat ttggatgccc ttcatttctt tctcttgtct gattgctcta 115080gctaggactt ccagtactct gttgaataac agtggggaaa gttaacatcc ttgttttgtt 115140tcagatctta tagccaatgc cttcagtttt tccaaattta gtatgatgct agctatgggt 115200ctgtcatata tggcttttgt tatgctgaag tatgctccct agttttttga aagtttttgt 115260cttttaagga agataaaaat tgaatgttat caaatgcttt tcatgtaaca attgaaatga 115320tcaagtgctt tttgtccttc attctgttga tatgatatat cacattgatt gacttagatg 115380tattttgagc catccttgca gcccttggta aatcccactt agtcatggtg aatgaacttt 115440ttaatgtgtt gttgaattca gtttgctagt attttcttga ggatttttgc atcaatgttt 115500atcagggata ttggcctata gttttccttt ttgtgtgtgt atattttgga ttttgttatc 115560aggttaatac tggccttgta gattgagttt ggaatgattc tctcctctat tttttgaaat 115620actttgaata ggattgatgt tactttttct taaaatgttt ggtaaaattc tgcactgaag 115680ccactgggtc ctggactttt tactgctgag aagacttttt gttacagctt caatcttatt 115740atttgttatt ggtctgttca agttttagat ttttttcgtg gttcaatctt cccaagttgt 115800ctgtttctcg aaatttatca atttattcta ggttttccaa tgtattgtca tatagttgct 115860catagtagcc tctaatgatc ccttgaattt ttgcagtaac cattgtaata tttccttttt 115920ttaaatctct gattttattt gagcattctc tttttttctt agtctagcta aatatttgtc 115980aatgttgttt cttcatccac aaaaccaact tttcgtttca ctgatgtttt ttgtattttt 116040tccttttaat tttatttatt tctactctga tctttatcat ttcatttatt ccagttattt 116100gagtttggtt tgctcttgct tttctagttc tttaatatgc attgttaggt tatttatttg 116160aactttttga tgtaggtgca tattgctata aactttcgtt ataatattgc ttttgctgga 116220tcccataggt tttagtatgc tgtttagtat gttttcaatt tggtacattt caataaattt 116280ttaaattttc ttctttattt attgacatag tcattccaga gtatactgtt taatttccat 116340gtggttggta tagtttccaa aattcctcgt gtttttgatt tctagtttta ttctattgtg 116400gtcagagaat aagcttgata tgattgcaat ttttaatact tttttaaaaa cttgttttgt 116460ggcctaagat atgatctgtc attgagaatg atctatatgc tgaggaaaga atgtatattc 116520tgcagccatt ggataaaatg gtctttaaat atctattatg tccatttaag acataatgca 116580ggccaggcgc ggtggctcaa gcctgtaatc ccagcacttt gggaggccga gacgggcgga 116640tcacgaggtc aagagatcga gaccatcctg gccgacacgg tgaaaccccg tctctactaa 116700aaaatacaga aaactagccg ggcgaggtgg cgggcgcctg tagtcccagc tactcgggag 116760gctgaggcag gagaatggcg taaacccggg aggcggagct tgcagtgagc cgagatccgg 116820ccactgcact ccagcctggg cgacagagcg agactccgtc tcaaaaaaaa aaaaaaaaag 116880acataatgcg gattaaggcc aatgtttcat tgttcatttt tctgtctgga taatcttttc 116940aatgctgaaa gtggggtgtt aaaatctcca aatgttattg tattgggatc tttctcttct 117000ttcaactctg ataatatttg ctttagatat ctgggtgctc cagtgttggg tgcatatata 117060cttaaaattg ttgtatcctc ctgatgaatt gaccctttta tcattatata atgaccttct 117120ttttctcttt gtgtagtgtt ggtcttgaaa tctattttgt ctgatattag tatagctgct 117180aatttttttg gtttccattt gcatgaaata tctttttcat tcctttattt tcaatcaatg 117240tgtttcttta tatttaatag gtgaaatatg tttcttgtaa ataaaaatta ttattttaac 117300atattttaaa aataatactt tttaaataat aacagttatt attatttttt aaattttcat 117360tagttttggg agcccaggtg gattttgatt acatgagtga gttctttagt agtggatttt 117420gagattttag tggagcagtc acctgagaag tgtacattac ccaacatgta gttgtatgta 117480tattatatat acagtatata tataaagcat atatacacac tatatatagt atatatgtac 117540atatagtata aatatatata gtatatatgc tttatatata gtgtatatat gctttataat 117600tgtatatata tgctttatat atgttgtgta tatctagtat atattgtata tatagtatat 117660ataatatata atgctttatg tattgtattt atatattgta taatatataa agcatatata 117720gtatatatac tatatataaa gcatatattt tgtatatata ttatatatgt tgtgtatata 117780tattatatat ataattaaat tctgggatac atgtgcagaa cttgcagttt tcttacatag 117840gtatacatgt gccatggtgg tttgctgcac ccatcaacct gccatataca ttaggtattt 117900ctcctaatgc tatccctccc ctagccccac cctactccct gacaggcccc agtgtgtgat 117960gtccccctcc ctgtgtccat gtgatctcat tgttcaactg ccacttatga gtgagaatat 118020gcggtgtttg gttttctgtt cttgtgttca ctgagaatga tggtttccag cttcatccat 118080gtccctgcaa aggacatgaa ctcatccttt tttatggcta catagtattc catggtgtat 118140aggtgccaca ttttctatat ccagtctatc actgatgggc atttcggttg gttccaagtc 118200catgctattg tgaatagtgc tgcaataaac atatgcgtgc atttgtcttt atagaagaat 118260ggtttataat cctttgggta tatacccagt aatgggattg ctgagtcaaa tggtatttct 118320ggttctagat ccttaaggaa ttgccacact gtcttccaca atggttgaac taatttatgc 118380tcccaccaac aatgtaaaaa cgttcctatt tcttcaaatc ctcactaaca tctgttattt 118440cctgactttt taatgatcac cattctaact ggcatgagat ggtatgtcat tgtggttttg 118500ctttgcattt ctctaatgac cagtgatgat gagctttttt tcatgtgtgt tggcagcata 118560aatgtcaaga agtgtctgtt catattcttc acccactttt ggatggggtt gtttggtttt 118620ttttttcttg taaatttgtt taagttcctt gtagattctg gatattaccc ctttgtcaga 118680tggatagatt gcaaaaattt tctcccattc tgtaggttgc ctcttcattc tgctgatagt 118740ttcttctgct gtgcagaagc tttttagttt aattagatcc catttgtcaa ttttggcttt 118800tgttgccatt gcttttggtg ttttagtcat gaagtctttg cccatgccca tgtcctgaat 118860ggtattgcct tggttttctt ctatggtttt tatggtttta ggtcttgcat ttaagtcttt 118920aatccatctt gagttaattt ttgtataaca tgtaaggaag gggtccagtt tcagttctct 118980gcgtgaggtt agccagtttt cccaacacca tttattaaat agagaatcct ttccccattg 119040cttgtttttg tcaagtttgt caaagatcag gtggttgtag atgtgtggtg ttatttctga 119100ggcctctcct gtgttccact tgtctatata tctgttttgg taccagtacc atgtggtttt 119160gggtaatgta cccttgtagt atggtttgaa gtcaggtagc gtgatgcctt cggctttggt 119220ctttttgttt aggattgtct tgactatatg agctcttttt tggttccata tgaaatttga 119280aaagtaaaca gtacaataag atgtaaatag aaacaacaaa gtgataacaa gcagagagat 119340gaattagaaa aaaatatttt ttttctaatt ctgtgaagaa agtcaatgat agcttattgg 119400ggatagcatt gaatctataa gttgctttgg gcagtgtggc cattttcatg ataatgattc 119460ttcctatcca tgagtatgga atgtttttcc atttgtttgt gtcctctctt atttccttga 119520gcaatggttt gtagttctcc ttaaagaggt atttcacatc cttgtgaatt gtattcctag 119580gtattttatt ctctttgtag caattgtgaa tggcggttca ttcatgattt gattctctgt 119640ctgttattgc tgtataggaa tgcttgtgat ttttgcaaat tgattttgta tactgagatt 119700ttgataaagt tgcttatcag ctttaaggat atttttgggt gaggtgatgg ggttttctaa 119760atatatggtc atgtcatctg caaacggaga caatttgact tcctctcttc ctatttgaat 119820acctttattt ctttctcttg cttgattgcc ctcactgtaa ctttcaatac tatgttgaat 119880aggattggtg aaagagagct tccttgtctt gcactggttt tcaaagggaa tgcttcagct 119940tttgcccatt cagtatgacc aatatgtagt cttttattcc tcaccttctc tcaaccccta 120000ccccaacgga gtcctcaagt cctttacatc actgtgtgtt attgcatcct catagcttag 120060ctcccactta taaatgagaa aatgcagtat ttggttttct attctttgct tacttaatta 120120gaataatggc ctccagctcc atccaggtgt cttgtttttc attcattcag ccagtctaca 120180tgttttgctt ggagagtttc gtccatttag attcagtgtt atgactgata actaaggact 120240tactcctgcc atttggttgt tttctggttg ttctgtggtc ttctcttcct tttttccttc 120300cttcctgtct gccttttagt gaaagtgatt ttctctggtg gtgtatttta ttttattttc 120360ttccttttta tttttatttt ttgtgtgtgt atttgttgta cgttattgat ttgaggttac 120420cgtgaggctt gcgcataata ttttctaact cattatttta aactgatgac aacttaacac 120480tctattgtgt aaaaaatcat ggaaagagaa aactaataaa aactgtacat tttaacttta 120540tcgctctgct tgttatcact ttgtcatttc tatttacatc ttactgtact gtttatgtct 120600tgaaaagtag tttcagttat tattttttat tggtccatct catagtcttt ctactcaaga 120660tatgagtagt tcacatacca caattacagt gttacaatat tctgtgtttt tctctgtact 120720tttaattacc agtgagtttt gtattttcag ataatttgtt attgctcact aacattctat 120780tctttcagat taaagaggtc cctttagcat tacttatagg aaaagtctgg tgttaatgaa 120840ttccttcagc ttttgtttgt ctgtgaaagt ctttattttt ccttcatgtt tcataggtat 120900tttcactgga tattctattc tattctaagg taaaaggttt ttttgtttgt ttgtttgttt 120960gttttcttca gccctttagg tatgtcatgc cactctctcc tgacctataa ggctaccact 121020gaaaagtctg ctgccagaca tatatgagct ccattttatg ttacttgttt cttttctctt 121080gttactttta ggatcctttc tttatccttg gacctttggg agtttgatta ttaaatgcct 121140tgaggtggtc ttttttggat taaatcttct tggtgttctg taactttctt gtacttggat 121200gttaatatct ttctctaggt ttgggaagtt ctctgttatt atccctttga ataaactttc 121260taccaagatg tctctctctc tctctccctc tctctctcat tcttaaggcc aataactctt 121320agatttgccc ttttgaggct attttctaga tctcgtaggt gtgcttcatt gtttgttatt 121380cttttttgtc tcttctgact acattttcaa atagcctgtt ttaaaactca ctaattcttt 121440cttctgcctg atcaattatg ttgttaagag actctgaggc attcttcagt gtgtcagttg 121500catttttcag caccagaatg tctgcttatt tttcttaatt atttccatct ctttgttaaa 121560tatatctgac agaattttga attctttctg tgttatcttt aatttccttg aatttcctca 121620acacatctat tttgaattat ctgtctgaaa ggtcacatat ctctattttt ccaggatggt 121680tatctggtgc tttatttagt tcattttgtg aggtcatgtt ttcctggatg gtgttaatgc 121740cagatgtttt tcagtgtctg agcattcaaa agttaggtgt ttattgtagt cttcacagtc 121800tgggcttgtt catacctgcc cttcttggga gactttccaa gtattccaag ggatttggat 121860tctgtgatct tagtctttgg tcactacagc catatctgct ttatggagca tcccatgctc 121920agtaatgctg tggctctttc agactcatag agttactgcc tgcatgctct tgggtaagag 121980ccaggaaaat tccctggatt accaagcaga gactcttgtt ctcttccctt acttcccccc 122040aaacagagta tctgtcgcat tctctttttc tctctttctc tctctctctc tctctctctc 122100gctcattctc tgccgacctg cctggatctg gggtagggat gacataatca catttgtagt 122160caccaccaat gggactgtgc taggtcagac ccaaagccag cacagcactg agtctcgccc 122220aaagcccaca gagaccactc cctgggtact gtccgtgctt gctcaaggcc caagggctgt 122280acaagctggt gaggccagcc tgtcttatgt ccttcccttc agggtgatga gttcttcaag 122340caggtcaagg gatggtgtcc aggagccaag gcctcgagct gtgactgagc tggcacccaa 122400tccataagac aacgattttt tccacacttt ccttcctttt tctcaagcaa aggagtctct 122460ccctgtggcc accaccaccc ccatgttcat ggcaagtatt gtctggctac caccaatctt 122520cactcaaggc ccaagcgttc tttagtcaac ttaaggtgaa tgctaccagg gctgggtctc 122580taccttcagg gaagtgggct cctctctggc ccagggcagg tccagaaata ccatccaaga 122640gccaaggcct gaaatcaggt tccccaagag cccatttggt gctctacccc cactgtggca 122700gaaccagtac ccaagctgca agacaaagtc ctctttactc ttccttctcc tttacagaga 122760ctctccctat agccaccaca gctaggaata tgctgggtca ctcttgaagc aagaacagct 122820ctgagtctca ctcaaaactc ctggcaagtg ctgcctggct accacactga ttattcaggg 122880cccaagggct ctttagtcag caggagttgc atcctgccag tactggttcc ttcccttcaa 122940ggcagccgat taccttctgg cccagtgtgt atctagaaat atcgtttggg agctagggcc 123000tggcatggtg acctcaggac tctgcctggt gcccttttct actgtggctg atgtagtgtc 123060caaattgtaa gacaaagtcc tctgtactct cccctctccc atctttaagc agaaggaaag 123120agtccaccct ggagttggga catgcattgc ctgagattgg aggaggggtg gcacaagcac 123180tctcttggtc acctcagctg gtgtttcact aggtcacatg ttccccaagt ccactggctc 123240tgagcccagc acaacaccag gagttgacca agaattgcaa ttcttgtggt ttagactgcc 123300tttcaagttt atttgggact gcagaccact ttagcccaca gtgacagggc ttgccagaat 123360ttagtttctg actgctgaga tgggcaattt gcctctgatt aggacggatc taagtgctcc 123420ttctgtgggc actggctgag ttctgctcca tgttgctttc tgctgtgaca gggcaacatt 123480gagtgccaat gcaagtccca caatcactgt aatcttcctc tcccaagcct actctgaaca 123540ccatgtggtt gctgctggga gattggcgag ggatgttgta ggcaattcaa gaatgtcttt 123600cctacccttt tcagtgcttc tttccttagt atgatgttaa aaccagttac tgtgattgct 123660catctgattt ttggttctta ggaaggtgct ttttgtgtgg atcactgttc aatttgttgt 123720gcctgcaggc aggggtgggg gacaattgct ggaggcttct ctttagccat cttgctccac 123780ctcttcccta gtattagaaa tttcaaagca gttaggatga gggtagaagg aaagggtgct 123840tggaatcaga aaatccatgt cttagctttg agccttagga aattcatttg acccttgtaa 123900gcctctgttg cttcatctgt aaaagagaaa taatatagtg actgaaaata tcaaaggtga 123960taatgctgtt gaaagcacta tagaaaatga tgaaatatca catgagtatt attttctagt 124020ttctaggagt ctccttacca ttgtacagga caaccatgtc tatttttaaa taaattatta 124080tttgcctctg agcacccctg caaagagttg cctataggag aaacagctta acttgcaaat 124140cactccactg ttttctttgt gtacagttta ttaatacata aggcacatgt cctccagtct 124200gtagtaacat tggaatgatt acctctttgg agtacctacc agagcttctc aaagtgaatt 124260ttgtatatca ccaccaaaaa tagtctgttg cagagataac ctccaaattc aatgacaata 124320tttccaatca cttttgcatg atacagaaat agacaaatat ataattttgg ttatacagat 124380aattattgtc tcccaacaag tgattagtag tcagaaaatg gccaagaaat accatggggt 124440gtgccttccc ataacaactt atctttgggt tttagttgca aggttactaa aagcctgtgt 124500agggttcatg gcaaaagtaa aacttgctcc aagagcaagc ccttgtttca ttgtctaatg 124560ttcttaatcc ccagcagaca tgatttggat ctggcatttg gcaacaggac agtttccaaa 124620gttgctgtat gcaacttgag gaagagaggt gatattattg gaatgaattt atttgttgta 124680agttataaat atatgggctt ttccaatccc atcaccctta aaaatttttc tgcagtaagg 124740gtgtctctct tgtctttaat atgcttgctt tgagttcatg gatgaacatt cttgcttggc 124800tgacatgtgg actctctgaa attgttctaa ggtctttttc tttgtttttt tcttgattcc 124860caagctgcca agggtagtac tggtagtggt gggcagacaa ggaggtgata gcaagctgaa 124920ctttgtcctc tggcttccct tgacccattg cattcattat ctaagggact ccaagtcagc 124980attccacaga atggccttac caaactcact gagactgaaa gagaaccaag attccaaaca 125040gccaatatga aaggaaagag agagagactt agggtttgca gaatgggata ctctgttgat 125100tatttttatt ccatacagat actaatattc tttaggaaaa cattaaaatc acatgatctt 125160ccaggacctg ggctgcttct ttaagaagca tgttacagag agctctcttg gccaacaaca 125220tattgaaaga taaattaatc aatcattcat tcaaataagg tatattcaga attgaggtat 125280attgtagcca gacagtgaga ctataaaaat gaatgcacct tacccttgtc tcttgcacaa 125340tctaatgagg gagataacca ctcttccaat ttatagtgac ctataacatt tcatacgctg 125400ctgaatatct ttacatgata atgacacaat agaaagattg caaaatagac agaggctggg 125460ggaagaagga ttgagtgtga atatagcctc tcataaatcg agggggaatg gtctgcatct 125520cctgatcatg cagaggtaat aaatacagaa atgatttcaa actaacaaac caaatgtgca 125580gaaaatactg agaatatagt gggcaggata cctgagtttt agttctatct ctgttattga 125640ctcattgtgt aatctgggtc aggtctgttc tgctctctgg atctcaccct ttcctatctg 125700taaaatgaga ttattgaatt agacgatatc tatagaggtt ctcgcctatt ctgacattca 125760aggagttttt ctttaagtaa taatatatgt gatctgtata gtgctttaca cttgacatga 125820tatttttgca tctattatct catgtgagaa aatcactgga ctgctggact gggaatgagg 125880acacctggat tcttgtccct attttgacac tgattcatgg tgtgaccttt aagcaaattc 125940tctgagtttc agtttctcaa tctgtaaaat agggaggtat gaggattgga ctaaatcagt 126000aggtctctaa aatgttccac aaagccctgg ggttggggac tcctacagag tttcactaag 126060gcaaaccaca aggctaggcc tgcatagaag aggagaaaaa gagtgacctg gcaagagaag 126120ttccaagttt cctatgccaa ccccaggcag attaggttta attttatctg ttttataaac 126180agagcttcta tgtaatgttt tattggtaaa aagactttac tataaaaaac tcaactagtt 126240tgatttttta aaattgcaca tttaagtgag atcatacagt cagtatttgt ctttctgtgg 126300ctggcttatt tcacttagca taatgtcctc cagcatcatc tatgttgctg caaatgacac 126360actcttcttt tcattaaagg cgatatagca ttccattgtg tatgcacacc acattttctg 126420ttttgtaact ttcattttag gttcaggggt tcatgagcat gtttgataca taggtaaact 126480gcatgtcaga gaggtttctt gtacagatta tttcatcacc caggtaataa gcatggtagc 126540atagtaccta atggattttt tttttctgat cctctccctt ctcccaccct ccaacctcag 126600gtaagccctg gtgtctgttg ttcccctctt tgtgtccatt acaccagatt ttctttatcc 126660acttatccat ccatggacac ttagtttgct tccatatgtt ggctattgtg aataatgacg 126720aaaaaagtca aactcataga agcagagagt agaatggtgg ttaccaggga ctgggaggca 126780gttcagtgag ctaggaaaag agagctaata aaagggtaca atgtgtgagt tatatagaag 126840gaataagtta tattgatcta ttgcccagca tcgtgaccat agttaaaaat aatgtattat 126900atgtcttagt attgctaaaa gagtagattt taaatattct aaccacaaaa aattataagt 126960aggtgaggtg atggatatgt taatttactt gatttaatct ttctacaatg catacatata 127020tcaaaatatc ccactgtatc ccataaatat atactattat tatttgtcaa ttaaaaaatt 127080taaaaacttg atttagatga gctctaaggc cttaagtatt aaaatattat taaagtgata 127140tgtaaccaag tatattgctt ggtaacttca tttttgttgt tgttttaaca aaccaatata 127200ttgtgaatat acttccaagt gaaaagaaaa aaagacatta cagtcatcat taattactgc 127260aaaatattcc tttgcatgaa tatggaataa ttcatttaat cattccctta atgttagaca 127320ttcaaatgtt tccaactttt tctgtttaaa taatgctaca ataaacttct attttgtgct 127380tattgtatta ttttcttata acacatccct agaagtggaa tttctagaag tttatagaca 127440tttccaattt ttttccaaat atgtgggaaa atttctctct aaagtattta tgttcctacc 127500agaaatacct ctttaccaac acacagtgtt taatctgtac caatctggct tgagaaaatg 127560atatttactt tgtatttctg tgatttctag ctaaattaaa taatcttcac atgcttattg 127620gtcattttta tttctttgaa ttgcctcttc ctgtctgttg cccatttttc tattgtgctg 127680tttattttta tatatcaaat atattgacca ttgattttac atacttgatg ctaataatta 127740gtnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 127800nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 127860nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnntttt gattttaact agtaatttaa 127920ctttattttc ttctccaaat gattcactag ttgttctgac attatttagt gaataattca 127980tccttttttc actgaattgg aatggcatat tccatatact gtgtctggtt ttggcttttc 128040tgttctcttc cactgatcaa cctaagctgg agccagtatc aaactgttat aatcattatg 128100gctttagata ctttaaatgt acagcaggga atgtcttatt actcttattt ttcacaaata 128160tcttgacact gtctcatgtt ttattccttc gataaatttt gggattcatt tgtgatgatt 128220ttgtctgagt tgttttaaat ttttagattt cactggggaa gaactgaaat ccttgaaata 128280ctgcttctta ttagccagga atatggtaca actttgcatt taattcaggt ctttccttaa 128340ataccacaat gaagtttttt gttttgttca tataggtcct gcattaacac tgtttatata 128400aagtgtaaga aagactatag tcctcaggct tctctatagg ttaacaatga agatgatgac 128460tcaacctttt ctttatttgc ataatgtgat gccactaata gtgggcaact tccctgtctt 128520acctcctctg ttccaaacag

gattttttgg aatgaacaag ttaaaagaat cgtaatcaga 128580cactaacccc aagccatact gcatggcagc accaacggga ctgacagaaa acaacagaaa 128640taggaaggaa gcctgcagaa aaacaaactt gaaagctgtc tcatggcctt tgttcctgct 128700ggagctttga gtcatactta agttttatga tggaagaata ggagtgtgaa gaaagataca 128760gagcaccatc agacagtcaa gaatttcaga gccagctggc atgcagtgga cctcatgcca 128820gcccattttg ttactattta ggtagtcaag gatttaagat tcttctaata agacagtttt 128880tatgcattta aatgagtgac ttctttgcag ctctagcgtg tggccttacc tacttcaaca 128940tgagaagatt tttgtatttt gtcactcatt tcacaatgac ttatagtgag cccttcatta 129000tacactgtgg atacaacttt gctgttggaa attaacagtg tcaaaaaact gggtataatg 129060tttgtagtat ctgaggaggg agagctgcct aggaagttgt attccctgtg ttaatttttc 129120agtctcttag gttatagaag accttctaga accaccttac agcaggccta gatctcattt 129180acacacttct tctgtcactt gaatacagag aagggatcca caaggtcata tacttcctag 129240acaaagagca aagatttcta ccacactcag aagactttgt cttcagactg taatcaccca 129300caccatattt cctttggatc cagtttccag atttttgtgc tggcactaac accaacttgc 129360tgtggcttgg ggcatgtaat ttcaatattt tgtgcccatt ttcttaactg aagagtcagg 129420catcacactg ggcattttaa gattctttac agcccaatga ttctgtgttt ctaattaggc 129480ccaatgggtt agagctataa ggaaacagtg agtttcctgg aaggaaagga cacataacac 129540agtccagaga taaaacgggc tgcattcaag aaaagattgg gcaatacttt gcagggatgc 129600tacagagaca attcaagcct tgtatggagg aatggatgtg atacaaccaa aaagtcttta 129660aaaattcttt ccaactaatc tgggattcat aaccttatgg actgtgattt gcagcaaacc 129720aaggatgtga tgccaggcag aacaatatct ctgatcaaca tcaatgcaag gttcctcaac 129780aaaagactag tattgtttct ggaatgcaag gatggttcaa catatgcaaa tcaataatat 129840taacagaatg aaggacaaaa actatatgat catctcaata gatgcagaaa aataatttga 129900caaaattcaa catcatttta tgatgaaatc tttcaagaaa ttgggtatta gaaggaatgt 129960ttctcaacac aataaaggcc atatcagaca agcccacagc taacattata ttcaatgacc 130020aggaatgaga taaggatgct cactctcatc acttctattt aacatagtac tggaagtcct 130080agccaatttc atattaatga gtctcatttt cttcatcata gaatgaagta tgtaataatc 130140cctattatac ttactttgca caattattat tattttatta ttattttgag acagggtctc 130200actctgtcac ccaggctgga gtgcagtacc acaatcacag cttacttaaa ccacgacctc 130260ccaggcacaa aggatccagc ccctcagcct cctgagtagc tgggacttca ggtgcacacc 130320accatgccta actaattttc tttttttcat ttttttatag agacggagtc tcactatgtt 130380acccaggctg gtctcaaact cctgtgctca agcaatcttt ccaccttggt ctcccaaagt 130440gctggtatta caggagtgag ccactgcacc tggccttgca gattattatt aaactttgta 130500aactaatcaa atgagagtga ttattgttac tgttaagaac tctaatagcc tcattcatat 130560atttggagaa attgaataaa taggaaagaa ataatagcag accaatgatt ttaccttggc 130620tctatcatca tttggggaag tgataattca gataggagaa gtgacttgta agcagtcttg 130680agagattacc tgttccatcc cctatatttg tccttaaacc aaattgtaca gataaataag 130740gtcttatttt taggacttac agaaaaaaag attcctttca tatccatctt tggaatcctc 130800agccacttct gtcactatta aatgtcattt taaacgttaa attcatcatt ctgctttgaa 130860ggaacacatg tgtcatgtgt acctatttgt atgttttggt gtgttttatg ctttatatga 130920tcacccacat atgcacagat aattagtgtg caggtgttgt attccctgtg ttaattattc 130980agtcacacac tctcacacac ctatgcactc acacatacat gaatacacac atgttcatta 131040gaatgtttat gcttatgttg catgtgactg gcaacatcag tgcctttcta aggcaatatt 131100aaccactttg agttttggga gagctttaga aaacaaagac aagagactaa atgattctag 131160atgtaagaga caatgttgca ataagttact atcctaaaaa gacagaatac aaggacaaga 131220gattattatt ttggataatt tcttgcttac cagtaatact taagtccttt acattaaaaa 131280aaaaaaaaca actctaaata tattacagaa gacatccaga tgtccttcaa gattcttaga 131340gttggaaaag attttaatga ctttccagtc caatctattt catgtaatca gtgggatcag 131400agaggcaaaa ggacttgtcc aaggtcatat agtgagttag tgataaggct gaacaaggat 131460tcagatgttg gggcttccag cccactgatc tgtctctcat ctgggacttg tatatttttg 131520ttcattagag attttcctct gtaacctcaa tatccaatgc agggccttgc acataataga 131580ttaccagtaa atgttaaatt aatatgtcat ggctttggtt ttactgggct ttgcacttac 131640tcctgagtaa attgtaaata atatctatgt tttaggtctc cttgttttag accaagatgt 131700acccagagaa aaggtatgaa ctatgctaag aaaattatct gagtcccaaa ttgaaaaaaa 131760aaaaaaaaaa tcatgctttt ccactatgac ctctctcatt cacagagtga ttctctttca 131820aaagggcaat gtagaaccat tctggcattc tgggagccat attccattgg ctgtgcaatc 131880atttattggc aaactggggt ccaggaaagt attttcctgg ggaagatgag atttctcaaa 131940gaagtcatgc actttctaac ctaagcttat ttcagtaatc agtgtagcaa actggtcttg 132000aggattgcag cagtaccaat actgtgggag tgtaccagtt ctagaacagc tacagcattg 132060gaattgaacg cactagaatt ggatacagga cctgtttttg aggagctaac acccaaaggc 132120tgaaagcact cgtagcactg tcctttctgt gcacatatcg tagtcctcag tttgcagcag 132180aaaaaaaagc tgttagcaaa ttatgtgctc tgtttatgca aataaaatcc tgtggtatac 132240tagaaagagc accggcctag aggccttagt tttctcatat gttaaaaaac cctaacacag 132300gcctggttca tagtaggcac ccaataaata ctagagtttt tcctttgggg gcctctgatt 132360cagtgtgctt cttcaggtaa ttcacttccc tggaactcct ccttgtaatg agagttgttc 132420tgttgtgatt tttaacagtt ccttcaagcc aagcattttg gaatcctttc ataaagggag 132480aaaggaagga aaggagaaag gaaaattaaa ggaaaaaaaa ggaaataaaa agttaaaaag 132540gaggaaagga aaaagaatcc tttactacaa taaatctaat ctcatgctct tgcaagtagc 132600actttaagta aaagaagttc tttgctgacc tggttactac tgaacctact acataaaata 132660gcctactgta acacatgcat ttctgtgcct aatcttcacc ttttagcctt agtaaatgta 132720gaggaatgct gatgtatagt taaatttatg tttttagttg cttttttttt ctactctcaa 132780atgtcaatca ctctttagtt tctctttctt tttccgaccg caagtattct tcctctgcct 132840aaagaagctt ccctaaaatc ccagtctatc cagtaaatca aagcacagca ataaatttga 132900ggaaacaata ccagagacaa aaaggagtga ggggatgcag aagctcaagc tggagcagga 132960ttgtaagcat gagaagttct gcgtgcttca gagcagcgaa ggatgtattt ttgcttattc 133020ctgctggtga ctctttgtct atgcatccat ctgctgcaat tgcatgttta gtcagtcaat 133080ccacgtttgt tgagagactg ctgtgtgcca ggattgtgct agcataaagg agcgaagtat 133140tgagcaaaat atgtttgagc agctgtaatt ctgaggatct ctaggtctga gcatgtgtat 133200gtgtatgcac ttctgtgtat ctgtgacaac tccaggtgtg catgacagtg atctttgtta 133260ctctgttggc ttcatcaaac ttccttttag ttgctgtgat tcactacata gagtgggctt 133320tatctctgat ttttataacc tgcatgacta ggggtatgat caccagaaat ctaaaaacag 133380ttagaaatcc catggagtta tcttttatag aagttttcct gtactaatat tatgaaaaat 133440aagcatcttg ttaacttgag tgtaattcta tgcatgatta caggtgtcaa taggaagaaa 133500cattgactga gttcagatct cttctacgcc atgctaaagg ggtgacaagt tccacaatgg 133560atcattttct catgggcatt tctggctttt ggtaaaagta gggcatctta ttttaaaaac 133620cagtgagtag tcctaataat ggagatatca tcaggatctg aattgttcat ccctaaaaaa 133680aaacaaaaaa aacaaaaaaa caaaaacaaa acaaaaaaaa aaaaaccaat ggaaatcaaa 133740taatatagtg ccaaattaaa ctgctttaat atttaggttc tgtaggatca aattgtttgg 133800tgccatactc tgtccacttt tctgtccact tttctcatgt gataggatat aattttatat 133860cttttctgtt ctagaaatac ccaaagaaag agactctgga aactcattaa caggtctgtc 133920cactcttgta tttgttatcc cagggaaaca gaagtacctg tgtgccagca gaaatgattg 133980cactattgat aaattccgaa ggaaaaattg tccatcttgc cgtcttcgga aatgttatga 134040agcagggatg actctgggag gtaagatact tttctttctc ttcttcctcc tccttcctgt 134100ctcccctttt cctccctcat tttctagtct ctctttaaac cagattttct tctttgatgc 134160ttccaagggg accagccatg ctccagacac aggcggaccc tttcatagcc aacgtggcca 134220tcagccagct ggtgcctttt tttttttaat ccttaactat accaatcccc attctggggc 134280tcagcattag agcaggaggt gtgaagcagg gataaggagc caacagaggg tgagtgagga 134340tgcatgtgac tgggcagggt ccccagggga cttaatggta ctgacctgat gttgttcaat 134400ggtagctagg atgagagaac taagaaatcc agaacagtca caggtgcagg atgacccagg 134460cataggtaca ggatgaccca ggcacagtct gaccctgaac acctgggaat atccctcagc 134520taactgctgc ctatgttgta gggccagcca cctggaatga gaagctgctt ctctttggag 134580cctgtgacta ggctgacaaa cagtgccaat ttcctatcct atctctccca aagatgaaca 134640ggtgttttaa tcatttcctt ttctttgcaa agctattgat catttccaaa agcatttttt 134700tttcagtagg acagtaacat tacagaagga agatacagct ctttcaaggg tgttcctcta 134760tcataaggct ctctgtccca tgaacctgtc tgccatgagt gttgtcatca ttccagaaag 134820gcttgacatc agttgattga catttatatt ttccctctcc aaactccccc atctctccat 134880gtttacatct gcccaatgcc agggtcatca ctgcagcctg ctgcttccaa aaatatgtgt 134940ctttccttag aaaaacaaga tcattaatct acttcaattt ggaaatggaa tttgaagaaa 135000ggcaagccta tttctgagtg cctgcaactg tagcctcata tccgattatt cattattagc 135060ctggaaaacc caagtgccta gaatccaacc ctttccccta tcctcttaag gctaatttag 135120accagttgtc tatcactggc tttctgtgag ttgttcaata ccttgtctgc ctatgtgcac 135180atctatagac aacaactagt gctcttatcc tggaacaggg ccatgtgtga atctatatgt 135240agataactat atccttccca tcctcacagg gcagtggtat tatttaaaca gaacaaagta 135300cctcaaatga attgacccag gctggatgag agacaatttc aaaagaatca tctcaagtag 135360catccagtac tcccaaacat cacaggtaga tattctgtga gtggctttcc aagcatccct 135420atcaaatgag aatcagatat ctgagaaaac tcaaccttgt tttggtttgc ttagtgtacc 135480ccaaagaaat ccaacaattg aggtctacag tggagaagaa gtaggactgg ggtcagggag 135540tacagaggca aaggcaggaa gggtgacaaa gtgattgaca agagaaaatg ttctccatat 135600gaatgttgca gccccatgtt gagggttctt atacactcag ctttcaatta tttagccttc 135660tgcgaattat gtatagtata agagatagag actctcaggt agggaacctc ttggctggtc 135720atctggcaat atgaattgca agtccacttt gatgcaggta aagtttaatg gtaacaaaag 135780tcctcataat atttggatac aaatcttaac attaattcca tgtctcagcc aacattctcc 135840attataaatc aggctgtgat atgattacag tgacccactt ttgaaaagga gcctgtgtat 135900aacagataat ttcactatac tatatagtac tcagatgcag gtttgtaaat taatttattg 135960gtgagaatgg ttcagtacat tttcaaattg atttattagt agagtactca aatttgagtg 136020ggcttggtga acacaatgaa gacaagctga gaagtgttgt gactggcctt catttcagtt 136080gcaggcccat gatattttga gcatcttcca tgtacaaggc accatgctag tcattagagc 136140ttgaggctgg caaacttcag gaaatgttca caagatacca gcattcttga tgttgtgtaa 136200atggccttgc ctttagagtc aggcagatct agtttaaagg ctcagctcct ttatttaatg 136260tgtgcccctc tgagcttcaa gatcttcgtc tgtgatttag aaataccatc ctcatagaat 136320tataatgaag atcagatgac atgatgaatg tgaacatcct tgataaatag caaaatgcta 136380gacaaatgtg ggggcttaat atgtcattga ggtcactagt aatttagctg gaaaggctgt 136440aacacagcac ttcccgatgg cttttaccct aagtaacttg gtatgccata taatatgtaa 136500cagatccaac aggcagagca tcgccagaaa acagtcttga ttacctcaaa ccaaaaagtt 136560ccaccaggat cctgttcaga agctaatttt agtaattaag ggaatcatat gctatgttca 136620agtaccatgc cagtaaaaac ccaattgtgt accttcttaa atcactgctt gaagagcaaa 136680tctttccact ttggtgaatg aacttatctc cacattccct gccctactga cacaactccc 136740tcccacgttt attgttaact tacacattca atgcacagca cacctttact caaacaacgg 136800aaaagaaagt gtcaatacaa agtggccctt gtctattcct taaggagtag acttccattt 136860tcatgagatg tggatttagc atagacatat tgattacctt gaagaagaat tcatataatt 136920ttatcttctg attctcatca ctcaaatcaa aattatataa tatatcccaa aatgacaact 136980agaaatgtgg ccttgggcaa gtcccttctc ttctctgatg cttggttttc ccatcataga 137040attggaattg tgggcttcac caaggacctt tctggtgcta acattttgtg attctgtgta 137100aaaagccacg cagaaaggat tgtttttcag ccctttctta gattgtctgt tccctgctcc 137160cagaagtata gataatgaga cttgagtgct ttgatacatc gtaattgtat ctacctccat 137220tcatacctac ttaagatatc tgtctaaaag tagactagac agattattga gagagtggag 137280ggcagaaggg ctgtctctgt atcttaaaga agctggcact tttcagctga tggctgcttg 137340gtcttgaggc ctcaagatct ctaatctggc tttctctata gtgtttcatt cactgtttgg 137400tgatggaatc tcttcagctc agagatactt aatagatata gctttttatt tcctgcttcc 137460aggcctacct acctgttcct tgcttttttt tttttttttt ttttttttat actagttgct 137520gttgtttctg aaagaatctt gagggtggtt ggagtctcag aatggcttcc ttaaagacta 137580ccttcaggct ctcagctgct catccacaac aaagataagc ctttatttgt agatgattca 137640ttcctggctg catttgaaaa ccacatattg ctaattgctt gaagaattta aatcccttga 137700ctacttttca tttcagaaaa cccttacaaa aaaagtccaa atgaggacct tccctccagt 137760gaattagctg tggctttctc acagtccata gttaggatta atgtaaagcc atctctcatt 137820tttctggaca cttcccaagg atacactcct tgtttccaaa atggaatgag aaagaaagaa 137880gtgcccttcc tgccatcttc tcccatgacc cttttctcct tcccactttc cctcctattc 137940ctcctcaaac atgatttatt tctgtgtttt gcaactcttg agttctcatc atttagtaaa 138000tggtgttggc ccctattgat tccttcctgt cctggaccat ggagagtagt aggcctttca 138060gaaatttcag gtagcagcca aaccctggaa gaagagaagg aacacggagt cctagaccat 138120gtgagaacct gaggtgtgca gcatttcctt cacagattcg tctagcatat ttgagaagta 138180tctttcccac taggagactg aactctgcat ctgagaaaaa aaaaaactta acatatctac 138240aggttttgac aacctctatg aattacctag ttgagaggat ggctcaagga gcctatggcc 138300atggtctgat gtcattatgg acactatgaa catccttgag gtttccattg ttgaagacag 138360ccctgatgcc agctgtctca tcattcccca tgttcaagag catcccagca tcgctacctc 138420aggatcccat gtcctgaatg caacagagtg atttcgctgc tgaattacta ttcatggcac 138480ggctcttcac agcatttatt catccatgtc catccgtcct tccagccagc caagaagctc 138540atgctttcat cttttcatcc tgagtaccaa ctatgtgcca gacactctgc taggcatttt 138600ggggaagcag aactgaataa gatatcattc ctttcctgaa aaatttaagc aagaggagaa 138660aggtagtgat aaggaatata ccttagccat aaaggaaaaa taataaatca cttagaagaa 138720gttgagtgag atggaaggaa aaggacatcc aaagcaaagg gtacagtttg aataaaggca 138780gagagacatg aacaaaatgc attgagggtt tgaggaacag caattggttt aacatggcca 138840gagctgggga aatggtaaag gcaagctgaa agcacattga aagcaaactt cgttactata 138900ctaggtagtt tagacttcaa agagttgaaa atctatgacc atgggacagg tatgatgaca 138960tattattttg tttattttct tttttttttt tttttttttt tgagacggag tctcgctctg 139020tcgcccaggc tggagtgcag tggccggatc tcagctcact gcaagctctg cctcccgggt 139080ttacgccatt ctcttgcctc agcctcccga gtagctggga ctacaggcgc ctgccacctc 139140gcccggctaa tttttttttt tgtatttttt agtagagacg gggtttcact gtgttagcca 139200ggatggtctc aatctcccga cctcgtgatc cgcccgtctc ggcctcccaa agtgctggga 139260ttacaggctt gagccaccgc gccgggcctt taatttgttt attttcatgt ttctttaaag 139320aaaactggca gcagcacaaa tgttttgttg atgagggctt aaattttaga aagtgagaca 139380attttagaaa ggccagctag agagaaattt ttagcatcaa gttttgctaa acacctagaa 139440tttattcctg gagctagtta cctccatttg ggttgttacc tgcaagtact gaccacgtat 139500atgaagaaat actggtttag accaaggcaa ttggctgtat aagaggccta ccctcatacc 139560aaaagccagt ttccttggtc taggccagtg tttaccagta tgtgttctga gaaaactagt 139620tccatgacat gttccatgaa aaatacgatt tctattctca aataagtgag agaaacttgc 139680atattatggt cctgctcagg aagatttaca gtccttatta gcatatcgca ggtcctggtg 139740aatactgcaa taaagtaacc tgaggagctt tgtaactcag gattcccaaa gttgattcaa 139800ccacagaacc tcatttattc acataacacc tgttatccta caaaaccact gttctctaga 139860atacactttc gaaaacttgg gtatagataa aaactctatc ctataggcag agaatacctc 139920tagctcaggt catcattttg cagatgtgtg tgtcattaag aatcaatcca taatgcatta 139980atgatcaaaa gcagaccatc cttaccacat ggtgcataag attatgctat tagctactaa 140040agccactgaa gttaatcatg ttgggtctgt aatattgttg ttatgcacaa aggataggct 140100gcaaaagtgt cctaggccaa agcatggcta ttgcccaagt tatctaatgt ctgcaggtac 140160atattcctga cctaaggatt gtgctaaaga agttatttct aagaaatata gtgacttcca 140220gcatcatgca gaatgatcat ttaatatttt gaatatctag acattttgct gtagaattta 140280atagtccttt tatacactgt ctgaccaaca ttttgacatt tactcagaat cccatcacag 140340tgctaccaca taacctcatt actaaagtag gaggcctaga aatcacagat ttgtagaaac 140400catccaatga ttgaatcccc tctacctcct gttcagcagg cagcagagtg tcataaataa 140460ttaacaatgt ggaactcagt tactgggatt tcttccattc tcctttggct ctctagacta 140520gattctaaag accctcaggc tggtaatgca agtggtaagt ctcatttctg agaaatgctg 140580cttcctacac acagttctct gatacctgag tgctttgact gatctgcata actgaggcat 140640gcaccaagga gcagaattac tctataaatt ttggcatcaa tatgtacaac gtgtgactca 140700gcactttgaa actctgggga tttttttgtt cggttggttt ttgttttaag aggtcctgtg 140760gtatagtgga aatcgtatgg tagactcaga tacagagagg ccttgtttct agtcttggtt 140820ctgtcactta ctatcttgat gaccttgggc aaatgactag aactctctga gcctcagttt 140880ctccaaccac actgtaggaa taataaaatc ttgtttacgg catttttgta aatacgtaga 140940gaaactggta cacagtaggc acacagtaaa tgtcaccata cccttcagtc cttcttttgt 141000ggatgaaaaa tggtctttct ttgtgctccc agtaaccact ggggtctgtt ctctctctct 141060gctggacagt gtggcttctg gttcttgttt ctttgttctt tggtctctaa attacccttg 141120aaacaaccct tgaaatttcc actcgatgac ctaaattgtc atccctaagt tggttacatg 141180catatttggt gacactttgg aggggaaaag ctttatgtct ctctaactgt agttcttaag 141240ggaatttgca tatggaaaaa caagagactc catctcttaa ttcctccaaa ccaaattatc 141300tgggatagta catatatgtt gtactctgtc tcttagcatt tgctcttaga gaaatatggt 141360tagagagaag taattttttc taatcataaa aattaatgat actgcatatc tgatacttga 141420atgagtacct ccttgtaaaa tttctactta aatccttgag tttttaaagt gtaatagcaa 141480tagaaagatt ttattattgt ttacttttgc tatgagtgct ccaaaatccc tcagtagctc 141540ttgagagagc aagatgatgt cataggcaat attttccaaa ggtagtaggc agaaaactaa 141600gtacacagca cacaataggc catatataca aaggcaagta ttttacaaat atagtaattc 141660aagaaaaaag tttcattttc actggtaacc tgactgtttg tttaaaaaca ttttattatt 141720tattatttaa aaagagtgtc acttgttaca gattgtggga tgtgttcctt aagatcacaa 141780aaatgtaaaa tattttcttt ttatattgaa cacatacata gacaactaac ctgagcaagc 141840tgctttttag agacatttgc acatcttttg ggatcacgtt gttaagaagt agaactaagg 141900gaaaaagaca cagccaccca gaaaccggta gagctttcag ttcatctgtt attaatattt 141960ccatgacaca gatatctagg aagtaaacag aaaatagcat cgctatcctg cgtcaccttt 142020tttggaatca ggttccattc ttctcagtcc agttcatcct tctgatactt ttaagatctc 142080aaccaagaca tagaaatatc atattttccc ttgcttaata ccccatggaa ccaatgcccc 142140tgtggctgaa gtaaaaatta attgttgagg gacatttcag ccctctagca gtcaacaatt 142200aaaaacatgt aagcaccgag cacctgcaga aaacttgcac tggcatttgg atctaagaag 142260aaaatctgca tcttaaacaa catgaaaagt cgccagccca agcttgtgca gtgaagtgtc 142320atgctggcca caatgaaacc gaaagagact gatgactctc ctcagggtgg aaaacgaggc 142380atggaagctt tgattagtga gctgttaggc acacagacat taatttcaaa gcattctcat 142440ctccagtctg agtaataatt cttgtagtat tatgcaattg tttggctgct gcaagaaatt 142500cagcagactc caacaagtag tctttcttgg tctctgagtg actgtaactt aaattctacc 142560tcccttctct tctcctacat cttcccactc cccacccgac ctcaccccac acacacacac 142620aattcttgta cactgtgttc agagagatgc acacacacat atatatgtat atatatagta 142680tatttgtcaa taaagcagaa aagaagaaag aactccaatt aacaattttc catttcccca 142740tctcacctct gtcttacaag tagataggaa aagagaaaac cccagtaaaa aatggcaacc 142800acccgcctcc ccaactttac atgctgcttc ctatgttaga ggacttggct taggcatctg 142860attgtggagc ctgctagata caagcccata tttagactgc tacattcaac aatgtctctc 142920tttcatatta gaaaaattcc gggttggcaa ttacaagcat ctcaaaatga ccagaacctg 142980aagaaaggct gacttgcctc gttcaaaatg agggctctgc tctagtggat agtccggaga 143040aacctggagt ctgaggctta ggagcttagg tttttgctcc tcaacacaga ctttgacgtt 143100ggggttgggg gctactctct tggttgctga ctccttccaa cgggaccaat agtgttttcc 143160tacctcacag ggatgttgtg aggacgggct atagaagtaa tagtggttac cattcatgta 143220gttatgagta tcatgattat tgtttcctgt aatgcggctt ggcattggca aagtgctttt 143280tgattgttct tgatcatata tgatggtggc caggcactga ctcaggcaga tgcagtgaag 143340ctctggctca gtcacttgct tttcgtggta tgttgctggg aagaaacttt gctgatggga 143400ctcaaggtgt caccttggac aagaaacaac tgtgtctgtc tgaggttcct gtggccatct 143460ttttttgttt attaggcaat tcgtatttcc cccttcggtt ctagccttcc agatccctgc 143520caaggaccta gatcttagcc tcaggcccca tcactgagct gaaggtagta gctgatccac 143580agaagttcag taaacaagga

ccagatttct gcttctcccg gagaagaagc cagccaaccc 143640ctctcttcaa acacactggg atactagagt cagactttcc ctcttacatc tagccttact 143700gtagccacac tccctgattg ctctttcaca tcacatgctt ctcttcgtca gttgtgaggc 143760cctctcattc ttctcccaag ccagactcaa acattatatt gatgtcaaag aagaatcact 143820tagagtttgg aataccttgt tctctctctg ctccatagct tccatattga aaccagtttc 143880tttctcgtgg agaagtggag tctgtgaagc cagagacagg cacatacgag agtcagaagc 143940actctccctg acttgcctgg ggcctgtctt tcccaccttc ttctccagtt tgtctaaact 144000ctctctctct ctctctctct ctctctctct ctctctcttt ctctcccccc cctacacaca 144060cacacacaca cacacacaca cacttttttc tctttcccct gactcagcaa cattctggag 144120aaaagccaag gaaggacttc aggaggggag tttctccttt ctcagggcag aattttaatc 144180tccagaccaa caagaaattc cctaatgtgg attgaaaggc taatgaggtt tatttttaac 144240tgctttctat ttgtttgaat gttgcatatt tctgctagtg aaattttccc ttaataaagc 144300cattaataca ccaatcgtat tttcttattt acaacagact gagagaatta atgctgttaa 144360cattggacct tttttctttt tttctgtttt cctttttttt ttttttcctt tttttctctc 144420ttgtttgctt tccaggtcat gctgacctgt tcagcttgga ctgtttcaca tttgttttta 144480atgtcagttt aaatgtaatt gtaaaagcat gtatgctcta aattcatgta gttacttttt 144540tcagtggaaa agcctggtat tcgaaagcat ttccaggctc cgcaatttca tatgagcagg 144600ttttcggtaa aatcttttgt ccctcactca ggatggtatc tggacagtga gcccctttct 144660tctggctcag tagtcagaga gaggagactt ggagacagtt tctgccggat cctgtgcttt 144720ggcaaggatg tgcagcattg catatcattc tatcattaat tacgtttact cctccatgaa 144780ctaaaaacca ttagactaaa tagtccaaca taaaccttga aagataaaat ttgatattct 144840ttcgcctggc catttctctg acccagaatt ggggctggga ggggaatgga gacttggggg 144900agagaatcaa ggaggcttct tgcctggggg aatttggcat gcacttatta atcccatttg 144960gttgtactcc ctactaatcc ctcactccat acctgccaag gattggcttt gctccctgct 145020tctcatcccg gtcctagttc ttcctcaacc atctccattt cccaccactg atccttctct 145080ccagtaagat gctattcaac ctgatgaaat ataaagagta gcaccaccct ggaagtcagg 145140ataccttagt tttagctcct gctctaccat tatctaactg tgtgaacttg ggtatgagtt 145200aacctttgcc ctttaatctg aacagtcttt aagaattggt ttataggaga aaggaaggga 145260tagacaagat ccaaggcctt tgaacccttt tttggaaatg aatccttttc ttcaaacaaa 145320atttgactca gagtcccaaa tataggtaca gaataaaatg ctgctgttct tgtttgaaag 145380gtggtggggt gcttggagcc acatgctcag gcccactttg ccacctctca ggaaccctcg 145440aaaaaactta taggactctt ggggctctac cattgtacta gactgatgtc tggggagtct 145500tctaactcca attttctctt ctgttacatt tcagtccttg tgaaaactct atatgtttca 145560tcagttcact ttttcagaaa gttcacctgc ttggggtaaa gggcatgcag tggagaatgt 145620ggggctcagt aactagcaat agtaaaaaac atcattggct ggcttacata atttactctg 145680ttctaagcat cttaaacaca tactcatctg aaaaatcaca acaaccttgt gaggtagatc 145740ctgttattat cttaggattc tgaaacctgc cagcttgact ctcaaccttt gacttgagac 145800cagtcgccca agatggaaag ttatactttt cacagtttac caccgtaagc agtttttcag 145860agtgacttct agctagagat ccattcttag aaaaagtcag aacctgccca ttagcatgca 145920ctatcaccgg gcgcagagta ccttcactgg gttcatccca tttcctccta aaaatagtcc 145980tatgcagtag tcaagtcata tcatcaccat tatataggtg agaaagctga ggtgtaggag 146040aaatcaagag atctgttcaa ggttacacat cccataagac tctgaatacc accatcaaga 146100ataataagcc ttttatgtga aaagcatttt agaacttcag tgtcattatt gcattctgcc 146160tcctggagtt cagtgcactt tttcaccatg ctttaatctt ggagtcctgg tggtacagaa 146220tctgccttct actctcaggc aacaccatag tgtctttatc cctcataaca aacatatgat 146280ttaagtaatg atattatccc cattttacaa attagttaac tgagataccg agaggctaag 146340tcttgcccaa agtcacaaag ctagtcagcg atagagccgg agttacaaat gaggcagcct 146400gactccagaa tatttgctct taactactac tctttataca tatgtaagga aactaaaagc 146460caaagaggga aagacgtccc tgaggtccca cattgagttc cccgactcat ccagtattct 146520tctgaccttc taatcctaaa gttatacagt aagatccctt gactctaatc ctcgtagatg 146580gaaagatggc tggcatgatt taagctacag gccacaaact ggctttcccg gagccagaaa 146640tcacctgcag aattctgttt gtccagcaca gtgtttgttt agaaaattga catagactgc 146700ccctaggcag ggcatcaatc actgtcactg tccccagccc tccctattta tgtttgccaa 146760gctttttttt ttttttctca tttatgtgtc tgcctgactt gtgaaggtat ttgagtttat 146820gacttttaga tttaagcatt ggaatatata agcactgcac atacacacat actcacatgc 146880attcacaaaa gtatagccta gtctagcttc acaaagaatt tgtagcccta caccaaacac 146940acctttatgt ttacttaaca tttagaatta gatttaagat ctgaatttag tttcacaggc 147000attcaagtgt ggaagaatct cggttattat tttttgtttc atactgtttc actcttgctt 147060tccctgctgt gtctggaccc ctgtcagtcc tgctttctgc cattctccat gcctgagtta 147120gggcccctgc aagccactca ctcattaatc tttaggaata gatggagagt ggaaaccagt 147180ttggagggtt caccatgtgc caggcatcct ctcatttagt tctcataagt gtcctaagag 147240acaggtggca gcacattcgt tttataaatg aggaaactaa atcttagaga agctcaacaa 147300agacctcaaa gtcattaagg tactaattaa cggagctggg atttgaatgc aagattgtcg 147360gactccagag cctattcttt tgccctatac cacagttcct tacaaggaag atgtattcgt 147420tttctattac tgcataacac attgccacaa atttagcagc ttcaaacatt tatcagctca 147480gttttgtaag tcagaagtct ggcacagcat ggctagattc tcagttcagg gtctctgaag 147540gatgaaggtg tttaccagga tgcattctaa tctgaagctc agggttctct tccaaactca 147600tgtaattatt gcaggattca gttatttgtg gttgtaggac taaggttccc acttcctttc 147660tggctaccag ccaagggcca ttcttagctc ctggaggctg ccctctttcc ttttcatgtg 147720gaccccaaca ccttcaaagc cagcaacaga gactcttcct tgtgttgaat gtttctcact 147780ctacggatgt ctttccagga gaatcccagt cctgtgaggg ctcacctgac gaggtcaggt 147840acatcaagaa taaccacact tcaaattcaa ctgaattagc accttaatta catctgccta 147900gttttttcaa cagcacctag gttagtgctt gactgaatga ctggaaggaa ggatgtgtat 147960gctcaggcct cagaatcttg ggggccatct tagaagtcag cctaccacag acgttgattg 148020ctttcatgtg tcaaatttca tagtgagaca gggagaacag aaatatcctt gaccttagat 148080agagcgattc aaactttcta agactttgga aacttcacat cactttcacc tttcccttga 148140tcatggttga gaaggcctat gtcttggagt ggcaaggagt gagactggaa cagtacctaa 148200aggttaagga gactaaagaa gttacagatt ggtcacatct gctcctccct aggaatgagc 148260catggaacct gatttgaatt ttttttttct ctggtgctat agagatagct cccacagggg 148320tctaatgccc caaggctgaa aagttcgttc cccataggat ccaggcatga tatcagacca 148380ggtgttacaa tctcctaaag aggaggtatg gacaggaaag ccccttgcca atgacccttt 148440cttgtcactg ctctgactca agactaatag ggcagagata gtgagcaact cacatactac 148500taaaactatc cacttatact gccccctttc tccttgcttt atcactccat ttaagtaagc 148560cagtgagtct ctgccttgac acagtggcaa gctgatctgt atcttatatg gaagaattag 148620atttgactct ggggctcagg tgcagagggc aggaggggca taggggtggc cctcatggaa 148680gaaaacaagt ccttggatac tgagtaacag ctgagactag caagccttat tgtccaggat 148740tccaagtcgt ctagcaacat ccttgcctct gctgcagaga gaacagagga tcccccggca 148800gaatgaatgg agtctgattt caattacgtt cagtnnnnnn nnnnnnnnnn nnnnnnnnnn 148860nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 148920nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 148980nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 149040nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn ngggtcctgg 149100aggcaagtgg gaatgcagct tctcttcctt aagcagatgc catataggcc tggggaggag 149160aatgtgagaa taccagccaa gttctcattg gcactatacg gagaaagggg aattatttca 149220tcttgatgga ttctccccac agtctctgca catattgatc ttacttgtaa tgagtttgtt 149280cagattcacg agtcatcatc ccagggagat ctgagtcatt ggtgggaaag tcgaggtgac 149340agattatatc tcgctgatct cactgtcacc aattgctctg tgtgtccctc caccttttga 149400aaaagcccat ggaatcattt gtgtataatt aatttggatt tatttcttat ttatcaatag 149460ctttagtggg gtattgtaaa tgggaaagct accccagaga acagtgtaca ttcacagtat 149520tattcaatag aactttctga gatgatgaaa atcttctata tcttatgttg tccagtataa 149580tacagccgct aactacatgt agcttttgaa cactgaacat gtggctagtg agactgaggg 149640attctatttt taatttttta atgttgtaat taatttaatt ttttaaaagt tttgctttct 149700attttatagc ttaataatta aactaaactt acatagccca catgtggcta gttggccact 149760atactggaca gtacaagtct agaaagatct cagagagaca catgctgaga tacagcagga 149820ataggttagt cagaaagaga gccaatgtaa catagggaat tctggattgg gaattagagc 149880cctggctcta atctcagctc tgccactagg tgaccttgcc ctctctggct tcagtctccc 149940catctttaac ttgaaaggtt aaactaacta acgtcaaaag tcccaaaatc gtggctatgg 150000actgaattca atttgggata cataagtttc aggaattttt ttaaaaatct attaatgcct 150060tctaggtgtg tgtatgcacg cttacaggca tgtacccatg cacaagcatg ggacggcagt 150120aaggcattca ttccagttca ccagtgtact aaccattcac acatacacac acacacacac 150180acacagacac atacacacac acgcatgcat acacacccta ctgtattgcc tatgtagacc 150240ctgaaggtct ttgaatctgt caccattgga taagataatt tctaacgacc cttcccgttt 150300tgtcctgctg aaaatcttta agccactata gtgtccccaa tctatttcaa tttgggcaga 150360tgactggagt attctcatag cttcctgtct cttcccctct gaatttgata ctagttatga 150420agtttggcgt caaggatgaa gaagggaggc agggaggata taaccccagc cccactcctt 150480aactccgctt ttggattaga agtagcgttc agggcttcag attccttggg gaggaagtag 150540agataatatg ggctttgtaa tcagaagatg gggttcagat gattgggttc tcactttttc 150600gatagctgtg ttacctcagt ttattcattt gtaaaatagg gataagaaat atctttaacc 150660tcctaagatc atgtggaatt aagtgatgta acgtgatgaa gcgaggcatg cagaaggccc 150720tgaaaaaata atagttaccc ttaagggaac taaatggtct ggcaacttgt gagctcaaag 150780ctagaaaggc ccggtgatgg ggaagatggg gtctttctgc aggaactaca gcaggggagc 150840agaacctgta agccaccagt ctgtggagct gtgtccaaga actcatgttt gcaacaagtt 150900caccaaatta caagatactg tggggtccag gcctctaact caagaagatg gtcttggccc 150960agatcatacc ttgcagcctg tgcctttggt gggatgtgag tgttggcagt ggctatgcat 151020atctccttat tactggctgt gcccaagccc tgcagaaatg attgttggac aaggtcatct 151080tgcactcagg gttggttttc caggcttcct tgttattttc cccttagttc ttctgtgctc 151140ctcttgcaac accaacccca ccatttccct cttccctacc ttagttgttg gtccaaacat 151200gtaatccatt cttgcagtga tttattgagt gataccgtaa ctggagtttg cattgaagga 151260cttatttttc taattagaac taaaagtcag ttccaggctg ggtgtagtgg ctcacgcctg 151320taatcccagc actttgggag gccgagatgg aaggattgct taaggccagg agtttgagtc 151380cagcctgggc aacatagtga gatcccatct ctacaaaaaa acatgttagc caggagtggt 151440agtgtacacc tctggtccca gctacttggg agactgagga gggagaattg cttgagccca 151500ggaagttgag gctacagtga gcttttatca tgccactgcc ctccagcttg ggtgacagag 151560ggagatcctc cctcaaaaaa taaataaaaa ctacaaaaaa aaatgtcact tccaggttgt 151620atcttttttc acaggggcca gacacagatg aggagtaggt tttgttgtat ttatccattt 151680aaattgagca atcagcttct ctctttggtt tatacctttc ttatttatta ttattatttt 151740aaaaggatta gagataaagt gctttatggt ctttctcagt gcaactgctt atgctagacc 151800tcagaattat gacctcttca attatttata tttccgtctt tataaatact ggaaaaaata 151860gtacaaagta aacatcggga tgcctaagga cctctaaatt gtgtgtgagc acctggggaa 151920gatggttctt aaggtttgag ttttggatta ttgtggttgt cttaaataat gttatttcta 151980tcattccttc caatggctgt ctcctagcat ggttcccatt ttacagactg atggtagagg 152040cagaaagatt ctctcacttc tttgatagta ttgaggattt cagcctttca ccgctcctct 152100cccctttgct aaaaaagaaa aaaatcaata tgtatgttat agtgtatgtt caactatgag 152160caactatgtg tattcaatga gaaatggaat accataaaat taccatagtt gaaccaaaat 152220gataggatag aattcgatag tctgaggatg gaagggaact tcaaggccac tttaaaaaac 152280cccattccta tataatgctt gaattcttaa ccactgtgca tctagtattt gatcatttcc 152340agtgatatgt gtgcctggca acttttccat ctcccagcgc tttaactatc aaaatgtatg 152400tatgtgtgtg tgtgcatgta tgtgtgtgtg tttagagaca gagagagaca gaaagagaaa 152460gagagattaa aatccaagtc actgttcttt ctgggaccca aaaaacaagt ctagtcattc 152520tccatttcta gtctctttcc ctagcaatcg gctagacatg ctagacatag acacatgtac 152580atcactcctt tgatttacag cattcagtat ttgtctatca cttataagat aaaacccata 152640cttacttttt atttttattt ttttagagac agtgttttac tatgtcaccc aggctagagc 152700atcagtggca caatcatagc tcactgcagc ctagaactgc tgggctcaag caatccttcc 152760acctctgcct cctgagtagc agagactaca gatgtgcacc accagacctg gctaatttag 152820ttttttacta attttgtgga gatggtgtag tgtcttgcta tgttgctcag gctgatattg 152880aggtcctggc ctcaagcact cctcccatct cagccttcca aaatgctggg attacaggta 152940tgaaccacct tactcagcca gatttcttaa tatgatatac atgctccttt aaaatcaagc 153000accatctttg ctttcaaccc cattattaac cactttccca tatacgcaac atatgcttca 153060gtcatactag tctctggttg ttccccaaac actcctcagt gcttttgttt atgccctttc 153120tgcccacctt tgcctggtga aatcctcatc aatcttcaaa ttctaggtca aatactatct 153180ttcatataaa gcattttcta aacccacctg tgtaaaaaga ttagtggttt cctattttgt 153240tgatgcctcc attgcagcat tttccagtct gactttttct agaattgact gtggcaaggc 153300taccagcctg ggccagggcc tgtgtctttt ctgtcaccca gaagcaaagg tctaacaatg 153360gatatctgct gaatgaatga atgaaaatga atcattaata tagtagtaaa tgagttaatt 153420aaaggttcca ggtatgaata ctgaagcctg cattgaggca gagctgaatc caagactatg 153480ttaggttggt ctggcacaag aatcagagtt ttcctctgca agctatgaaa aatttgggtt 153540tagcacggat ttgggatgac gaattataca ttcaaccagt gttgaatgag cacttgtcct 153600taaggagttt agagtctgtg accagggaga atgatgattt tcttagctcg ggcagttttt 153660ctaacaaggt agttgcattg tgtgtttttg aacactgatg ataaattcaa gtttctcttc 153720ctgccccata gcccggaagc tgaagaaact tggtaatctg aaactacagg aggaaggaga 153780ggcttccagc accaccagcc ccactgagga gacagcccag aagctgacag tgtcacacat 153840tgaaggctat gaatgtcagc ccatctttct gaatgtcctg gaggccattg agccaggtgt 153900ggtgtgtgct ggacatgaca acaaccagcc cgactccttc gcagccttgc tctctagcct 153960caatgaactg ggagagagac agcttgtaca tgtggtcaag tgggccaagg ccttgcctgg 154020taaggaaaag ggaagtggga gcatgagata agggggatca tatttagtga acgctcctat 154080gggccagcca ccacgtctgg tgcttttctg cccattaact caggtagtct tcgtcgtaac 154140cctatgggag agggattgtt ataaatctca ctttaaacat acagggattg agactcagaa 154200agcaaagaga aagataatat tataaggtgt cctatgtggc ccacattgat gcacagcagt 154260catgctttca catttaactc acagaaatgg tcagcaaaat ttcccttaat cacaaaatca 154320catagacata tccatatatg ccttaggata ctcttctata tttgcacaca caggctcacc 154380ccaaagataa tctccagcct gactgacatt ctgtcttcag tgtcaccttt aggaactata 154440tcatgggaac tctcataata tgatatggta gaaagaacat gaggttggga atcagaacac 154500ttcagatcta cttttagttc tgctagtaac ttattgtgtg attccttccc cttctgggtc 154560tcagtttctc tatctgtata atgtataagg catggtttgt accaaattga tggttttcaa 154620attttgcttc gagaaatgct ttgtgcactt taaactacct aaggaatcat aataggagga 154680aagattaggt gatagtgaaa gaattatcaa ctgttggtct aacagaagtt ggataacaga 154740agttccccag tgatggggaa ctcacttctt tcttatgtca tctgttgctt aaacaagtct 154800ggttattaaa atattacagc ttaaggaatt cttagagatc ctctatccaa tgattcacaa 154860actttcattt aacagccaag tgctttattt ctcaaaagaa ttgtacacag atatgagtgg 154920agctagttta tttaaagcca gagtctgtgg cttgggcctc accagttcag cctctttctc 154980tctatcccag ggaagccccc aggtcactct tgcaaaatct tagggctccg aggaacacag 155040tttgaaaacc agtgaagtat atgctcttta aaggttctcc taatcttgca attatgattt 155100aaagactctt ttggaataat aacaactaaa ccttctcttg tggagtcaaa gattaaccgg 155160cctttcaata ataactgcca ttcaggtaga aatgtatagt gaacagagca attttgtata 155220tattacctga attgattctt ataggaatcc tataaaatga gattctttct cctgttttac 155280agaccaaata gggaagctgt gagaataatg tgattgacct atagttacat agtcagaaaa 155340tagcaggacc agaacttgag cccaggttct ctcctgattc caaatcctcc ctttattcca 155400ctccacctgt aggctgcagc accactgcag ttctgtaact ctgggcttta cagtgagggg 155460ccaaggcttc actgaaggcc acttgggtca tactgtgggc ttgctgcatt tgaagacatt 155520gcatgttggc tgtcaagtct tagatttgta tttccaactc acaggttagg cctggtcaca 155580gccctaacca tctcttgcac cttctcagct tgggaagctg aggttgacta ggcaataaga 155640tcactgggaa ggaaacccaa ggactctgat tggatatgtt ctgtgccaaa gcagagggtt 155700cacacagaga ggaaaaatat aaaaaagaaa aaggagaaag ctgctttaat tcttatcact 155760ttttcatctg gatattttga tatcatgtgt ttgacaaaga ttcaaagttt aatcttccca 155820agcagtttcc aaacacttat ctcattttat aagttacaga gctttttcat atatatgatc 155880ccagttaatc ctcacaacaa ttctatgaat catagagact attatttcca tttcacatgc 155940caaggctcaa agaggataac taacttgctc catttggtca cttaacacat ggaaccagaa 156000cttgacctag accttcaggt ttctaaattg gttatcttga caataaccta gtgcaaaact 156060ctatagcaga atttgtatga cttgggatca ctggggcttt ccttggccca gccaccagga 156120tggaaagtcc cctcccctta cattaacaaa tctgcaaacc aatatcagtt caccatctag 156180cttgccagac taagtgatct ctgactccga atcttttaaa agaatagctt caaaagaaag 156240ccaattacca cattcataag aactgttctt catattatct ataattacct acaagttcaa 156300gtaattcact aattcaatag attgagttct tgacctgtaa aatgaactgt gctaggcctc 156360taataagata aattttgttg taagttttct acgacagtaa tgatgtatgg aaattgccta 156420gtagagtacc tggcacatta ataaatgata actattaatt tagagtgggt gagtagactg 156480ggtgtgcaca gtatatttag aatctaattt atctggtttg gaatcctagc tatggactat 156540ttctgtgacc ttgagtaaat cacatgtctt ctctgtgctt ctgtgtcctc atttgtaaga 156600tgatagaata atcgctacct ttcaaattgt cgtcaacaaa gagattatgt ataaagagca 156660cctagtaagg tagcctgaaa catagtaaat gctctgtaaa tggtggttta ttattatgag 156720acttgagtgc taagccactg ctttaatgaa actcaatttt agctaccact tgccttgcct 156780gctcatgcat ggaccacaag gtgaaattgt cttctctgaa gaccttggca ggcagatgca 156840ctacagcagc aaagatttcc aaactggcct ttctttgagc ctattctccc agaccagaca 156900tgagactaca agtttctgct gcacatgaaa aaaatatgat gtcagttgga ttctagtgag 156960aaaacagagt gtctaataaa ctgcttctgc tccctagcct gtttaatgtg tttcaaaacc 157020tgagaatgac tcctctctgt ttctccagaa cagcctaaca caatggcaaa tgggcattga 157080gtgaatgcat acttaaggaa atctgtaggg ctgcggctac tctttcctca agtaatccct 157140tgatagtcat gcaggctact tcagagattg ggcattagag aacagagtca ggtattataa 157200tcagattaga ctctagggag attagccagc catattgctg atatgtgcac agttactggg 157260cttccgtgct aagcagctct cattaagcac agttaattaa tattatggcc aacttaagct 157320ttcccttttc tctcctgttt gttagttcgg cagcatttta gggagaaaaa aataagcatc 157380agtatggaca atttgcttca tacctgtacg atttaattct catccttcca tgggccttca 157440cattcacaca ctccactaga agaccaaggt tcaccagcca aagacttttc ttgctcccca 157500ctgcctccta cccaagatat tcagggttca acctcccagg cctcttctct aagagatccc 157560tggttgctac atgcctagac cctgcttctt atttcctact gagaagggtc agtccaaggc 157620attctgtgct acagaagggt tccagacagg aactactctg ggatctgagg ctccagccag 157680tctgtcagtg tgtcattacg gtgaaggtgg gaagcacagg cctgggagct aagactgcca 157740agatgaggta ctctagaatc cctgatatct ggaaggctta ggatctaaag gaaaagaaca 157800gtgaaatggg gctatatgag tggacaggga ccaaccaagc agaacaatgt atctggataa 157860tgtagacttc agacctgatc ctatggctga caaaagttgg tgaccttggt ggttcctgag 157920ctgtaacctt cagcagtgga gtagaaaaaa cactggagaa cagaatcaga acacctgggt 157980tctagtatta gttcagccac atataaacca tatgaccttg ggcaagtcaa tttatttctc 158040tggccctcat gttccttgtt ggtaaaataa gtgtcacatc acctaacctc tgggattatt 158100gtgagagtta aattaggtca tcaacaggaa agtgagaagt ttggtctaca tttggggaag 158160cattcctaat gaggtatgat gacaaaattt cagataattc tggatttgtt agtgagaaga 158220gagagtgttg gtagggatga gctctgaggt gatgccttta taactttaag catccaactg 158280tttcagaacc tccaggagaa catggccatg tctgtactac ctgtgtgtta ttgtagaggt 158340agcatctggg agcctctgct ctctgagctt aagggaggta atttggagat catttaattc 158400tcattttata aaaggaaaac aaattgagga tctttaggcc atttgtttag gtttcttaag 158460tgcccactca aatacgtgga ctgtactaag tactagggag gtaaacttga atatgaagat 158520atggtccctg tcttcaagaa gctctaagtc ttgtggggga gacagacatg tatgtacata 158580gatttcaatg ctgtgtaatg agtgctataa ctgtgtgagg ctacacaagg agcaatgaga 158640atgtaaaata agaatcttta

agccttcttc ttggatgagt tggaaaagcc ttcacagaag 158700aggtagcctt tgagtgaaga cttgaaagat gagtaggtgt ttaaccggat gaaagacctg 158760agaaggagga atgcattcta ggcaaaagca actgcctgtg cagagataac agagatatag 158820aggcatgtga gagggcaagt ggcaacagat cagtctaggc agcaggtcat aaagggcctg 158880ttcatatata atgatggcag taagatgggg atggcagtaa ggtgggaaac tagtagggcc 158940aggctaccta ttgagtagaa aagaatggag aggaactgcc aggcagaaag tgggatggac 159000gcaagaaagg gaacatgaaa gtggtcaaca ggaggcagtg gctgtcaaga catctctcca 159060tacactgtac actgtatgta atatccgtct cccagggttg ttagaagggt caaaccagct 159120catagctgga aaagagcttt gtgaagtgaa aactgtttat gtgggagaaa tgatgttatc 159180ctgcatcttc ggaaaggtag agtgatcaag agcacagacc ttggaatctg actgctttgc 159240tttggaactt ggtctaccaa ttactagctg tatgatcttg gacaagttcc ttaatctctc 159300tctgactcac ttgtactggt tcacagaatg gagataataa tagtacctac tttactaatt 159360gttgtgaata ttaaatgaga taatataagt aaagtgctta gaaaagagtt aaatgtgccc 159420cataaataca tacaactatc atatacccaa aatatttttt aagttttttt aaaaaagcaa 159480tccaatggaa atcaaaagaa aaaaagtttg ctcgtatatg cagtcaataa gtgttagatt 159540atttttctct tacaactgac aatgcccttt ttttctccat catcatctca tttgagcagc 159600tcagtgatgt agggaggaca acgaatatta tcctcaccat atagtttgtg cttttcccca 159660ccacccctca gtggccagtc tggatggtcc ctggggatcc ttaggggatg tccaaatgcc 159720agagcatctc tacccagcag gggctcagac ttagctcagc ccgtcagtac ccagattgac 159780cactgcctct gcctcttctt ctccaggctt ccgcaactta cacgtggacg accagatggc 159840tgtcattcag tactcctgga tggggctcat ggtgtttgcc atgggctggc gatccttcac 159900caatgtcaac tccaggatgc tctactttgc ccctgatctg gttttcaatg agtaagtgct 159960cctggggccc agacctcact aaaatacagc agcttggcca gacccagttg gtggtgatgg 160020tgatggagtg acagtgaagc ttacctcatt tgacctgcag gtgtggcatt ggatgcccca 160080gccagccaac tcggtatgag gcagctttgc cctggctttc agccaactgg taggagctga 160140ggaggatggt gctgagacta cccctttcac acccaagaac caatcctggt cgtgtttctg 160200gtctccttta cagcttatct cagaaccaca tggaaagatt cctccccttc actttgagca 160260acatataaaa gaggcagaaa gactctggct ttaagggctg aagtttcttg ggttctgttg 160320ctaccaccaa aggctactgc tagtcaccac ttgctgagca attagtttgt gccaagaata 160380tgctagatac tttctaaatc ctatctcatt gagtcctcat ggtgacctga cctccccttt 160440ttatagataa ctctattttt tttatggacg gggaaagtca ggctcagcaa agtaaagtga 160500ctcacccaaa gtcacagagc tagtgcctgt tggagagaag attcaaatgt atttccgtgt 160560gaatcccagc tcttctgcgt catggtggta actgatgggg aggagtacct ctaccactct 160620ctgtctgtgt gaccttggta ctgccatttt ctttctctta aacagcttta attaatacct 160680gccctgccac tagctctata taacatcatg aatttggcca gtggctcaga ttttggaatt 160740acatttttct ccactaaaat ctcagttcta ttattttctt aatcagcatc tttgggaaag 160800acccttaact tttctgaccc ccaatttctt catcaattaa tgataataga accttcataa 160860gtaatttctt atgataacta aatgggaact gacagatgtg gaatgtctgg cccatagtgg 160920gcaagaagaa aaaaaaaaaa gtccctttct gatccaccat tccctaagag tgatattttt 160980ttccccccaa gatggagttt ggcgctgcca cccaggctgg agggtggtgg tgcaatgatc 161040tcggcccact gcaacctcca cctctctggt tcaagcaatt ctcctgcctc agcttcccga 161100gtagctgggc ttatagatgc cagccagcaa tgtccagcta atttttgtat ttttggtaga 161160gatgggattt caccatgtta gccaggctgg tcttgaactc ctgacctcat tatctgccca 161220cctcagccag gcatgataat cttttctatg tctgctgtat gaggtccctc gatggcataa 161280tgaatggagc tggccagaga aatcttccca aggaccttga gctagtctcc ccacagagaa 161340tccttccagt caggacagga attgaccttc ccccctcttc agccctctaa cccagaagag 161400tcttaaaata aaatctacag gccagtggtt ccttccagta cagcactgca atgtgaggga 161460gagtgagcgt ccccagctgc cctctcccaa ccctgccagc ctggtagcca gaagctaaga 161520ataaccacta ggcttttggc acaaactgct ttgtggtttt cagacctcca aaaagttgcc 161580tatgatgcca tcttctgggg caggccttga aaagccccct aactgttcat ctcccatcct 161640caaacccctg ctgcccttaa gcaattgaat caactccatg agcacctgct ctaccttccc 161700cagagctctg agacctttgg agctttgaaa agtgataatt ggctgttctc taaatcctca 161760tttccttttc tacctctgag taagcatgtg gcatcccacc tcagcttcct ggtccagtct 161820tgttcagctt ataaaaaggc ctccccacag ggtcagaggc ctagacccat caaatcccag 161880ggctcctgaa acaataggac ccctattcct cctgtaggaa gccactatgt tagaactctc 161940agggtgtcta caaacatcta gataagtgtt tctcaacatg gattattttg acatattggg 162000aaaaataatt ttgtcaatat gtagaatatg gttgacatac ctggcaccag cctactttat 162060accaaagagg attccagtca ttctgacagc ccaaactgct cccacgcatt tctaacaccc 162120actgaagaag cagtactctc cagttgagag tgactaattg ctgccagcct ccctaaggtg 162180ctaatgggga gcctcagacc caaagaggga gataagaact tgttcaaagt aggtcaaccc 162240atttgctgat ctcttcaaca ccaaactcta ttatcagccc tgttttttcc tttccttctg 162300tctttgtaga gatcacatgt tgtgaggata atgagcctga actttagctg tgtgaccttg 162360ggcaaattac tgaacttcta tatgcctcaa attttatctg gagactgctg aagagtatta 162420taatagcacc tttctacatg tcatttatgg aacacctgct atgtgtcagg cactgtgctt 162480agtgttttcc aatcttcatt tctcatctta ttttctctct tgcactccca ccaaccctgc 162540tctcctccta aattccattc ctgcctcatt tttataccct ccattctcct ctctcttcct 162600tcctttaact gtctccctag tattttttcc ctttttcccc ctttcttgtc cccttcccct 162660atgaatttcc tccctttcct ttccccttct ctttcctcca ttccccactt tttctgcccc 162720gaggcctgca gcaatgttaa aggaatcctc attccagcat tgtgatttca atggtaaaaa 162780aagattgcag cactgtcatc aacagaggtg ggaaagtaca ttggagactg gagcagggcc 162840agacctcagg gtcagccaat cttactaaaa aattctctat agtgaaagag cttggagcaa 162900cactgttctg ctcaattgat ttgtgatacc atctaaacac ttcctctttc cagttgggct 162960tcagcctgag ttgaataatt ctacaccatc tgcccccttc tctctttctc caggacagcc 163020aagatctctc tgagatagga tgctgagttt ccacccagac aataccaggc cttctcatcc 163080tgtggagtag gctagtggct tggaaaccaa aatgtcaaac catagccttt aggctccatc 163140tgggaggtct ttgtcctcac cacttaagtg ggtgtcagat ttccttccct ttctgcacat 163200gctgcacaat caatttctgt cttacacaca cacacacaca cacacacaca cacacacaca 163260caatttttga agtgctgaaa actagaaagc ctactagcat gaggatgctg tgtcttctct 163320tagaggtatg ccatggtcag ccatggaacc aagagggtgc tcttccttga aaagttggcc 163380aagcattggc cacctccccg tataatttat aggtgataat gtggtgatct gttcagaagt 163440aactataata aatgcagctc acatatgtct acagtttcca aactgtggta aggagcagcc 163500agcatatgag ggaatgggct ccccttcagc aggggacatt taaattagac attcaaaaac 163560actccctggc agatttaaca ttgaaactca ttttgaaaga acaatgtgga atctccttca 163620ctggaagttt ttgaagaaat attaaatttc tagtattcca ggccagaggc aaaggggtca 163680acaggatgac caaacacttc gggtcacttg caaatcctgg tgtcctgatg ttaagagctg 163740actactgggg cttctcctaa aaatccttca tgttgagctg cctgggaggc aggttcttgt 163800tctggctgta gatgggatat tagaactgta gtcagggaga ccatgtgcct gccccattgt 163860gttcatttgg ttaggctttc ttgtccccga ctcagaaaac agaaggggca cagagacctg 163920gaaattccat gtgctaaccc atatcctggc cagggaagat agtagtaatc aggatgtcag 163980gattttggaa aagagagaga taaaaaaaaa acaaaaaaac aaaaaaaaaa acagaccaac 164040aaacaaacaa aaacctcatc ctgatccctg aagcaccagc aggagaaaca gcaagctctt 164100cttggagaac ctggggagga agggcaatca gagacattcc ctctgggctt attgcaagcc 164160tcccctcatt cctttttcct ctatgtatct ccttcccagg taccgcatgc acaaatcccg 164220gatgtacagc cagtgtgtcc gaatgaggca cctctctcaa gagtttggat ggctccaaat 164280caccccccag gaattcctgt gcatgaaagc gctgctactc ttcagcatta gtaagtgcct 164340agaggtgcag ggaatgcccc tgagggcaca gagactcaga gaggaccact tttgacatta 164400aaacgttatt agggagaagc cagctccttg acatttccct tcttcatttc ccctccccat 164460ccccactgta ctctccctca gtatcattct tctaacaaga aacaatttca tgactagaag 164520ccaatgtatt tgctagaagt cagcttccat cagattcccc acctatccct agtctatctt 164580tgggacaagg cctttttgac tggttatagc aggtctgtga atttctccac agcttctgct 164640atagaaacaa acatgggcca ccttgtattc cttgcagggc agtaaagcag gaggcatttc 164700ctcctggaaa gatttcctct tctgccaaca ggaggaggtc tatgtaagca actcaggtag 164760gatttatttg gcagccaagg aacttttctt taatatcttt tctaacaaga gccctttctt 164820agcctctgtt gagggagaaa ggcaaaattt gatattcaaa gctatgtgtt ttagttgtct 164880aaatcagggt ttgactgtaa atgacataaa agcttaggtc ctaaaaaatg agtatatgag 164940aagagtagaa aaagaaaaga ttcaggaaat ttgatttact tgactccctt cagattggat 165000ccagctatcc tttcccctga gatctccctg acagactgaa gtccccaagc ccacagactt 165060caactaacag gaagccaagt agatggttcc ctgtgggggt gggggtcaag tttgtggtca 165120gaaaacttgg tgctttgtct aatgttcctt cgtgggcatg cttcccctcc ccattctgtc 165180ttcatcccac atcagttcca gtggatgggc tgaaaaatca aaaattcttt gatgaacttc 165240gaatgaacta catcaaggaa ctcgatcgta tcattgcatg caaaagaaaa aatcccacat 165300cctgctcaag gcgtttctac cagctcacca agctcctgga ctccgtgcag cctgtaagca 165360aacgatggag ggtgctttat cagggagaac agcctgatag agccaatgat aatatgcttc 165420tctagggtct ggcaccacct gttgggaggt gcttccattc ccctctggct ttgagtgtgg 165480tccaggaaga aaatgtggtg aagaaaggaa cacgggtcac agtgtcccag ctggatattg 165540tgaaaggggt ggaggagttg agaacagagc agttgggact cagggaaggg acttacagca 165600gatgaattct ctaggcagac aaaacagacc tggatgtttc tcccctcttc tttgagtcat 165660gttcatgtga gtttgtgtgt gtgtgtgcgc gcgcgtgtgt gtgtgtgtgt gtgtgtgaca 165720gagagagaga ggagagaggg agagagagag agagagagag agatggagtg cagaggctgg 165780ggtgagagca caagctggag aagtcttgag tcagaaagct tacaatggta taagacatcg 165840cttgggagcc ctcagtgact cnnnnnnnnn nnnnnnnnnn nctctctctc tctctctctc 165900tctctctctc tcactcacac acacacacac acacacacac acacacacac acacacacac 165960gacctcatgg gggaggacca aggaaggaca gggaaggggg aggaaacaaa agactgaaag 166020accaaaaatc aaaggttagg gaagagtcta gcagagccca cctccttgtc aaccctgttt 166080ttctctctct tattgttccc tacagattgc gagagagctg catcagttca cttttgacct 166140gctaatcaag tcacacatgg tgagcgtgga ctttccggaa atgatggcag agatcatctc 166200tgtgcaagtg cccaagatcc tttctgggaa agtcaagccc atctatttcc acacccagtg 166260aagcattgga aatccctatt tcctcacccc agctcatgcc ccctttcaga tgtcttctgc 166320ctgttataac tctgcactac tcctctgcag tgccttgggg aatttcctct attgatgtac 166380agtctgtcat gaacatgttc ctgagttcta tttgctgggc tttttttttc tctttctctc 166440ctttcgtttt cttcttccct ccctatctaa tcctcccatg gcaacttcag actttgctcc 166500ccattgtgac tcctatctgt gttttgaatg gtgttgtatg cctttaaatc tgtgatgatc 166560ctcatgtggc ccagtatcaa gttgtgcttg tttacagcac tactctctgc cagccacaca 166620aacgtttact tatcttatgc cacgggaagt ttagagagct aagattatct ggggaaatca 166680aaacaaaagc aagcaaaaaa aaaaaaaaag gcaaaaacaa aacgaaaaat aagccaaaaa 166740accttgctag tgttttttcc tcaaaaataa ataaataaat aaataattac acacatacaa 166800acaaatatat agaaatcccc aaagaggcca atagtgacta gaaggtgaaa attgcaggcc 166860cctgggaagt tactgatttt ttcatctcct ccctccatgg gagactttat tttctgccaa 166920tggctgttgc cattagaggg cagagtgacc ccagagctga gttgggcagg gggctggaca 166980gagagagagg agaggacaag gagggcagat ggaacatcag tacctgccca cagccttggc 167040ccctgggggc tagactgctc aactgtagag caattcatta tactgaaaat gtgcttgttg 167100ttgaaaattt gtctgcatgt taatgcctca cccccaaacc cttttctttc tcactctctg 167160cctccaacct caaattgact ttcaatagtt tttctaagac ctttgaactg aatgttctct 167220ttagccaaaa cttggtgact tccacagaaa agtcagacca ctgagaagaa ggggagcaga 167280gatttaaccc tttgtaaggc cccatttgga tccaggtctg ctttctcatg tgtgagtcag 167340agaggagctg gagccagagg agaagaaagt gatagcttga ctgttctcct gcttaggaca 167400ctgactgaat agttaaactt tcactgccac tacattttcc ccacctttaa aagacctgaa 167460tgaagttttc tgccaaactc cgtgaagcca caagcacctt atgtcctcca ttcagtgttt 167520tgtaggcccg aacttcatca cactgcattt cagccatggt ggtcaagcct gtttgcttct 167580tttgggcatg ttcacagatt ctctgctaag agctcccccc atcaagaagg ttagcaggcc 167640aacagctctg acatctatct gtagatgcca gtagtcacaa agatttctta ccaactgtca 167700gatcgctgga gcccttagac aaactggaaa gaaggcatca aagggatcag acaaactggg 167760tgtcttgtcc ttgtccccca gagatgacac ccttccagca agtggagaag ttctcacttc 167820cttctttaga gcagctaaag gggctgccca gatcagggtt gaagagaaaa ctcaattacc 167880agggtgggaa gaatgaaggc actagaacca gaaaccctgc aaatgctctt cttgccaccc 167940agcatatcca cctgcagaag tcatgagaag agagaaggaa caaagaggag actttgacta 168000ctgaattaaa atcttcagcg gcaaagccta aagtcagatg aacaccatct ggtgagttca 168060ctcatcatcc tcctctgctg ctgattctgg gctctgacat tgcccatact cactcagatt 168120ccccaccttt gttgctgcct cttagtcaga gggaggccaa accattgaga ctttctatag 168180aaccatggtt tcttccggaa aggtctggtt ggtgtggctc caatacattg ccacccatga 168240actcaaggtg tgccctggga cactggtttc atctagtctt ttggcacgcc tgtgttctgt 168300tgacttcatt ctccaacccc aagtgcaagg caaaatgtcc acctactttc tcatcttggc 168360cactgcctcc ttacttagct cttaatctca tctgttgaac tcaagaaatc aagggccagt 168420catcaagctg cccattttaa ttggttcact ctgtttgttg agaggatagt ttctgagtga 168480catgatatga tccacaaggg tttccttccc tgatttctgc attgatatta atagccaaac 168540gaacttgcaa aacagcttct ttaaataaca agggagaggg gaacctaaga tgagtaatat 168600gccaatccaa gactgctgga caaaactaaa gctaacaggt tccctttctg ggatgggata 168660gacacattct ggttttcttt attactacac catctggctc atgtacagga tcacttttag 168720ctgttttaaa cagaaaaaaa ttccaccact cttttcagtt acactaggtt acattttaat 168780aggtccttta catctgtttt ggaatgattt tcatcttttg tgatacatgg attgaattat 168840atcattctca tatctctcct tgtaaatact agaagctctc ctttacattt ctctatcaaa 168900tgtttcatct ttatgggttt cccagttgtg actcttgtct ctatgaatat atgtttttca 168960tttgcaaaag ccaaaaatca gtgaaacagc agtgtaatta aaagcaacaa ctggattact 169020ccaaatttcc aaatgacaag actagggaaa aatagcctac acaaggcttt aggccttctc 169080tttctgtgct tggatttgag tgaacaaagg aggttttagc ttggctctgt tctcccatgg 169140atgaaaggag gaggattatt ttttttttct tttggccatt gatgttctag ccaatgtaat 169200tgacagaagt ctcattttgc atgcactctg ctctacaaac agagttggta tggttggtat 169260actgtactca cctgtgaagg actggccact cagacccact taactggcga gctagaagat 169320gaggatcact caccggaaaa gtcacgagga ccatctccaa acaagttggc agtgcttgat 169380gtggatgaag agtgaggaag agaaaaagaa ggagcaccag ggaaaagacc tcgtctgtgc 169440caggcagcag actgctgcca ggatcacgaa ctctgtagtc aaagaaaaga gtcgtgtggc 169500ggtttcagct ctcgttcatt gggcagctcg cctgggccca gcctctgtgt tgacatggga 169560gttgttggat tctttgtttc atagcttttt ctatgccaca ggcaatgttg ttgttcttgg 169620aaagtttatt atttttttta attcccttac tctgagaaag ggatattttg aaggactgtc 169680atatatcttt gaaaaaagaa aatctgtaat acatatattt ttatgtatgt tcactggcac 169740taaaaaaata tagagagctt cattctgtcc tttgggtagt tgctgaggta attgtccagg 169800ttgaaaaaca atgtgctgat gctagagtcc ctctctgtcc atactctact tccaaatgga 169860tataggcata cataataagt tttattcgac ttgtacttta agagaaaata tgtccaccat 169920ccacatgata ctgacacaaa tgagctaaca ttgagcttca agtagcttct aagtgttcat 169980ttcactaggc acagcacaga tgtggccttt ccccccttct ctcccttgat atctggcagg 170040gcataaaggc ccaggccact tcctctgccc cttcccagcc ctgcaccaaa gctgcatttc 170100aggagactct ctcgagacag tccagtaact accggagcat ggcccctgca tagccctgga 170160aaaataagag gctggctgtc tacgaatcat cttgtgccag ttgcccaggt gagagggcac 170220tgggccaagg gagtggtttt catgtttgac ccactacaag gggtcatggg aatcaggaat 170280gccaaagtac cagatcaaat ccaaaactta aagtcaaaat aagccattca gcatgttcag 170340tttcttggaa aaggaagttt ctacccctga tgcctttgta ggcagatctg ttctcaccat 170400taatcttttt gaaaatcttt taaagcagtt tttaaaaaga aagatgaaag catcacatta 170460tgtaaccaaa gattacattg tatctgctaa gataccaaaa ttcacaaggg cagggaggga 170520gcaagcatta gtgcctcttt gataagctgt ccaaagacag actaaaggac tttgctggtg 170580actgacttat aagagttttg tggggttttt tttccctaat aatatacatg tttggaagag 170640ttgaaaataa ttttgggaaa atgggtttat gggtccttca ctaagtgatt ttataagtag 170700aactggcttt ccttttcttt agtagttgct gagcaaattc ttgaagctcc atcattgcat 170760ggttggaaat ggagctattc ttagccactg tgtttgctag tgcccatgtt agcttatctg 170820aagatgtgaa acccttgctg ataaggaatc atttaaagta ctagattttg cactagaggg 170880acagcaggca gaaatcctta tttctgccca ctttggatgg cacaagaagt tatctgcagt 170940tgaaggcaga aagttgaaat atattgtaaa tgaatatttg tattcatgtt tcaaaattga 171000aatatatata tatatatttt atatatatat atatacacac acacacatat atagtgtgtg 171060tgtgtgtgtg tgcgcgcgcg cgcgcgtgtg tgtgttctga tagctttacc tttctctgga 171120tctttatact tggttccaga tcacacctga tgccatgtac ttgtgagaga ggatgcagtt 171180atgttatgga agctctctca gaacagacaa gacatgtaga ttaatcagat aactgaaagt 171240tttctcccct attgggtctg acccacaggt cctgtgaagg agcagagggg taaaaagagt 171300agaggacatg atacattgta ctttactagt tcaagacaga tgaatgtgga aagtgtaaaa 171360actcaatgga actgattgag atttaccaca gggaaggccc aaacttgggg ccaaaagcct 171420actcaagtga ttgaccagtg gcgccctaat gggacctgag ctattgggag aagagaactg 171480ttctttggtc ttcaccatcc ttgtgagaga aggacagttt cctgcattgg aacctggagc 171540aagcgctcca tctttcacac aaattccctc acctgagatt gaggtgctcc tgttaatggg 171600tgtctgtgtg ctgtaattct ggttttggat atgttctgta aagattttga caaatgaaaa 171660tatgttttta tctgttaaaa cttgtcagag tactagaagt tgtatctctg taggtgcagg 171720tccatttctg cccacgggta gggtgttttt ctttgactaa gagattgaca ccgggatctg 171780ttgcccaggg cctcccaact caaccatttc taggtgaagg cagaaaaatc cacattagtc 171840actcctcttc agacatttca gctgagataa caaatcattt ggaatttctt cacccataga 171900aagagtggta gatatttgaa tttagtaggt ggagttttat agaaaaaaca gcttttgcct 171960cagttttgat ttatcctcat ttgatttggc cagaacgtag gtaatatgca tcgattggct 172020tctgattcca attcagtata gcagggtgct gggttttttc ttttccccac ccgtctctta 172080gcctagggaa ttaaataaga agccttagaa tgggtggccc ttgtgacctg aaacacttcc 172140tacataagct acttaacaag attgtcatgt agctgcagat tcctttgccc accaaagact 172200agaacacacg catatccata aaccaaagga aagacaactc tgaaatgctg tttctctggt 172260ggttccctct ctggctgttg cttcacagta tgggaacctg tactctgcat aggtgacagg 172320ccagatttgc attctcttac aaccttagcc cttggtgtta actgtcctac agtgaagtgc 172380ctgtggagtt gtcctatccc agaagccact tggatgctga gagcagccac catcagaacg 172440acccacgcga aaaaaaaaaa attaaaaagt cccctcacaa cccagtgaca cctttctgct 172500ttcctctaga ctggaacatt gattagggag tgcctcagac atgacattct tgtgctgtcc 172560ttggaattaa tctgacagca ggagggcgca gactatgtaa acagagataa gaattaattt 172620tcaaagttga aggggaaaaa aagaaagaaa aaagaagaga gagagaaaga aagcatcgta 172680caaagatttt cttaaaaaaa acaattttgc ttgaaatttc tttagatggg gctcagttgt 172740cacagtggca cttggcctcc actgggcagc aggaccagct ccaagcgcta gtgttctgtt 172800ctctttttgt aatcttggaa tcttttgttg ctctaaatac aattaaaaat ggtagaaact 172860tgtttgttgg actaaatgtg tgactttggg tctgtctctg cctctgcttt cagaaatgtc 172920atccattgtg taaaatattg gcttgctggt ctgccagcta aaacttggcc acatcccctg 172980ttgtggctgc aggatcgagt tattgttaac aaagagaccc aagaaaagct gctaatgtcc 173040tcttatcatt gttgttaatt tgttaaaaca taaagaaatc taaaatttca gatgaatgtc 173100atcagagttc ttttaattag ctctttttat tggctgtttt tattgaagtc aagagttggt 173160atcatgccca gttgtgtttt atgctatttt gattttcata tatttttaaa agtctttgca 173220caaggcttac aaatttgccc tgtggtggcc ttagcataag ctgacctggg accaccaaaa 173280taacaaggaa tttgggctag aaagcacaga tggacactgg cggcccatca caacttctct 173340tgaaaaacac caaacttgtc agctggggaa aagccacaca aagcccagtt gcctactttc 173400acaaccttat ccatgtggga gcataaaatg gtggcatcac tgcccagttc taaccaagct 173460tcagttaaag aatgggtacc ttcacatcct cactattttt caggggcctt accatcctca 173520accacccaag taaaatctaa atcagccttc ttttgggttc ttcagttcaa gtaaggcctc 173580ttcttgtggc ctctcagtgt gaatacttac gaggttccag attgaatttt tgggcctgag 173640atacaaggca tcaatgaggt gtgacaaaac atgtcaacga ataataagaa aattctctat 173700tcttccatat cctcccctgt

aataagggtt gtcagaatgc cttctttctc ggctgagttg 173760aagattcagt gagaacatat gtgacacagc tggtgggcta ttaagctctg gctttgctcc 173820ctgttaaaat gccagaaccc ttgagaggga tcccacattc agccatgttt atcattgacc 173880accttagaat ggatggattt ctcagatttt tcctgagatc agtgcttgat ggagaggaga 173940ggagaacaat agattcttgg gatgtgtgct ttgcatgtgt ttaagtaaga gacagagagt 17400019027DNAArtificial SequenceSynthetic oligonucleotide 190gcgtttgctc ttcttcttgc gtttttt 2719116DNAArtificial SequenceSynthetic oligonucleotide 191tctggaacag attctg 1619216DNAArtificial SequenceSynthetic oligonucleotide 192gcttcatctc cacaga 1619316DNAArtificial SequenceSynthetic oligonucleotide 193ggctactacg ccgtca 1619416DNAArtificial SequenceSynthetic oligonucleotide 194gagaaccatc ctcacc 1619516DNAArtificial SequenceSynthetic oligonucleotide 195ggaccaggta gcctgt 1619616DNAArtificial SequenceSynthetic oligonucleotide 196cccctggact cagatg 1619716DNAArtificial SequenceSynthetic oligonucleotide 197gcacaaggag tgggac 1619816DNAArtificial SequenceSynthetic oligonucleotide 198gctgtgaaga gagtgt 1619916DNAArtificial SequenceSynthetic oligonucleotide 199tttgacacaa gtggga 1620016DNAArtificial SequenceSynthetic oligonucleotide 200gtgacaccca gaagct 1620116DNAArtificial SequenceSynthetic oligonucleotide 201catccctgct tcataa 1620224DNAArtificial SequenceSynthetic oligonucleotide 202tggggagaac catcctcacc ctgc 2420324DNAArtificial SequenceSynthetic oligonucleotide 203tccaggacca ggtagcctgt gggg 2420424DNAArtificial SequenceSynthetic oligonucleotide 204tgttcccctg gactcagatg ctcc 2420524DNAArtificial SequenceSynthetic oligonucleotide 205tggggcacaa ggagtgggac gcac 2420624DNAArtificial SequenceSynthetic oligonucleotide 206ttcggctgtg aagagagtgt gcca 2420724DNAArtificial SequenceSynthetic oligonucleotide 207cgcttttgac acaagtggga ctgg 2420824DNAArtificial SequenceSynthetic oligonucleotide 208catagtgaca cccagaagct tcat 2420924DNAArtificial SequenceSynthetic oligonucleotide 209gagtcatccc tgcttcataa catt 2421014DNAArtificial SequenceSynthetic oligonucleotide 210ctgtgaagag agtg 1421112DNAArtificial SequenceSynthetic oligonucleotide 211tgtgaagaga gt 1221214DNAArtificial SequenceSynthetic oligonucleotide 212ttgacacaag tggg 1421312DNAArtificial SequenceSynthetic oligonucleotide 213tgacacaagt gg 1221414DNAArtificial SequenceSynthetic oligonucleotide 214tgacacccag aagc 1421512DNAArtificial SequenceSynthetic oligonucleotide 215gacacccaga ag 12

Claims

What is claimed:

1. A single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising an at least .[.12.]. .Iadd.11.Iaddend. contiguous nucleobase portion of SEQ ID NO: 12 or 175, wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1 and comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

2. The single-stranded modified oligonucleotide of claim 1, wherein each internucleoside linkage is a phosphorothioate linkage.

3. The single-stranded modified oligonucleotide of claim 1, wherein the modified sugar comprises a 2'-O-methoxyethyl sugar.

4. The single-stranded modified oligonucleotide of claim 1, wherein the modified sugar comprises a bicyclic sugar.

5. The single-stranded modified oligonucleotide of claim 4, wherein the bicyclic sugar comprises a group selected from: .[.4'-CH(CH3)-O-2'.]. .Iadd.4'-CH(CH.sub.3)--O-2'.Iaddend., .[.4'-CH2-O-2'.]. .Iadd.4'-CH.sub.2--O-2'.Iaddend., and .[.4'-(CH2)2-O-2'.]. .Iadd.4'-(CH.sub.2).sub.2--O-2'.Iaddend..

6. The single-stranded modified oligonucleotide of claim 1, wherein each cytosine is a 5-methylcytosine.

7. The single-stranded modified oligonucleotide of claim 1, wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1.

8. The single-stranded modified oligonucleotide of claim 1, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.

9. The single-stranded modified oligonucleotide of claim 8, wherein the modified sugar comprises a 2'-O-methoxyethyl sugar.

10. The single-stranded modified oligonucleotide of claim 8, wherein the modified sugar comprises a bicyclic sugar.

11. The single-stranded modified oligonucleotide of claim 10, wherein the bicyclic sugar comprises a group selected from: .[.4'-CH(CH3)-O-2'.]. .Iadd.4'-CH(CH.sub.3)--O-2'.Iaddend., .[.4'-CH2-O-2'.]. .Iadd.4'-CH.sub.2--O-2'.Iaddend., and .[.4'-(CH2)2-O-2'.]. .Iadd.4'-(CH.sub.2).sub.2--O-2'.Iaddend..

12. A single-stranded modified oligonucleotide consisting of 16 to 30 linked nucleosides having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

13. The single-stranded modified oligonucleotide of claim 12, wherein each internucleoside linkage is a phosphorothioate linkage.

14. The single-stranded modified oligonucleotide of claim 12, wherein the modified sugar comprises a 2'-O-methoxyethyl sugar.

15. The single-stranded modified oligonucleotide of claim 12, wherein the modified sugar comprises a bicyclic sugar.

16. The single-stranded modified oligonucleotide of claim 15, wherein the bicyclic sugar comprises a group selected from: .[.4'-CH(CH3)-O-2'.]. .Iadd.4'-CH(CH.sub.3)--O-2'.Iaddend., .[.4'-CH2-O-2'.]. .Iadd.4'-CH.sub.2--O-2'.Iaddend., and .[.4'-(CH2)2-O-2'.]. .Iadd.4'-(CH.sub.2).sub.2--O-2'.Iaddend..

17. The single-stranded modified oligonucleotide of claim 12, wherein each cytosine is a 5-methylcytosine.

18. The single-stranded modified oligonucleotide of claim 12, wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1.

19. The single-stranded modified oligonucleotide of claim 12, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.

20. The single-stranded modified oligonucleotide of claim 12, wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175.

21. The single-stranded modified oligonucleotide of claim 20, wherein each internucleoside linkage is a phosphorothioate linkage.

22. The single-stranded modified oligonucleotide of claim 20, wherein the modified sugar comprises a 2'-O-methoxyethyl sugar.

23. The single-stranded modified oligonucleotide of claim 20, wherein the modified sugar comprises a bicyclic sugar.

24. The single-stranded modified oligonucleotide of claim 23, wherein the bicyclic sugar comprises a group selected from: .[.4'-CH(CH3)-O-2'.]. .Iadd.4'-CH(CH.sub.3)--O-2'.Iaddend., .[.4'-CH2-O-2'.]. .Iadd.4'-CH.sub.2--O-2'.Iaddend., and .[.4'-(CH2)2-O-2'.]. .Iadd.4'-(CH.sub.2).sub.2--O-2'.Iaddend..

25. The single-stranded modified oligonucleotide of claim 20, wherein each cytosine is a 5-methylcytosine.

26. The single-stranded modified oligonucleotide of claim 20, wherein the modified oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 43, 124, 150, 155, 169, or 175, and wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5' wing segment consisting of 3 linked nucleosides; and a 3' wing segment consisting of 3 linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; wherein each nucleoside of each wing segment comprises a constrained ethyl nucleoside; wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage; and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine.

27. A method of treating cancer in a subject comprising administering to the subject the compound of claim 26, thereby treating cancer in the subject.

28. The method of claim 27, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer, or bladder cancer.

29. The method of claim 27, wherein the cancer is castrate-resistant prostate cancer.

30. The method of claim 29, wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700, and VT464.

.Iadd.31. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, wherein the modified oligonucleotide comprises: a gap segment consisting of 9 linked deoxynucleosides; a 5' wing segment consisting of three linked nucleosides; and a 3' wing segment consisting of four linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; wherein the sugars of the three linked nucleosides of the 5' wing segment are each a constrained ethyl (cEt) sugar; wherein the sugars of the four linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine..Iaddend.

.Iadd.32. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO: 39 and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, wherein the modified oligonucleotide comprises: a gap segment consisting of 7 linked deoxynucleosides; a 5' wing segment consisting of four linked nucleosides; and a 3' wing segment consisting of five linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment; wherein the sugars of the four linked nucleosides of the 5' wing segment are a 2'-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5' to 3' direction; wherein the sugars of the five linked nucleosides of the 3' wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2'-O-methoxyethyl sugar, and a 2'-O-methoxyethyl sugar in the 5' to 3' direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine..Iaddend.

.Iadd.33. A composition comprising the compound of claim 31 or claim 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier..Iaddend.

.Iadd.34. A combination comprising the compound of claim 31 or claim 32, or a pharmaceutically acceptable salt thereof, and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464..Iaddend.

.Iadd.35. The combination of claim 34, wherein the anti-androgenic agent is MDV3100..Iaddend.

.Iadd.36. A method of treating cancer comprising administering to a subject having cancer a compound or salt of claim 31 or claim 32, thereby treating cancer in the subject..Iaddend.

.Iadd.37. The method of claim 36, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer or bladder cancer..Iaddend.

.Iadd.38. The method of claim 36, wherein the cancer is castrate-resistant prostate cancer..Iaddend.

.Iadd.39. The method of claim 38, wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464..Iaddend.

.Iadd.40. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a compound or salt of claim 31 or claim 32 and an anti-androgenic agent..Iaddend.

.Iadd.41. The method of claim 40, wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464..Iaddend.

.Iadd.42. The method of claim 40, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell..Iaddend.

.Iadd.43. The method of claim 40, wherein the patient is administered an amount of the compound and an amount of anti-androgenic agent that are each or both less in combination than the amount of either the compound or anti-androgenic agent alone effective in inhibiting the growth or proliferation of said prostate cancer cell..Iaddend.

.Iadd.44. A method of inhibiting growth or proliferation of an androgen receptor (AR)-positive breast cancer cell comprising contacting the breast cancer cell with a compound or salt of claim 31 or claim 32 wherein the growth or proliferation of the breast cancer cell is inhibited..Iaddend.

.Iadd.45. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a composition of claim 33 and an anti-androgenic agent..Iaddend.

.Iadd.46. The method of claim 45, wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464..Iaddend.

.Iadd.47. The method of claim 41, wherein the anti-androgenic agent is MDV3100..Iaddend.

.Iadd.48. The method of claim 47, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell..Iaddend.

.Iadd.49. The method of claim 46, wherein the anti-androgenic agent is MDV3100..Iaddend.

.Iadd.50. The method of claim 49, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell..Iaddend.

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