AU2004229519B2

AU2004229519B2 - iRNA conjugates

Info

Publication number: AU2004229519B2
Application number: AU2004229519A
Authority: AU
Inventors: Sayda Elbashir; Jens Harborth; Muthiah Manoharan
Original assignee: Alnylam Pharmaceuticals Inc
Current assignee: Alnylam Pharmaceuticals Inc
Priority date: 2003-04-09
Filing date: 2004-04-09
Publication date: 2011-07-21
Anticipated expiration: 2024-04-09
Also published as: WO2004091515A2; WO2004091515A3; CA2521464A1; AU2004229519A1; CA2521464C

Abstract

Therapeutic iRNA agents and methods of making and using are enclosed.

Description

WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 iRNA CONJUGATES RELATED APPLICATIONS The present application claims the benefit of U.S. Provisional Application No. 60/462,097, filed April 9, 2003; U.S. Provisional Application No. 60/461,915, filed 5 April 10, 2003; UJ.S. Provisional Application No. 60/463,772, filed April 17, 2003; U.S. Provisional Application No. 60/465,802, filed April 25, 2003; U.S. Provisional Application No. 60/493,986, filed August 8, 2003; U.S. Provisional Application No. 60/494,597, filed August 11, 2003; U.S. Provisional Application No. 60/506,341, filed September 26, 2003; U.S. Provisional Application No. 60/518,453, filed November 7, 2003; U.S. Provisional Application 10 No. 60/469,612, filed May 9, 2003; U.S. Provisional Application No. 60/510,246, filed October 9, 2003; U.S. Provisional Application No. 60/510,318, filed October 10, 2003; U.S. Provisional Application No. 60/465,665, filed April 25, 2003; U.S. Provisional Application No. 60/462,894, filed April 14, 2003; International Application No. PCT/US4/07070, filed March 8, 2004; and International Application No. [xxxxxxJ, filed April 5, 2004. The contents of these applications 15 are hereby incorporated by reference in their entirety. TECHNICAL FIELD The invention relates to RNAi and related methods, e.g., methods of making and using iRNA agents. It includes methods and compositions for silencing genes expressed in the liver, and methods and compositions for directing iRNA agents to the liver. 20 BACKGROUND RNA interference or "RNAi" is a term initially coined by Fire and co-workers to describe the observation that double-stranded RNA (dsRNA) can block gene expression when it is introduced into worms (Fire et al., Nature 391:806-811, 1998). Short dsRNA directs gene specific, post-transcriptional silencing in many organisms, including vertebrates, and has 25 provided a new tool for studying gene function. RNAi may involve mRNA degradation. 1 2 Work in this field is typified by comparatively cumbersome approaches to delivery of dsRNA to live mammals. E.g., McCaffrey et al. (Nature 418:38-39, 2002) demonstrated the use of dsRNA to inhibit the expression of a luciferase reporter gene in mice. The dsRNAs were administered by the method of hydrodynamic tail vein injections (in addition, inhibition 5 appeared to depend on the injection of greater than 2 mg/kg dsRNA). The inventors have discovered, inter alia, that the unwieldy methods typical of some reported work are not needed to provide effective amounts of dsRNA to mammals and in particular not needed to provide therapeutic amounts of dsRNA to human subjects. The advantages of the current invention include practical, uncomplicated methods of administration and therapeutic applications, e.g., at 10 dosages of less than 2 mg/kg. SUMMARY The present invention provides the following items (1) to (15): 15 (1) An iRNA agent comprising a sense strand and an antisense strand, wherein the sense and antisense strands are complementary to each other, and wherein the sense strand comprises a sequence that is substantially identical to a sequence provided in Table 13, and the antisense strand comprises a sequence that is substantially identical to a sequence provided in Table 13, and wherein each strand of the iRNA agent is less 20 than 30 nucleotides in length. (2) The iRNA agent of item (1), wherein the sense strand and the antisense strand are selected from the group consisting of SEQ ID NO: 5497 and SEQ ID NO: 5544; 25 SEQ ID NO: 5499 and SEQ ID NO: 5546; SEQ ID NO: 5530 and SEQ ID NO: 5577; SEQ ID NO: 5533 and SEQ ID NO: 5580; SEQ ID NO: 5535 and SEQ ID NO: 5582; SEQ ID NO: 5558 and SEQ ID NO: 5511; 30 SEQ ID NO: 5503 and SEQ ID NO: 5550; SEQ ID NO: 5585 and SEQ ID NO: 5538; SEQ ID NO: 5573 and SEQ ID NO: 5526; SEQ ID NO: 5556 and SEQ ID NO: 5509; and SEQ ID NO: 5548 and SEQ ID NO: 5501. 35 2a (3) The iRNA agent of item (2), wherein the sense strand and the antisense strand are selected from the group consisting of SEQ ID NO: 5497 and SEQ ID NO: 5544; SEQ ID NO: 5530 and SEQ ID NO: 5577; s SEQ ID NO: 5533 and SEQ ID NO: 5580; SEQ ID NO: 5535 and SEQ ID NO: 5582; SEQ ID NO: 5558 and SEQ ID NO: 5511; SEQ ID NO: 5585 and SEQ ID NO: 5538; and SEQ ID NO: 5548 and SEQ ID NO: 5501. 10 (4) The iRNA agent of any one of items (1) to (3), for use in a method for reducing beta-catenin levels in a subject comprising administering to the subject the iRNA agent. (5) A method for reducing beta-catenin levels in a subject comprising administering 15 to the subject an iRNA agent of any one of items (1) to (3). (6) Use of an iRNA agent of any one of items (1) to (3) in the manufacture of a medicament for reducing beta-catenin levels in a subject. 20 (7) The iRNA agent of item (4), the method of item (5), or the use of item (6), wherein the subject has a disorder characterized by unwanted cellular proliferation in the liver or in a tissue of the liver. (8) The iRNA agent, method or use of item (7), wherein said disorder is chosen 25 from the group consisting of a hepatocellular carcinoma, a hepatic metastasis, and a hepatoblastoma. (9) The iRNA agent, method or use of any one of items (1) to (8), wherein said iRNA agent comprises one or more cholesterol moieties. 30 (10) The iRNA agent, method or use of item (9), wherein at least one cholesterol moiety is coupled to a sense strand of the iRNA agent. (11) The iRNA agent, method or use of any one of items (1) to (10), wherein the 35 sense strand and the antisense strand are at least 15 nucleotides in length. 2664219_1 (GHMatters) P58824.AU 2b (12) The iRNA agent, method or use of any one of items (1) to (11), wherein a duplex region of the iRNA agent is at least 15 nucleotides in length. (13) The iRNA agent, method or use of item (12), wherein a duplex region of the 5 iRNA agent is 19 to 21 nucleotides in length. (14) The iRNA agent, method or use of any one of items (1) to (13), wherein the iRNA agent comprises an overhang at one or both ends of the iRNA agent. 1o (15) The iRNA agent, method or use of item (14), wherein the overhang at one or both ends of the iRNA agent is two nucleotides in length. Described herein are compositions and methods for silencing genes expressed in the liver, e.g., to treat disorders of or related to the liver. An iRNA agent composition 15 of the invention can be one which has been modified to alter the distribution in favor of the liver. A composition of the invention includes an iRNA agent, e.g., an iRNA agent or sRNA agent described herein. Described herein is a method for reducing apoB-100 levels in a subject, e.g., a mammal, such as a human. The method includes administering to a subject an iRNA agent which targets apoB-100. The iRNA agent can be one described here, and can be a dsRNA that is substantially identical to a region of the apoB-100 gene. The iRNA can be less than 30 nucleotides in length, e.g., 21-23 nucleotides. Preferably, the iRNA is 21 nucleotides in length. In one embodiment, the iRNA is 21 nucleotides in length, and the duplex region of the iRNA is 19 nucleotides. In another embodiment, the iRNA is greater than 30 nucleotides in length. In a preferred embodiment, the subject is treated with an iRNA agent which targets one of the sequences listed in Tables 9 or 10. In a preferred embodiment it targets both sequences of a palindromic pair provided in Tables 9 or 10. The most preferred targets are listed in descending order of preferrability, in other words, the more preferred targets are listed earlier in Tables 9 or 10. 2864219.1 (GHMatters) P58824.AU WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In a preferred embodiment the iRNA agent will include regions, or strands, which are complementary to a pair in Tables 9 or 10. In a preferred embodiment the iRNA agent will include regions complementary to the palindromic pairs of Tables 9 or 10 as a duplex region. In a preferred embodiment the duplex region of the iRNA agent will target a sequence 5 listed in Tables 9 or 10 but will not be perfectly complementary with the target sequence, e.g., it will not be complementary at at least 1 base pair. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, in total, or per strand, which do not hybridize with the target sequence. The iRNA agent that targets apoB-100 can be administered in an amount sufficient to reduce expression of apoB-100 mRNA. In one embodiment, the iRNA agent is administered in 10 an amount sufficient to reduce expression of apoB-100 protein (e.g., by at least 2%, 4%, 6%, 10%, 15%, 20%). Preferably, the iRNA agent does not reduce expression of apoB-48 mRNA or protein. This can be effected, e.g., by selection of an iRNA agent which specifically targets the nucleotides subject to RNA editing in the apoB-100 transcript. The iRNA agent that targets apoB-100 can be administered to a subject, wherein the 15 subject is suffering from a disorder characterized by elevated or otherwise unwanted expression of apoB- 100, elevated or otherwise unwanted levels of cholesterol, and/or disregulation of lipid metabolism. The iRNA agent can be administered to an individual at risk for the disorder to delay onset of the disorder or a symptom of the disorder. These disorders include HDL/LDL cholesterol imbalance; dyslipidemias, e.g., familial combined hyperlipidemia (FCHL), acquired 20 hyperlipidemia; hypercholestorolemia; statin-resistant hypercholesterolemia; coronary artery disease (CAD) coronary heart disease (CHD) atherosclerosis. In one embodiment, the iRNA that targets apoB-100 is administered to a subject suffering from statin-resistant hypercholesterolemia. The apoB-100 iRNA agent can be administered in an amount sufficient to reduce levels 25 of serum LDL-C and/or HDL-C and/or total cholesterol in a subject. For example, the iRNA is administered in an amount sufficient to decrease total cholesterol by at least 0.5%, 1%, 2.5%, 5%, 10% in the subject. In one embodiment, the iRNA agent is administered in an amount sufficient to reduce the risk of myocardial infarction the subject. In a preferred embodiment the iRNA agent is administered repeatedly. Administration of 30 an iRNA agent can be carried out over a range of time periods. It can be administered daily, once every few days, weekly, or monthly. The timing of administration can vary from patient to 3 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 patient, depending on such factors as the severity of a patient's symptoms. For example, an effective dose of an iRNA agent can be administered to a patient once a month for an indefinite period of time, or until the patient no longer requires therapy. In addition, sustained release compositions containing an iRNA agent can be used to maintain a relatively constant dosage in 5 the patient's blood. In one embodiment, the iRNA agent can be targeted to the liver, and apoB expression level are decreased in the liver following administration of the apoB iRNA agent. For example, the iRNA agent can be complexed with a moiety that targets the liver, e.g., an antibody or ligand that binds a receptor on the liver. 10 The iRNA agent, particularly an iRNA agent that targets apoB, beta-catenin or glucose-6 phosphatase RNA, can be targeted to the liver, for example by associating, e.g., conjugating the iRNA agent to a lipophilic moiety, e.g., a lipid, cholesterol, oleyl, retinyl, or cholesteryl residue. Other lipophilic moieties that can be associated, e.g., conjugated with the iRNA agent include cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis 15 O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3 propanediol, heptadecyl group, palmitic acid, myristic acid,03-(oleoyl)lithocholic acid, 03 (oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine. In one embodiment, the iRNA agent can be targeted to the liver by associating, e.g., conjugating, the iRNA agent to a low-density lipoprotein (LDL), e.g., a lactosylated LDL. In another embodiment, the iRNA agent can be 20 targeted to the liver by associating, e.g., conjugating, the iRNA agent to a polymeric carrier complex with sugar residues. In another embodiment, the iRNA agent can be targeted to the liver by associating, e.g., conjugating, the iRNA agent to a liposome complexed with sugar residues. A targeting agent that incorporates a sugar, e.g., galactose and/or analogues thereof, is particularly useful. These 25 agents target, in particular, the parenchymal cells of the liver (see Table 1). In a preferred embodiment, the targeting moiety includes more than one galactose moiety, preferably two or three. Preferably, the targeting moiety includes 3 galactose moieties, e.g., spaced about 15 angstroms from each other. The targeting moiety can be lactose. A lactose is a glucose coupled to a galactose. Preferably, the targeting moiety includes three lactoses. The targeting moiety can 30 also be N-Acetyl-Galactosamine, N-Ac-Glucosamine. A mannose, or mannose-6-phosphate targeting moiety can be used for macrophage targeting. 4 The targeting agent can be linked directly, e.g., covalently or non covalently, to the iRNA agent, or to another delivery or formulation modality, e.g., a liposome. E.g., the iRNA agents with or without a targeting moiety can be incorporated into a delivery modality, e.g., a liposome, with or without a targeting moiety. 5 It is particularly preferred to use an iRNA conjugated to a lipophilic molecule to conjugate to an iRNA agent that targets apoB, beta-catenin or glucose-6-phosphatase iRNA targeting agent. In one embodiment, the iRNA agent has been modified, or is associated with a delivery agent, e.g., a delivery agent described herein, e.g., a liposome, which has been modified to alter 10 distribution in favor of the liver. In one embodiment, the modification mediates association with a serum albumin (SA), e.g., a human serum albumin (HSA), or a fragment thereof. The iRNA agent, particularly an iRNA agent that targets apoB, beta-catenin or glucose-6 phosphatase RNA, can be targeted to the liver, for example by associating, e.g., conjugating the iRNA agent to an SA molecule, e.g., an HSA molecule, or a fragment thereof. In one 15 embodiment, the iRNA agent or composition thereof has an affinity for an SA, e.g., HSA, which is sufficiently high such that its levels in the liver are at least 10, 20, 30, 50, or 100% greater in the presence of SA, e.g., HSA, or is such that addition of exogenous SA will increase delivery to the liver. These criteria can be measured, e.g., by testing distribution in a mouse in the presence or absence of exogenous mouse or human SA. 20 The SA, e.g., HSA, targeting agent can be linked directly, e.g., covalently or non covalently, to the iRNA agent, or to another delivery or formulation modality, e.g., a liposome. E.g., the iRNA agents with or without a targeting moiety can be incorporated into a delivery modality, e.g., a liposome, with or without a targeting moiety. It is particularly preferred to use an iRNA conjugated to an SA, e.g., an HSA, molecule 25 wherein the iRNA agent is an apoB, beta-catenin or glucose-6-phosphatase iRNA targeting agent. Also described herein is a method for reducing glucose-6-phosphatase levels in a subject, e.g., a mammal, such as a human. The method includes administering to a subject an iRNA agent which targets glucose-6-phosphatase. The iRNA agent can be a dsRNA 30 that has a sequence that is substantially identical to a sequence of the glucose-6 phosphatase gene. 5 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In a preferred embodiment, the subject is treated with an iRNA agent that targets one of the sequences listed in Table 11. In a preferred embodiment it targets both sequences of a palindromic pair provided in Table 11. The most preferred targets are listed in descending order of preferability, in other words, the more preferred targets are listed earlier in Table 11. 5 In a preferred embodiment the iRNA agent will include regions, or strands, which are complementary to a pair in Table 11. In a preferred embodiment the iRNA agent will include regions complementary to the palindromic pairs of Table 11 as a duplex region. In a preferred embodiment the duplex region of the iRNA agent will target a sequence listed in Table 11 but will not be perfectly complementary with the target sequence, e.g., it will 10 not be complementary at at least 1 base pair. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, in total, or per strand, which do not hybridize with the target sequence In a preferred embodiment the iRNA agent includes overhangs, e.g., 3' or 5' overhangs, preferably one or more 3' overhangs. Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in length. The overhangs can be complementary to the gene 15 sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. Table 11 refers to sequences from human glucose-6-phosphatase. Table 12 refers to sequences from rat glucose-6-phosphatase. The sequences from table t2 can be used, e.g., in 20 experiments with rats or cultured rat cells. In a preferred embodiment iRNA agent can have any architecture, e.g., architecture described herein. E.g., it can be incorporated into an iRNA agent having an overhang structure, overall length, hairpin vs. two-strand structure, as described herein. In addition, monomers other than naturally occurring ribonucleotides can be used in the selected iRNA agent. 25 The iRNA that targets glucose-6-phosphatase can be administered in an amount sufficient to reduce expression of glucose-6-phosphatase mRNA. The iRNA that targets glucose-6-phosphatase can be administered to a subject to inhibit hepatic glucose production, for the treatment of glucose-metabolism-related disorders, such as diabetes, e.g., type-2-diabetes mellitus. The iRNA agent can be administered to an individual at 30 risk for the disorder to delay onset of the disorder or a symptom of the disorder. 6 In other embodiments, iRNA agents having sequence similarity to the following genes can also be used to inhibit hepatic glucose production. These other genes include "forkhead homologue in rhabdomyosarcoma (FKHR); glucagon; glucagon receptor; glycogen phosphorylase; PPAR-Gamma Coactivator (PGC-1); Fructose-1,6-bisphosphatase; glucose-6 5 phosphate locator; glucokinase inhibitory regulatory protein; and phosphoenolpyruvate carboxykinase (PEPCK). In one embodiment, the iRNA agent can be targeted to the liver, and RNA expression levels of the targeted genes are decreased in the liver following administration of the iRNA agent. 10 The iRNA agent can be one described herein, and can be a dsRNA that has a sequence that is substantially identical to a sequence of a target gene. The iRNA can be less than 30 nucleotides in length, e.g., 21-23 nucleotides. Preferably, the iRNA is 21 nucleotides in length. In one embodiment, the iRNA is 21 nucleotides in length, and the duplex region of the iRNA is 19 nucleotides. In another embodiment, the iRNA is greater than 30 nucleotides in length. 15 Described herein is a method for reducing beta-catenin levels in a subject, e.g., a mammal, such as a human. The method includes administering to a subject an iRNA agent that targets beta-catenin. The iRNA agent can be one described herein, and can be a dsRNA that has a sequence that is substantially identical to a sequence of the beta-catenin gene. The iRNA can be less than 30 nucleotides in length, e.g., 21-23 nucleotides. Preferably, the 20 iRNA is 21 nucleotides in length. In one embodiment, the iRNA is 21 nucleotides in length, and the duplex region of the iRNA is 19 nucleotides. In another embodiment, the iRNA is greater than 30 nucleotides in length. In a preferred embodiment, the subject is treated with an iRNA agent which targets one of the sequences listed in Table 13. In a preferred embodiment it targets both sequences of a 25 palindromic pair provided in Table 13. The most preferred targets are listed in descending order of preferrability, in other words, the more preferred targets are listed earlier in Table 13. In a preferred embodiment the iRNA agent will include regions, or strands, which are complementary to a pair in Table 13. In a preferred embodiment the iRNA agent will include regions complementary to the palindromic pairs of Table 13 as a duplex region. 30 In a preferred embodiment the duplex region of the iRNA agent will target a sequence listed in Table 13 but will not be perfectly complementary with the target sequence, e.g., it will 7 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 not be complementary at at least 1 base pair. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, in total, or per strand, which do not hybridize with the target sequence In a preferred embodiment the iRNA agent includes overhangs, e.g., 3' or 5' overhangs, preferably one or more 3' overhangs. Overhangs are discussed in detail elsewhere herein but are 5 preferably about 2 nucleotides in length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. The iRNA agent that targets beta-catenin can be administered in an amount sufficient to 10 reduce expression of beta-catenin mRNA. In one embodiment, the iRNA agent is administered in an amount sufficient to reduce expression of beta-catenin protein (e.g., by at least 2%, 4%, 6%, 10%, 15%, 20%). The iRNA agent that targets beta-catenin can be administered to a subject, wherein the subject is suffering from a disorder characterized by unwanted cellular proliferation in the liver 15 or of liver tissue, e.g., metastatic tissue originating from the liver. Examples include, a benign or malignant disorder, e.g., a cancer, e.g., a hepatocellular carcinoma (HCC), hepatic metastasis, or hepatoblastoma. The iRNA agent can be administered to an individual at risk for the disorder to delay onset of the disorder or a symptom of the disorder 20 In a preferred embodiment the iRNA agent is administered repeatedly. Administration of an iRNA agent can be carried out over a range of time periods. It can be administered daily, once every few days, weekly, or monthly. The timing of administration can vary from patient to patient, depending on such factors as the severity of a patient's symptoms. For example, an effective dose of an iRNA agent can be administered to a patient once a month for an indefinite 25 period of time, or until the patient no longer requires therapy. In addition, sustained release compositions containing an iRNA agent can be used to maintain a relatively constant dosage in the patient's blood. In one embodiment, the iRNA agent can be targeted to the liver, and beta-catenin expression level are decreased in the liver following administration of the beta-catenin iRNA 30 agent. For example, the iRNA agent can be complexed with a moiety that targets the liver, e.g., an antibody or ligand that binds a receptor on the liver. 8 Described herein are methods to treat liver disorders, e.g., disorders characterized by unwanted cell proliferation, hematological disorders, disorders characterized by inflammation disorders, and metabolic or viral diseases or disorders of the liver. A proliferation disorder of the liver can be, for example, a benign or malignant disorder, e.g., a cancer, e.g, a 5 hepatocellular carcinoma (HCC), hepatic metastasis, or hepatoblastoma. A hepatic hematology or inflammation disorder can be a disorder involving clotting factors, a complement-mediated inflammation or a fibrosis, for example. Metabolic diseases of the liver can include dyslipidemias, and irregularities in glucose regulation. Viral diseases of the liver can include hepatitis C or hepatitis B. In one embodiment, a liver disorder is treated by administering one or 10 more iRNA agents that have a sequence that is substantially identical to a sequence in a gene involved in the liver disorder. In one embodiment an iRNA agent to treat a liver disorder has a sequence which is substantially identical to a sequence of the beta-catenin or c-jun gene. In another embodiment, such as for the treatment of hepatitis C or hepatitis B, the iRNA agent can have a sequence that is 15 substantially identical to a sequence of a gene of the hepatitis C virus or the hepatitis B virus, respectively. For example, the iRNA agent can target the 5' core region of HCV. This region lies just downstream of the ribosomal toe-print straddling the initiator methionine. Alternatively, an iRNA agent described herein can target any one of the nonstructural proteins of HCV: NS3, 4A, 4B, 5A, or 5B. For the treatment of hepatitis B, an iRNA agent can target the 20 protein X (HBx) gene, for example. In a preferred embodiment, the subject is treated with an iRNA agent which targets one of the sequences listed in Table 14. In a preferred embodiment it targets both sequences of a palindromic pair provided in Table 14. The most preferred targets are listed in descending order of preferrability, in other words, the more preferred targets are listed earlier in Table 14. 25 In a preferred embodiment the iRNA agent will include regions, or strands, which are complementary to a pair in Table 14. In a preferred embodiment the iRNA agent will include regions complementary to the palindromic pairs of Table 14 as a duplex region. In a preferred embodiment the duplex region of the iRNA agent will target a sequence listed in Table 14, but will not be perfectly complementary with the target sequence, e.g., it will 30 not be complementary at at least 1 base pair. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, in total, or per strand, which do not hybridize with the target sequence 9 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In a preferred embodiment the iRNA agent includes overhangs, e.g., 3' or 5' overhangs, preferably one or more 3' overhangs. Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The 5 first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. In another aspect, an iRNA agent can be administered to modulate blood clotting, e.g., to reduce the tendency to form a blood clot. In a preferred embodiment the iRNA agent targets Factor V expression, preferably in the liver. One or more iRNA agents can be used to target a 10 wild type allele, a mutant allele, e.g., the Leiden Factor V allele, or both. Such administration can be used to treat or prevent venous thrombosis, e.g., deep vein thrombosis or pulmonary embolism, or another disorder caused by elevated or otherwise unwanted expression of Factor V, in, e.g., the liver. In one embodiment the iRNA agent can treat a subject, e.g., a human who has Factor V Leiden or other genetic trait associated with an unwanted tendency to form blood clots. 15 In a preferred embodiment administration of an iRNA agent which targets Factor V is with the administration of a second treatment, e.g, a treatment which reduces the tendency of the blood to clot, e.g., the administration of heparin or of a low molecular weight heparin. In one embodiment, the iRNA agent that targets Factor V can be used as a prophylaxis in patients, e.g., patients with Factor V Leiden, who are placed at risk for a thrombosis, e.g., those 20 about to undergo surgery, in particular those about to undergo high-risk surgical procedures known to be associated with formation of venous thrombosis, those about to undergo a prolonged period of relative inactivity, e.g., on a motor vehicle, train or airplane flight, e.g., a flight or other trip lasting more than three or five hours. Such a treatment can be an adjunct to the therapeutic use of low molecular weight (LMW) heparin prophylaxis. 25 In another embodiment, the iRNA agent that targets Factor V can be administered to patients with Factor V Leiden to treat deep vein thrombosis (DVT) or pulmonary embolism (PE). Such a treatment can be an adjunct to (or can replace) therapeutic uses of heparin or coumadin. The treatment can be administered by inhalation or generally by pulmonary routes. In a preferred embodiment, an iRNA agent administered to treat a liver disorder is 30 targeted to the liver. For example, the iRNA agent can be complexed with a targeting moiety, e.g., an antibody or ligand that recognizes a liver-specific receptor. 10 Also described herein are ;preparations, including substantially pure or pharmaceutically acceptable preparations of iRNA agents which silence any of the genes discussed herein and in particular for any of apoB-100, glucose-6-phosphatase, beta-catenin, factor V, or any of the HVC genes discussed herein 5 The methods and compositions described herein e.g., the methods and compositions to treat diseases and disorders of the liver described herein, can be used with any of the iRNA agents described. In addition, the methods and compositions of the invention can be used for the treatment of any disease or disorder described herein, and for the treatment of any subject, e.g., any animal, any mammal, such as any human. 10 The methods and compositions of the invention, e.g., the methods and iRNA compositions to treat liver-based diseases described herein, can be used with any dosage and/or formulation described herein, as well as with any route of administration described herein. A "substantially identical" sequence includes a region of sufficient homology to the target gene, and is of sufficient length in terms of nucleotides, that the iRNA agent, or a fragment 15 thereof, can mediate down regulation of the target gene. Thus, the iRNA agent is or includes a region which is at least partially, and in some embodiments fully, complementary to a target RNA transcript. It is not necessary that there be perfect complementarity between the iRNA agent and the target, but the correspondence must be sufficient to enable the iRNA agent, or a cleavage product thereof, to direct sequence specific silencing, e.g., by RNAi cleavage of the 20 target RNA, e.g., mRNA. Complementarity, or degree of homology with the target strand, is most critical in the antisense strand. While perfect complementarity, particularly in the antisense strand, is often desired some embodiments can include, particularly in the antisense strand, one or more but preferably 6, 5, 4, 3, 2, or fewer mismatches (with respect to the target RNA). The mismatches, particularly in the antisense strand, are most tolerated in the terminal regions and if 25 present are preferably in a terminal region or regions, e.g., within 6, 5, 4, or 3 nucleotides of the 5' and/or 3' terminus. The sense strand need only be sufficiently complementary with the antisense strand to maintain the over all double strand character of the molecule. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, and advantages of 30 the invention will be apparent from this description, and from the claims. This application 11 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 incorporates all cited references, patents, and patent applications by references in their entirety for all purposes. BRIEF DESCRIPTION OF THE DRAWINGS 5 FIG 1 is a structural representation of base pairing in psuedocomplementary siRNA. FIG. 2 is a schematic representation of dual targeting siRNAs designed to target the HCV genome. FIG. 3 is a schematic representation of psuedocomplementary, bifunctional siRNAs designed to target the HCV genome. 10 FIG. 4 is a general synthetic scheme for incorporation of RRMS monomers into an oligonucleotide. FIG. 5 is a table of representative RRMS carriers. Panel 1 shows pyrroline-based RRMSs; panel 2 shows 3-hydroxyproline-based RRMSs; panel 3 shows piperidine-based RRMSs; panel 4 shows morpholine and piperazine-based RRMSs; and panel 5 shows decalin 15 based RRMSs. R1 is succinate or phosphoramidate and R2 is H or a conjugate ligand. FIG. 6A is a graph depicting blood glucose levels in mice treated with nonspecific Renilla RNA or not treated with siRNA. Mice treated with nonspecific Renilla RNA were injected on Day 7. FIG 6B is a graph depicting blood glucose levels in mice treated with siRNA targeting 20 glucose 6-phosphatase. Mice treated with siRNA targeting glucose 6-phosphatase were injected on Day 7. FIG 6C is a graph depicting blood glucose levels in mice that were either not injected with siRNA, or were injected but the injection failed. Mice that were injected, were injected on Day 7. 25 FIG 7 is a graph depicting average blood glucose levels in four mice treated with siRNA targeting glucose 6-phosphatase, and in four mice either treated with nonspecific Renilla RNA or not treated with siRNA (triangles). siRNA or Renilla RNA was administered on day 7 by hydrodynamic tail vein injection. FIG 8A is a graph depicting levels of luciferase mRNA in livers of CMV-Luc mice 30 (Xanogen) following intervenous injection (iv) of buffer or siRNA into the tail vein. Each bar represents data from one mouse. RNA levels were quantified by QuantiGene Assay 12 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (Genospectra, Inc.; Fremont, CA)). The Y axis represents chemiluminescence values in counts per second (CPS). FIG. 8B is a graph depicting levels of luciferase mRNA in livers of CMV-Luc mice (Xanogen). The values are averaged from the data depicted in FIG. 8A. 5 FIG 9 is a graph depicting the pharmacokinetics of cholesterol-conjugated and unconjugated siRNA. The diamonds represent the amount of unconjugated 33P-labeled siRNA (ALN-3000) in mouse plasma over time; the squares represent the amount of cholesterol conjugated 33 P-labeled siRNA (ALN-3001) in mouse plasma overtime. "L1163" is equivalent to ALN3000; "Ll163Chol" is equivalent to ALN-3001. 10 FIG. 10 is a graph indicating the amount of cholesterol-conjugated (dark bars) and unconjugated siRNA (light bars) detected in mouse whole liver tissue isolated over a period of time following intravenous tail vein injection. The amount of siRNA is represented as a percentage of the total dose or 33 P-labeled siRNA delivered to the mouse. "L1163" is equivalent to ALN3000 (light bars); "L1163Chol" is equivalent to ALN-3001 (dark bars). 15 FIG. 11 is a graph indicating the amount of cholesterol-conjugated siRNA detected in various tissues of two different CMV-Luc mice ("Mouse 69" (light bars) and "Mouse 63" (dark bars)). Mice were injected with 50 mg/kg AL-3001 siRNA by intravenous tail vein injection, and tissue was harvested 22 hours later. SiRNA was detected by RNAse protection, and phosphorimager scanning was used to quantitate the siRNA. The amount of siRNA is expressed 20 as ug/g liver tissue. FIG. 12 is a gel of U/U siRNA (see Table 19) detected in the liver of Balbc mice at increasing time points following hydrodynamic (hd) tail vein injection. U/U siRNA was injected at a concentration of 4 mg/kg. siRNA was detected by RNAse protection assay. Lanes labeled "stand." were loaded with clean siRNA to serve as size and quality standards. "non" represents 25 control samples isolated from livers of mice that were not injected with U/U siRNA. The control samples were further used in parallel RNAse protection assays. FIG. 13 is a gel comparing different siRNA species detected in the livers of Balbc mice at increasing time points following hydrodynamic (hd) or nonhydrodynamic (iv) tail vein injection. U/U siRNA was injected by hd and by iv injection. 3'C/3'C and 3'C/U (see Table 19) were each 30 injected by iv injection. at a concentration of 4 mg/kg. siRNA was detected by RNAse protection assay. Lanes labeled "stand." were loaded with clean siRNA to serve as size and 13 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 quality standards. "non" represents control samples isolated from livers of mice that were not injected with siRNA. The control samples were further used in parallel RNAse protection assays. FIG. 14 is a graph depicting the percentage of luciferase activity in liver extracts of CMV 5 Luc mice injected with siRNA (ALN-3001). Percentage of luciferase activity was relative to activity in CMV-Luc mice injected with PBS, pH 4.7. "Bufferl siRNA1," "Buffer2 siRNA2," and "Buffer3 siRNA3" represent the average activity observed in three separate experiments. DETAILED DESCRIPTION 10 Double-stranded (dsRNA) directs the sequence-specific silencing of mRNA through a process known as RNA interference (RNAi). The process occurs in a wide variety of organisms, including mammals and other vertebrates. It has been demonstrated that 21-23 nt fragments of dsRNA are sequence-specific mediators of RNA silencing, e.g., by causing RNA degradation. While not wishing to be bound 15 by theory, it may be that a molecular signal, which may be merely the specific length of the fragments, present in these 21-23 nt fragments recruits cellular factors that mediate RNAi. Described herein are methods for preparing and administering these 21-23 nt fragments, and other iRNAs agents, and their use for specifically inactivating gene function. The use of iRNAs agents (or recombinantly produced or chemically synthesized oligonucleotides of the same or 20 similar nature) enables the targeting of specific mRNAs for silencing in mammalian cells. In addition, longer dsRNA agent fragments can also be used, e.g., as described below. Although, in mammalian cells, long dsRNAs can induce the interferon response which is frequently deleterious, sRNAs do not trigger the interferon response, at least not to an extent that is deleterious to the cell and host. In particular, the length of the iRNA agent strands in an sRNA 25 agent can be less than 31, 30, 28, 25, or 23 nt, e.g., sufficiently short to avoid inducing a deleterious interferon response. Thus, the administration of a composition of sRNA agent (e.g., formulated as described herein) to a mammalian cell can be used to silence expression of a target gene while circumventing the interferon response. Further, use of a discrete species of iRNA 14 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 agent can be used to selectively target one allele of a target gene, e.g., in a subject heterozygous for the allele. Moreover, in one embodiment, a mammalian cell is treated with an iRNA agent that disrupts a component of the interferon response, e.g., double stranded RNA (dsRNA)-activated 5 protein kinase PKR. Such a cell can be treated with a second iRNA agent that includes a sequence complementary to a target RNA and that has a length that might otherwise trigger the interferon response. In a typical embodiment, the subject is a mammal such as a cow, horse, mouse, rat, dog, pig, goat, or a primate. The subject can be a dairy manual (e.g., a cow, or goat) or other farmed 10 animal (e.g., a chicken, turkey, sheep, pig, fish, shrimp). In a much preferred embodiment, the subject is a human, e.g., a normal individual or an individual that has, is diagnosed with, or is predicted to have a disease or disorder. Further, because iRNA agent mediated silencing persists for several days after administering the iRNA agent composition, in many instances, it is possible to administer the 15 composition with a frequency of less than once per day, or, for some instances, only once for the entire therapeutic regimen. For example, treatment of some cancer cells may be mediated by a single bolus administration, whereas a chronic viral infection may require regular administration, e.g., once per week or once per month. A number of exemplary routes of delivery are described that can be used to administer an 20 iRNA agent to a subject. In addition, the iRNA agent can be formulated according to an exemplary method described herein. Liver Diseases Exemplary diseases and disorders that can be treated by the methods and compositions of the invention are liver-based diseases. 25 Disorders involving the liver include, but are not limited to, hepatic injury; jaundice and cholestasis, such as bilirubin and bile formation; hepatic failure and cirrhosis, such as cirrhosis, portal hypertension, including ascites, portosystemic shunts, and splenomegaly; infectious disorders, such as viral hepatitis, including hepatitis A-E infection and infection by other 15 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 hepatitis viruses, clinicopathologic syndromes, such as the carrier state, asymptomatic infection, acute viral hepatitis, chronic viral hepatitis, and fulminant hepatitis; autoimmune hepatitis; drug and toxin-induced liver disease, such as alcoholic liver disease; inborn errors of metabolism and pediatric liver disease, such as hemochromatosis, Wilson disease, al-antitrypsin deficiency, and 5 neonatal hepatitis; intrahepatic biliary tract disease, such as secondary biliary cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, and anomalies of the biliary tree; circulatory disorders, such as impaired blood flow into the liver, including hepatic artery compromise and portal vein obstruction and thrombosis, impaired blood flow through the liver, including passive congestion and centrilobular necrosis and peliosis hepatis, hepatic vein outflow obstruction, 10 including hepatic vein thrombosis (Budd-Chiari syndrome) and veno-occlusive disease; hepatic disease associated with pregnancy, such as preeclampsia and eclampsia, acute fatty liver of pregnancy, and intrehepatic cholestasis of pregnancy; hepatic complications of organ or bone marrow transplantation, such as drug toxicity after bone marrow transplantation, graft-versus host disease and liver rejection, and nonimmunologic damage to liver allografts; tumors and 15 tumorous conditions, such as nodular hyperplasias, adenomas, and malignant tumors, including primary carcinoma of the liver and metastatic tumors. An iRNA agent can also be administered to inhibit Factor V expression in the liver. Two to five percent of the United States population is heterozygous for an allele of the Factor V gene that encodes a single amino acid change at position 1961. These heterozygous individuals have a 20 3-8 fold increased risk of venous thrombosis, a risk that is associated with increased factor V activity. The increased activity leads to increased thrombin generation from the prothrombinase complex. An iRNA agent directed against Factor V can treat or prevent venous thrombosis or treat a human who has Factor V Leiden. The iRNA agent that targets Factor V can be also be used as a prophylaxis in patients with Factor V Leiden who undergo high-risk surgical 25 procedures, and this prophylaxis can be an adjunct to the therapeutic use of low molecular weight (LMW) heparin prophylaxis. An iRNA agent that targets Factor V can also be administered to patients with Factor V Leiden to treat deep vein thrombosis (DVT) or pulmonary embolism (PE), and this treatment can be an adjunct to therapeutic uses of heparin or coumadin. Any other disorder caused by elevated 30 or otherwise unwanted levels of Factor V protein can be treated by administering an iRNA agent against Factor V. 16 iRNA agents described herein can be targeted to any gene whose overexpression is associated with the liver diseases. Targeting to the Liver 5 The iRNA agents described herein are particularly useful when targeted to the liver. An iRNA agent can be targeted to the liver through a composition that includes the iRNA agent and a liver-targeting agent. For example, a liver-targeting agent can be a lipophilic moiety. Preferred lipophilic moieties include lipid, cholesterols, oleyl, retinyl, or cholesteryl residues (see Table 1). Other lipophilic moieties that can function as liver-targeting agents include cholic acid, 10 adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3 propanediol, heptadecyl group, palnitic acid, myristic acid,03-(oleoyl)lithocholic acid, 03 (oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine. An iRNA agent can also be targeted to the liver by association with a low-density 15 lipoprotein (LDL), such as lactosylated LDL. Polymeric carriers complexed with sugar residues can also function to target iRNA agents to the liver. A targeting agent that incorporates a sugar, e.g., galactose and/or analogues thereof, is particularly useful. These agents target, in particular, the parenchymal cells of the liver (see Table 1). For example, a targeting moiety can include more than one or preferably two or three 20 galactose moieties, spaced about 15 angstroms from each other. The targeting moiety can alternatively be lactose (e.g., three lactose moieties), which is glucose coupled to a galactose. The targeting moiety can also be N-Acetyl-Galactosamine, N-Ac-Glucosamine. A mannose or mannose-6-phosphate targeting moiety can be used for macrophage targeting. Conjugation of an iRNA agent with a serum albumin (SA), such as human serum 25 albumin, can also be used to target the iRNA agent to the liver. An iRNA agent can be targeted to a particular cell type in the liver by using specific targeting agents, which recognize particular receptors in the liver. Exemplary targeting moieties and their associated receptors are presented in Table 1. 17 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Table 1 Targeting agents (Ligands) and their associated receptors Liver Cells Ligand Receptor 1) Parenchymal Cell (PC) Galactose ASGP-R (Hepatocytes) (Asiologlycoprotein receptor) Gal NAc ASPG-R (n-acetyl-galactosamine) Gal NAc Receptor Lactose Asialofetuin ASPG-r 2) Sinusoidal Endothelial Hyaluronan Hyaluronan receptor Cell (SEC) Procollagen Procollagen receptor Negatively charged Scavenger receptors molecules Mannose Mannose receptors N-acetyl Glucosamine Scavenger receptors Immunoglobulins Fc Receptor LPS CD14 Receptor Insulin Receptor mediated transcytosis Transferrin Receptor mediated transcytosis Albumins Non-specific Sugar-Albumin conjugates Mannose-6-phosphate Mannose-6-phosphate receptor 3) Kupffer Cell (KC) Mannose Mannose receptors Fucose Fucose receptors Albumins Non-specific Mannose-albumin conjugates 5 iRNA AGENT STRUCTURE Described herein are isolated iRNA agents, e.g., RNA molecules, (double-stranded; single-stranded) that mediate RNAi. The iRNA agents preferably mediate RNAi with respect to an endogenous gene of a subject or to a gene of a pathogen. An "RNA agent" as used herein, is an unmodified RNA, modified RNA, or nucleoside 10 surrogate, all of which are defined herein (see, e.g., the section below entitled RNA Agents). While numerous modified RNAs and nucleoside surrogates are described, preferred examples 18 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 include those which have greater resistance to nuclease degradation than do unmodified RNAs. Preferred examples include those which have a 2' sugar modification, a modification in a single strand overhang, preferably a 3' single strand overhang, or, particularly if single stranded, a 5' modification which includes one or more phosphate groups or one or more analogs of a 5 phosphate group. An "iRNA agent" as used herein, is an RNA agent which can, or which can be cleaved into an RNA agent which can, down regulate the expression of a target gene, preferably an endogenous or pathogen target RNA. While not wishing to be bound by theory, an iRNA agent may act by one or more of a number of mechanisms, including post-transcriptional cleavage of a 10 target mRNA sometimes referred to in the art as RNAi, or pre-transcriptional or pre-translational mechanisms. An iRNA agent can include a single strand or can include more than one strands, e.g., it can be a double stranded iRNA agent. If the iRNA agent is a single strand it is particularly preferred that it include a 5' modification which includes one or more phosphate groups or one or more analogs of a phosphate group. 15 The iRNA agent should include a region of sufficient homology to the target gene, and be of sufficient length in terms of nucleotides, such that the iRNA agent, or a fragment thereof, can mediate down regulation of the target gene. (For ease of exposition the term nucleotide or ribonucleotide is sometimes used herein in reference to one or more monomeric subunits of an RNA agent. It will be understood herein that the usage of the term "ribonucleotide" or 20 "nucleotide", herein can, in the case of a modified RNA or nucleotide surrogate, also refer to a modified nucleotide, or surrogate replacement moiety at one or more positions.) Thus, the iRNA agent is or includes a region which is at least partially, and in some embodiments fully, complementary to the target RNA. It is not necessary that there be perfect complementarity between the iRNA agent and the target, but the correspondence must be sufficient to enable the 25 iRNA agent, or a cleavage product thereof, to direct sequence specific silencing, e.g., by RNAi cleavage of the target RNA, e.g., mRNA. Complementarity, or degree of homology with the target strand, is most critical in the antisense strand. While perfect complementarity, particularly in the antisense strand, is often desired some embodiments can include, particularly in the antisense strand, one or more but 19 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 preferably 6, 5, 4, 3, 2, or fewer mismatches (with respect to the target RNA). The mismatches, particularly in the antisense strand, are most tolerated in the terminal regions and if present are preferably in a terminal region or regions, e.g., within 6, 5, 4, or 3 nucleotides of the 5' and/or 3' terminus. The sense strand need only be sufficiently complementary with the antisense strand to 5 maintain the over all double strand character of the molecule. As discussed elsewhere herein, an iRNA agent will often be modified or include nucleoside surrogates in addition to the RRMS. Single stranded regions of an iRNA agent will often be modified or include nucleoside surrogates, e.g., the unpaired region or regions of a hairpin structure, e.g., a region which links two complementary regions, can have modifications 10 or nucleoside surrogates. Modification to stabilize one or more 3'- or 5'-terminus of an iRNA agent, e.g., against exonucleases, or to favor the antisense sRNA agent to enter into RISC are also favored. Modifications can include C3 (or C6, C7, C12) amino linkers, thiol linkers, carboxyl linkers, non-nucleotidic spacers (C3, C6, C9, C12, abasic, triethylene glycol, hexaethylene glycol), special biotin or fluorescein reagents that come as phosphoramidites and 15 that have another DMT-protected hydroxyl group, allowing multiple couplings during RNA synthesis. iRNA agents include: molecules that are long enough to trigger the interferon response (which can be cleaved by Dicer (Bernstein et al. 2001. Nature, 409:363-366) and enter a RISC (RNAi-induced silencing complex)); and, molecules which are sufficiently short that they do not 20 trigger the interferon response (which molecules can also be cleaved by Dicer and/or enter a RISC), e.g., molecules which are of a size which allows entry into a RISC, e.g., molecules which resemble Dicer-cleavage products. Molecules that are short enough that they do not trigger an interferon response are termed sRNA agents or shorter iRNA agents herein. "sRNA agent or shorter iRNA agent" as used herein, refers to an iRNA agent, e.g., a double stranded RNA agent 25 or single strand agent, that is sufficiently short that it does not induce a deleterious interferon response in a human cell, e.g., it has a duplexed region of less than 60 but preferably less than 50, 40, or 30 nucleotide pairs. The sRNA agent, or a cleavage product thereof, can down regulate a target gene, e.g., by inducing RNAi with respect to a target RNA, preferably an endogenous or pathogen target RNA. 20 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Each strand of an sRNA agent can be equal to or less than 30, 25, 24, 23, 22, 21, or 20 nucleotides in length. The strand is preferably at least 19 nucleotides in length. For example, each strand can be between 21 and 25 nucleotides in length. Preferred sRNA agents have a duplex region of 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs, and one or more 5 overhangs, preferably one or two 3' overhangs, of 2-3 nucleotides. In addition to homology to target RNA and the ability to down regulate a target gene, an iRNA agent will preferably have one or more of the following properties: (1) it will be of the Formula 1, 2, 3, or 4 set out in the RNA Agent section below; (2) if single stranded it will have a 5' modification which includes one or more 10 phosphate groups or one or more analogs of a phosphate group; (3) it will, despite modifications, even to a very large number, or all of the nucleosides, have an antisense strand that can present bases (or modified bases) in the proper three dimensional framework so as to be able to form correct base pairing and form a duplex structure with a homologous target RNA which is sufficient to allow down regulation of the target, e.g., by 15 cleavage of the target RNA; (4) it will, despite modifications, even to a very large number, or all of the nucleosides, still have "RNA-like" properties, i.e., it will possess the overall structural, chemical and physical properties of an RNA molecule, even though not exclusively, or even partly, of ribonucleotide based content. For example, an iRNA agent can contain, e.g., a sense and/or an antisense strand 20 in which all of the nucleotide sugars contain e.g., 2' fluoro in place of 2' hydroxyl. This deoxyribonucleotide-containing agent can still be expected to exhibit RNA-like properties. While not wishing to be bound by theory, the electronegative fluorine prefers an axial orientation when attached to the C2' position of ribose. This spatial preference of fluorine can, in turn, force the sugars to adopt a Cr-endo pucker. This is the same puckering mode as 25 observed in RNA molecules and gives rise to the RNA-characteristic A-family-type helix. Further, since fluorine is a good hydrogen bond acceptor, it can participate in the same hydrogen bonding interactions with water molecules that are known to stabilize RNA structures. (Generally, it is preferred that a modified moiety at the 2' sugar position will be able to enter into 21 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 H-bonding which is more characteristic of the OH moiety of a ribonucleotide than the H moiety of a deoxyribonucleotide. A preferred iRNA agent will: exhibit a C'-endo pucker in all, or at least 50, 75,80, 85, 90, or 95 % of its sugars; exhibit a Cr-endo pucker in a sufficient amount of its sugars that it can give rise to a the RNA-characteristic A-family-type helix; will have no more 5 than 20, 10, 5, 4, 3, 2, or1 sugar which is not a C 3 ,-endo pucker structure. These limitations are particularly preferably in the antisense strand; (5) regardless of the nature of the modification, and even though the RNA agent can contain deoxynucleotides or modified deoxynucleotides, particularly in overhang or other single strand regions, it is preferred that DNA molecules, or any molecule in which more than 50, 60, 10 or 70 % of the nucleotides in the molecule, or more than 50, 60, or 70 % of the nucleotides in a duplexed region are deoxyribonucleotides, or modified deoxyribonucleotides which are deoxy at the 2' position, are excluded from the definition of RNA agent. A "single strand iRNA agent" as used herein, is an iRNA agent which is made up of a single molecule. It may include a duplexed region, formed by intra-strand pairing, e.g., it may 15 be, or include, a hairpin or pan-handle structure. Single strand iRNA agents are preferably antisense with regard to the target molecule. In preferred embodiments single strand iRNA agents are 5' phosphorylated or include a phosphoryl analog at the 5' prime terminus. 5' phosphate modifications include those which are compatible with RISC mediated gene silencing. Suitable modifications include: 5'-monophosphate ((HO)2(O)P-O-5'); 5'-diphosphate 20 ((HO)2(O)P-0-P(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)P-O-(HO)(O)P-O-P(HO)(O)-0-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-0-5'-(HO)(O)P-O-(HO)(O)P-0 P(HO)(O)-0-5'); 5'-adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-0-5'-(HO)(O)P-O-(HO)(O)P-0-P(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)P-0-5'); 5'-monodithiophosphate (phosphorodithioate; 25 (HO)(HS)(S)P-0-5'), 5'-phosphorothiolate ((HO)2(O)P-S-5'); any additional combination of oxygen/sulfur replaced monophosphate, diphosphate and triphosphates (e.g. 5'-alpha thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoramidates ((HO)2(O)P-NH-5', (HO)(NH2)(O)P-O-5'), 5'-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-O-5'-, (OH)2(O)P-5'-CH2-), 5'-alkyletherphosphonates 22 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g. RP(OH)(O)-O-5'-). (These modifications can also be used with the antisense strand of a double stranded iRNA.) A single strand iRNA agent should be sufficiently long that it can enter the RISC and participate in RISC mediated cleavage of a target mRNA. A single strand iRNA agent is at least 5 14, and more preferably at least 15, 20, 25, 29, 35, 40, or 50nucleotides in length. It is preferably less than 200, 100, or 60 nucleotides in length. Hairpin iRNA agents will have a duplex region equal to or at least 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs. The duplex region will preferably be equal to or less than 200, 100, or 50, in length. Preferred ranges for the duplex region are 15-30, 17 to 23, 19 to 23, and 19 10 to 21 nucleotides pairs in length. The hairpin will preferably have a single strand overhang or terminal unpaired region, preferably the 3', and preferably of the antisense side of the hairpin. Preferred overhangs are 2-3 nucleotides in length. A "double stranded (ds) iRNA agent" as used herein, is an iRNA agent which includes more than one, and preferably two, strands in which interchain hybridization can form a region 15 of duplex structure. The antisense strand of a double stranded iRNA agent should be equal to or at least, 14, 15, 16 17, 18, 19, 25, 29, 40, or 60 nucleotides in length. It should be equal to or less than 200, 100, or 50, nucleotides in length. Preferred ranges are 17 to 25, 19 to 23, and 19 to21 nucleotides in length. 20 The sense strand of a double stranded iRNA agent should be equal to or at least 14, 15, 16 17, 18, 19, 25, 29, 40, or 60 nucleotides in length. It should be equal to or less than 200, 100, or 50, nucleotides in length. Preferred ranges are 17 to 25, 19 to 23, and 19 to21 nucleotides in length. The double strand portion of a double stranded iRNA agent should be equal to or at least, 25 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotide pairs in length. It should be equal to or less than 200, 100, or 50, nucleotides pairs in length. Preferred ranges are 15-30, 17 to 23, 19 to 23, and 19 to 21 nucleotides pairs in length. 23 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In many embodiments, the ds iRNA agent is sufficiently large that it can be cleaved by an endogenous molecule, e.g., by Dicer, to produce smaller ds iRNA agents, e.g., sRNAs agents It may be desirable to modify one or both of the antisense and sense strands of a double strand iRNA agent. In some cases they will have the same modification or the same class of 5 modification but in other cases the sense and antisense strand will have different modifications, e.g., in some cases it is desirable to modify only the sense strand. It may be desirable to modify only the sense strand, e.g., to inactivate it, e.g., the sense strand can be modified in order to inactivate the sense strand and prevent formation of an active sRNA/protein or RISC. This can be accomplished by a modification which prevents 5'-phosphorylation of the sense strand, e.g., 10 by modification with a 5'-O-methyl ribonucleotide (see Nykanen et al., (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell 107, 309-321.) Other modifications which prevent phosphorylation can also be used, e.g., simply substituting the 5'-OH by H rather than O-Me. Alternatively, a large bulky group may be added to the 5' phosphate turning it into a phosphodiester linkage, though this may be less desirable as 15 phosphodiesterases can cleave such a linkage and release a functional sRNA 5'-end. Antisense strand modifications include 5' phosphorylation as well as any of the other 5' modifications discussed herein, particularly the 5' modifications discussed above in the section on single stranded iRNA molecules. It is preferred that the sense and antisense strands be chosen such that the ds iRNA agent 20 includes a single strand or unpaired region at one or both ends of the molecule. Thus, a ds iRNA agent contains sense and antisense strands, preferable paired to contain an overhang, e.g., one or two 5' or 3' overhangs but preferably a 3' overhang of 2-3 nucleotides. Most embodiments will have a 3' overhang. Preferred sRNA agents will have single-stranded overhangs, preferably 3' overhangs, of 1 or preferably 2 or 3 nucleotides in length at each end. The overhangs can be 25 the result of one strand being longer than the other, or the result of two strands of the same length being staggered. 5' ends are preferably phosphorylated. Preferred lengths for the duplexed region is between 15 and 30, most preferably 18, 19, 20, 21, 22, and 23 nucleotides in length, e.g., in the sRNA agent range discussed above. sRNA agents can resemble in length and structure the natural Dicer processed products from long 24 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 dsRNAs. Embodiments in which the two strands of the sRNA agent are linked, e.g., covalently linked are also included. Hairpin, or other single strand structures which provide the required double stranded region, and preferably a 3' overhang are also within the invention. The isolated iRNA agents described herein, including ds iRNA agents and sRNA agents 5 can mediate silencing of a target RNA, e.g., mRNA, e.g., a transcript of a gene that encodes a protein. For convenience, such mRNA is also referred to herein as mRNA to be silenced. Such a gene is also referred to as a target gene. In general, the RNA to be silenced is an endogenous gene or a pathogen gene. In addition, RNAs other than mRNA, e.g., tRNAs, and viral RNAs, can also be targeted. 10 As used herein, the phrase "mediates RNAi" refers to the ability to silence, in a sequence specific manner, a target RNA. While not wishing to be bound by theory, it is believed that silencing uses the RNAi machinery or process and a guide RNA, e.g., an sRNA agent of 21. to 23 nucleotides. As used herein, "specifically hybridizable" and "complementary" are terms which are 15 used to indicate a sufficient degree of complementarity such that stable and specific binding occurs between a compound of the invention and a target RNA molecule. Specific binding requires a sufficient degree of complementarity to avoid non-specific binding of the oligomeric compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, or in the 20 case of in vitro assays, under conditions in which the assays are performed. The non-target sequences typically differ by at least 5 nucleotides. In one embodiment, an iRNA agent is "sufficiently complementary" to a target RNA, e.g., a target mRNA, such that the iRNA agent silences production of protein encoded by the target mRNA. In another embodiment, the iRNA agent is "exactly complementary" (excluding 25 the RRMS containing subunit(s))to a target RNA, e.g., the target RNA and the iRNA agent anneal, preferably to form a hybrid made exclusively of Watson-Crick basepairs in the region of exact complementarity. A "sufficiently complementary" target RNA can include an internal region (e.g., of at least 10 nucleotides) that is exactly complementary to a target RNA. Moreover, in some embodiments, the iRNA agent specifically discriminates a single-nucleotide 25 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 difference. In this case, the iRNA agent only mediates RNAi if exact complementary is found in the region (e.g., within 7 nucleotides of) the single-nucleotide difference. As used herein, the term "oligonucleotide" refers to a nucleic acid molecule (RNA or DNA) preferably of length less than 100, 200, 300, or 400 nucleotides. 5 RNA agents discussed herein include otherwise unmodified RNA as well as RNA which have been modified, e.g., to improve efficacy, and polymers of nucleoside surrogates. Unmodified RNA refers to a molecule in which the components of the nucleic acid, namely sugars, bases, and phosphate moieties, are the same or essentially the same as that which occur in nature, preferably as occur naturally in the human body. The art has referred to rare or unusual, 10 but naturally occurring, RNAs as modified RNAs, see, e.g., Limbach et al., (1994) Summary: the modified nucleosides of RNA, Nucleic Acids Res. 22: 2183-2196. Such rare or unusual RNAs, often termed modified RNAs (apparently because the are typically the result of a post transcriptionally modification) are within the term unmodified RNA, as used herein. Modified RNA as used herein refers to a molecule in which one or more of the components of the nucleic 15 acid, namely sugars, bases, and phosphate moieties, are different from that which occur in nature, preferably different from that which occurs in the human body. While they are referred to as modified "RNAs," they will of course, because of the modification, include molecules which are not RNAs. Nucleoside surrogates are molecules in which the ribophosphate backbone is replaced with a non-ribophosphate construct that allows the bases to the presented in the 20 correct spatial relationship such that hybridization is substantially similar to what is seen with a ribophosphate backbone, e.g., non-charged mimics of the ribophosphate backbone. Examples of all of the above are discussed herein. Much of the discussion below refers to single strand molecules. In many embodiments of the invention a double stranded iRNA agent, e.g., a partially double stranded iRNA agent, is 25 required or preferred. Thus, it is understood that that double stranded structures (e.g. where two separate molecules are contacted to form the double stranded region or where the double stranded region is formed by intramolecular pairing (e.g., a hairpin structure)) made of the single stranded structures described below are within the invention. Preferred lengths are described elsewhere herein. 26 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 As nucleic acids are polymers of subunits or monomers, many of the modifications described below occur at a position which is repeated within a nucleic acid, e.g., a modification of a base, or a phosphate moiety, or the a non-linking 0 of a phosphate moiety. In some cases the modification will occur at all of the subject positions in the nucleic acid but in many, and 5 infact in most cases it will not. By way of example, a modification may only occur at a 3' or 5' terminal position, may only occur in a terminal regions, e.g. at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand. A modification may occur in a double strand region, a single strand region, or in both. A modification may occur only in the double strand region of an RNA or may only occur in a single strand region of an RNA. E.g., a 10 phosphorothioate modification at a non-linking 0 position may only occur at one or both termini, may only occur in a terminal regions, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or may occur in double strand and single strand regions, particularly at termini. The 5' end or ends can be phosphorylated. In some embodiments it is particularly preferred, e.g., to enhance stability, to include 15 particular bases in overhangs, or to include modified nucleotides or nucleotide surrogates, in single strand overhangs, e.g., in a 5' or 3' overhang, or in both. E.g., it can be desirable to include purine nucleotides in overhangs. In some embodiments all or some of the bases in a 3' or 5' overhang will be modified, e.g., with a modification described herein. Modifications can include, e.g., the use of modifications at the 2' OH group of the ribose sugar, e.g., the use of 20 deoxyribonucleotides, e.g., deoxythymidine, instead of ribonucleotides, and modifications in the phosphate group, e.g., phosphothioate modifications. Overhangs need not be homologous with the target sequence. 27 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Modifications and nucleotide surrogates are discussed below. II 5 BASE 0 -I WOH (2' OH) X P-Y L BASE 0 3 OH (2' OH) FORMULA 1 5 The scaffold presented above in Formula 1 represents a portion of a ribonucleic acid. The basic components are the ribose sugar, the base, the terminal phosphates, and phosphate intemucleotide linkers. Where the bases are naturally occurring bases, e.g., adenine, uracil, guanine or cytosine, the sugars are the unmodified 2' hydroxyl ribose sugar (as depicted) and W, X, Y, and Z are all 0, Formula 1 represents a naturally occurring unmodified 10 oligoribonucleotide. Unmodified oligoribonucleotides may be less than optimal in some applications, e.g., unmodified oligoribonucleotides can be prone to degradation by e.g., cellular nucleases. Nucleases can hydrolyze nucleic acid phosphodiester bonds. However, chemical modifications 28 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 to one or more of the above RNA components can confer improved properties, and, e.g., can render oligoribonucleotides more stable to nucleases. Umodified oligoribonucleotides may also be less than optimal in terms of offering tethering points for attaching ligands or other moieties to an iRNA agent. 5 Modified nucleic acids and nucleotide surrogates can include one or more of: (i) alteration, e.g., replacement, of one or both of the non-linking (X and Y) phosphate oxygens and/or of one or more of the linking (W and Z) phosphate oxygens (When the phosphate is in the terminal position, one of the positions W or Z will not link the phosphate to an additional element in a naturally occurring ribonucleic acid. However, for simplicity of 10 terminology, except where otherwise noted, the W position at the 5' end of a nucleic acid and the terminal Z position at the 3'end of a nucleic acid, are within the term "linking phosphate oxygens" as used herein.); (ii) alteration, e.g., replacement, of a constituent of the ribose sugar, e.g., of the 2' hydroxyl on the ribose sugar, or wholesale replacement of the ribose sugar with a structure other 15 than ribose, e.g., as described herein; (iii) wholesale replacement of the phosphate moiety (bracket ) with "dephospho" linkers; (iv) modification or replacement of a naturally occurring base; (v) replacement or modification of the ribose-phosphate backbone (bracket II); (vi) modification of the 3' end or 5' end of the RNA, e.g., removal, modification or 20 replacement of a terminal phosphate group or conjugation of a moiety, e.g. a fluorescently labeled moiety, to either the 3' or 5' end of RNA. The terms replacement, modification, alteration, and the like, as used in this context, do not imply any process limitation, e.g., modification does not mean that one must start with a reference or naturally occurring ribonucleic acid and modify it to produce a modified ribonucleic 25 acid bur rather modified simply indicates a difference from a naturally occurring molecule. 29 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 It is understood that the actual electronic structure of some chemical entities cannot be adequately represented by only one canonical form (i.e. Lewis structure). While not wishing to be bound by theory, the actual structure can instead be some hybrid or weighted average of two or more canonical forms, known collectively as resonance forms or structures. Resonance 5 structures are not discrete chemical entities and exist only on paper. They differ from one another only in the placement or "localization" of the bonding and nonbonding electrons for a particular chemical entity. It can be possible for one resonance structure to contribute to a greater extent to the hybrid than the others. Thus, the written and graphical descriptions of the embodiments of the present invention are made in terms of what the art recognizes as the 10 predominant resonance form for a particular species. For example, any phosphoroamidate (replacement of a nonlinking oxygen with nitrogen) would be represented by X = 0 and Y = N in the above figure. Specific modifications are discussed in more detail below. The Phosphate Group 15 The phosphate group is a negatively charged species. The charge is distributed equally over the two non-linking oxygen atoms (i.e., X and Y in Formula 1 above). However, the phosphate group can be modified by replacing one of the oxygens with a different substituent. One result of this modification to RNA phosphate backbones can be increased resistance of the oligoribonucleotide to nucleolytic breakdown. Thus while not wishing to be bound by theory, it 20 can be desirable in some embodiments to introduce alterations which result in either an uncharged linker or a charged linker with unsymmetrical charge distribution. Examples of modified phosphate groups include phosphorothioate, phosphoroselenates, borano phosphates, borano phosphate esters, hydrogen phosphonates, phosphoroamidates, alkyl or aryl phosphonates and phosphotriesters. Phosphorodithioates have both non-linking oxygens 25 replaced by sulfur. Unlike the situation where only one of X or Y is altered, the phosphorus center in the phosphorodithioates is achiral which precludes the formation of oligoribonucleotides diastereomers. Diastereomer formation can result in a preparation in which the individual diastereomers exhibit varying resistance to nucleases. Further, the hybridization affinity of RNA containing chiral phosphate groups can be lower relative to the corresponding 30 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 unmodified RNA species. Thus, while not wishing to be bound by theory, modifications to both X and Y which eliminate the chiral center, e.g. phosphorodithioate formation, may be desirable in that they cannot produce diastereomer mixtures. Thus, X can be any one of S, Se, B, C, H, N, or OR (R is alkyl or aryl). Thus Y can be any one of S, Se, B, C, H, N, or OR (R is alkyl or 5 aryl). Replacement of X and/or Y with sulfur is preferred. The phosphate linker can also be modified by replacement of a linking oxygen (i.e., W or Z in Formula 1) with nitrogen (bridged phosphoroamidates), sulfur (bridged phosphorothioates) and carbon (bridged methylenephosphonates). The replacement can occur at a terminal oxygen (position W (3') or position Z (5'). Replacement of W with carbon or Z with nitrogen is 10 preferred. Candidate agents can be evaluated for suitability as described below. The Sugar Group A modified RNA can include modification of all or some of the sugar groups of the ribonucleic acid. E.g., the 2' hydroxyl group (OH) can be modified or replaced with a number of 15 different "oxy" or "deoxy" substituents. While not being bound by theory, enhanced stability is expected since the hydroxyl can no longer be deprotonated to form a 2' alkoxide ion. The 2' alkoxide can catalyze degradation by intramolecular nucleophilic attack on the linker phosphorus atom. Again, while not wishing to be bound by theory, it can be desirable to some embodiments to introduce alterations in which alkoxide formation at the 2' position is not possible. 20 Examples of "oxy"-2' hydroxyl group modifications include alkoxy or aryloxy (OR, e.g., R = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar); polyethyleneglycols (PEG),

O(CH

2

CH

2 O)nCH 2

CH

2 OR; "locked" nucleic acids (LNA) in which the 2' hydroxyl is connected, e.g., by a methylene bridge, to the 4' carbon of the same ribose sugar; O-AMINE (AMINE =

NH

2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino, or 25 diheteroaryl amino, ethylene diamine, polyamino) and aminoalkoxy, O(CH 2 )nAMINE, (e.g., AMINE = NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino, or diheteroaryl amino, ethylene diamine, polyamino). It is noteworthy that oligonucleotides containing only the methoxyethyl group (MOE), (OCH 2

CH

2 0CH 3 , a PEG 31 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 derivative), exhibit nuclease stabilities comparable to those modified with the robust phosphorothioate modification. "Deoxy" modifications include hydrogen (i.e. deoxyribose sugars, which are of particular relevance to the overhang portions of partially ds RNA); halo (e.g., fluoro); amino (e.g. NH 2 ; 5 alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino, diheteroaryl amino, or amino acid); NH(CH 2

CH

2 NH)nCH 2

CH

2 -AMlNE (AMINE =NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino,or diheteroaryl amino), NHC(O)R (R = alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), cyano; mercapto; alkyl-thio alkyl; thioalkoxy; and alkyl, cycloalkyl, aryl, alkenyl and alkynyl, which may be optionally 10 substituted with e.g., an amino functionality. Preferred substitutents are 2'-methoxyethyl, 2' OCH3, 2'-O-allyl, 2'-C- allyl, and 2'-fluoro. The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a modified RNA can include nucleotides containing e.g., arabinose, as the sugar. 15 Modified RNAs can also include "abasic" sugars, which lack a nucleobase at C-i'. These abasic sugars can also be further contain modifications at one or more of the constituent sugar atoms. To maximize nuclease resistance, the 2' modifications can be used in combination with one or more phosphate linker modifications (e.g., phosphorothioate). The so-called "chimeric" 20 oligonucleotides are those that contain two or more different modifications. The modificaton can also entail the wholesale replacement of a ribose structure with another entity at one or more sites in the iRNA agent. These modifications are described in section entitled Ribose Replacements for RRMSs. 32 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 Candidate modifications can be evaluated as described below. Replacement of the Phosphate Group The phosphate group can be replaced by non-phosphorus containing connectors (cf Bracket I in Formula 1 above). While not wishing to be bound by theory, it is believed that since 5 the charged phosphodiester group is the reaction center in nucleolytic degradation, its replacement with neutral structural mimics should impart enhanced nuclease stability. Again, while not wishing to be bound by theory, it can be desirable, in some embodiment, to introduce alterations in which the charged phosphate group is replaced by a neutral moiety. Examples of moieties which can replace the phosphate group include siloxane, carbonate, 10 carboxymethyl, carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino. Preferred replacements include the methylenecarbonylamino and methylenemethylimino groups. Candidate modifications can be evaluated as described below. 15 Replacement of Ribophosphate Backbone Oligonucleotide- mimicking scaffolds can also be constructed wherein the phosphate linker and ribose sugar are replaced by nuclease resistant nucleoside or nucleotide surrogates (see Bracket II of Formula 1 above). While not wishing to be bound by theory, it is believed that the absence of a repetitively charged backbone diminishes binding to proteins that recognize 20 polyanions (e.g. nucleases). Again, while not wishing to be bound by theory, it can be desirable in some embodiment, to introduce alterations in which the bases are tethered by a neutral surrogate backbone. Examples include the mophilino, cyclobutyl, pyrrolidine and peptide nucleic acid (PNA) nucleoside surrogates. A preferred surrogate is a PNA surrogate. 25 Candidate modifications can be evaluated as described below. 33 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Terminal Modifications The 3' and 5' ends of an oligonucleotide can be modified. Such modifications can be at the 3' end, 5' end or both ends of the molecule. They can include modification or replacement of an entire terminal phosphate or of one or more of the atoms of the phosphate group. E.g., the 3' 5 and 5' ends of an oligonucleotide can be conjugated to other functional molecular entities such as labeling moieties, e.g., fluorophores (e.g., pyrene, TAMRA, fluorescein, Cy3 or Cy5 dyes) or protecting groups (based e.g., on sulfur, silicon, boron or ester). The functional molecular entities can be attached to the sugar through a phosphate group and/or a spacer. The terminal atom of the spacer can connect to or replace the linking atom of the phosphate group or the C-3' 10 or C-5' 0, N, S or C group of the sugar. Alternatively, the spacer can connect to or replace the terminal atom of a nucleotide surrogate (e.g., PNAs). These spacers or linkers can include e.g., (CH 2 ),-, -(CH 2 )nN-, -(CH 2 )nO-, -(CH 2 )nS-, O(CH 2

CH

2

O),CH

2

CH

2 OH (e.g., n = 3 or 6), abasic sugars, amide, carboxy, amine, oxyamine, oxyimine, thioether, disulfide, thiourea, sulfonamide, or morpholino, or biotin and fluorescein reagents. When a spacer/phosphate-functional 15 molecular entity-spacer/phosphate array is interposed between two strands of iRNA agents, this array can substitute for a hairpin RNA loop in a hairpin-type RNA agent. The 3' end can be an OH group. While not wishing to be bound by theory, it is believed that conjugation of certain moieties can improve transport, hybridization, and specificity properties. Again, while not wishing to be bound by theory, it may be desirable to introduce terminal alterations that improve 20 nuclease resistance. Other examples of terminal modifications include dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic carriers (e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl 25 group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine)and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption 30 facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, 34 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles). Terminal modifications can be added for a number of reasons, including as discussed elsewhere herein to modulate activity or to modulate resistance to degradation. Terminal 5 modifications useful for modulating activity include modification of the 5' end with phosphate or phosphate analogs. E.g., in preferred embodiments iRNA agents, especially antisense strands, are 5' phosphorylated or include a phosphoryl analog at the 5' prime terminus. 5'-phosphate modifications include those which are compatible with RISC mediated gene silencing. Suitable modifications include: 5'-monophosphate ((HO)2(O)P-0-5'); 5'-diphosphate ((HO)2(O)P-0 10 P(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)P-O-(HO)(O)P-O-P(HO)(O)-0-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-0-5'-(HO)(O)P-O-(HO)(O)P-0-P(HO)(O)-O-5'); 5' adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-0-5' (HO)(O)P-O-(HO)(O)P-0-P(HO)(O)-0-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)P-0-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-0-5'), 5' 15 phosphorothiolate ((HO)2(O)P-S-5'); any additional combination of oxgen/sulfur replaced monophosphate, diphosphate and triphosphates (e.g. 5'-alpha-thiotriphosphate, 5'-gamma thiotriphosphate, etc.), 5'-phosphoramidates ((HO)2(O)P-NH-5', (HO)(NH2)(O)P-0-5'), 5' alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-O-5'-, (OH)2(O)P-5'-CH2-), 5'-alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), 20 ethoxymethyl, etc., e.g. RP(OH)(O)-O-5'-). Terminal modifications can also be useful for monitoring distribution, and in such cases the preferred groups to be added include fluorophores, e.g., fluorscein or an Alexa dye, e.g., Alexa 488. Terminal modifications can also be useful for enhancing uptake, useful modifications for this include cholesterol. Terminal modifications can also be useful for cross 25 linking an RNA agent to another moiety; modifications useful for this include mitomycin C. Candidate modifications can be evaluated as described below. 35 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 The Bases Adenine, guanine, cytosine and uracil are the most common bases found in RNA. These bases can be modified or replaced to provide RNA's having improved properties. E.g., nuclease resistant oligoribonucleotides can be prepared with these bases or with synthetic and natural 5 nucleobases (e.g., inosine, thymine, xanthine, hypoxanthine, nubularine, isoguanisine, or tubercidine) and any one of the above modifications. Alternatively, substituted or modified analogs of any of the above bases, e.g., "unusual bases" and "universal bases," can be employed. Examples include without limitation 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil 10 and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 5-halouracil, 5-(2-aminopropyl)uracil, 5-amino allyl uracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5 trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 15 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, dihydrouracil, 3-deaza-5 azacytosine, 2-aminopurine, 5-alkyluracil, 7-alkylguanine, 5-alkyl cytosine,7-deazaadenine, N6, N6-dimethyladenine, 2,6-diaminopurine, 5-amino-allyl-uracil, N3-methyluracil, substituted 1,2,4-triazoles, 2-pyridinone, 5-nitroindole, 3-nitropyrrole, 5-methoxyuracil, uracil-5-oxyacetic acid, 5-methoxycarbonylmethyluracil, 5-methyl-2-thiouracil, 5-methoxycarbonylmethyl-2 20 thiouracil, 5-methylaminomethyl-2-thiouracil, 3-(3-amino-3carboxypropyl)uracil, 3 methylcytosine, 5-methylcytosine, N 4 -acetyl cytosine, 2-thiocytosine, N6-methyladenine, N6 isopentyladenine, 2-methylthio-N6-isopentenyladenine, N-methylguanines, or 0-alkylated bases. Further purines and pyrimidines include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in the Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, 25 Kroschwitz, J. I., ed. John Wiley & Sons, 1990, and those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613. Generally, base changes are less preferred for promoting stability, but they can be useful for other reasons, e.g., some, e.g., 2,6-diaminopurine and 2 amino purine, are fluorescent. Modified bases can reduce target specificity. This should be taken into consideration in the 30 design of iRNA agents. 36 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 Candidate modifications can be evaluated as described below. Evaluation of Candidate RNA's One can evaluate a candidate RNA agent, e.g., a modified RNA, for a selected property by exposing the agent or modified molecule and a control molecule to the appropriate conditions 5 and evaluating for the presence of the selected property. For example, resistance to a degradent can be evaluated as follows. A candidate modified RNA (and preferably a control molecule, usually the unmodified form) can be exposed to degradative conditions, e.g., exposed to a milieu, which includes a degradative agent, e.g., a nuclease. E.g., one can use a biological sample, e.g., one that is similar to a milieu, which might be encountered, in therapeutic use, e.g., blood or a 10 cellular fraction, e.g., a cell-free homogenate or disrupted cells. The candidate and control could then be evaluated for resistance to degradation by any of a number of approaches. For example, the candidate and control could be labeled, preferably prior to exposure, with, e.g., a radioactive or enzymatic label, or a fluorescent label, such as Cy3 or Cy5. Control and modified RNA's can be incubated with the degradative agent, and optionally a control, e.g., an inactivated, e.g., heat 15 inactivated, degradative agent. A physical parameter, e.g., size, of the modified and control molecules are then determined. They can be determined by a physical method, e.g., by polyacrylamide gel electrophoresis or a sizing column, to assess whether the molecule has maintained its original length, or assessed functionally. Alternatively, Northern blot analysis can be used to assay the length of an unlabeled modified molecule. 20 A functional assay can also be used to evaluate the candidate agent. A functional assay can be applied initially or after an earlier non-functional assay, (e.g., assay for resistance to degradation) to determine if the modification alters the ability of the molecule to silence gene expression. For example, a cell, e.g., a mammalian cell, such as a mouse or human cell, can be co-transfected with a plasmid expressing a fluorescent protein, e.g., GFP, and a candidate RNA 25 agent homologous to the transcript encoding the fluorescent protein (see, e.g., WO 00/44914). For example, a modified dsRNA homologous to the GFP mRNA can be assayed for the ability to inhibit GFP expression by monitoring for a decrease in cell fluorescence, as compared to a control cell, in which the transfection did not include the candidate dsRNA, e.g., controls with no agent added and/or controls with a non-modified RNA added. Efficacy of the candidate agent on 37 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 gene expression can be assessed by comparing cell fluorescence in the presence of the modified and unmodified dsRNA agents. In an alternative functional assay, a candidate dsRNA agent homologous to an endogenous mouse gene, preferably a maternally expressed gene, such as c-mos, can be injected 5 into an immature mouse oocyte to assess the ability of the agent to inhibit gene expression in vivo (see, e.g., WO 01/36646). A phenotype of the oocyte, e.g., the ability to maintain arrest in metaphase II, can be monitored as an indicator that the agent is inhibiting expression. For example, cleavage of c-nos mRNA by a dsRNA agent would cause the oocyte to exit metaphase arrest and initiate parthenogenetic development (Colledge et al. Nature 370: 65-68, 1994; 10 Hashimoto et al. Nature, 370:68-71, 1994). The effect of the modified agent on target RNA levels can be verified by Northern blot to assay for a decrease in the level of target mRNA, or by Western blot to assay for a decrease in the level of target protein, as compared to a negative control. Controls can include cells in which with no agent is added and/or cells in which a non modified RNA is added. 15 References General References The oligoribonucleotides and oligoribonucleosides used in accordance with this invention may be with solid phase synthesis, see for example "Oligonucleotide synthesis, a practical approach", Ed. M. J. Gait, IRL Press, 1984; "Oligonucleotides and Analogues, A Practical 20 Approach", Ed. F. Eckstein, IRL Press, 1991 (especially Chapter 1, Modern machine-aided methods of oligodeoxyribonucleotide synthesis, Chapter 2, Oligoribonucleotide synthesis, Chapter 3, 2'-O--Methyloligoribonucleotide- s: synthesis and applications, Chapter 4, Phosphorothioate oligonucleotides, Chapter 5, Synthesis of oligonucleotide phosphorodithioates, Chapter 6, Synthesis of oligo-2'-deoxyribonucleoside methylphosphonates, and. Chapter 7, 25 Oligodeoxynucleotides containing modified bases. Other particularly useful synthetic procedures, reagents, blocking groups and reaction conditions are described in Martin, P., Helv. Chin. Acta, 1995, 78, 486-504; Beaucage, S. L. and Iyer, R. P., Tetrahedron, 1992, 48, 2223 2311 and Beaucage, S. L. and Iyer, R. P., Tetrahedron, 1993, 49, 6123-6194, or references referred to therein. 38 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Modification described in WO 00/44895, WO01/75164, or W002/44321 can be used herein. The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference. 5 Phosphate Group References The preparation of phosphinate oligoribonucleotides is described in U.S. Pat. No. 5,508,270. The preparation of alkyl phosphonate oligoribonucleotides is described in U.S. Pat. No. 4,469,863. The preparation of phosphoramidite oligoribonucleotides is described in U.S. Pat. No. 5,256,775 or U.S. Pat. No. 5,366,878. The preparation of phosphotriester 10 oligoribonucleotides is described in U.S. Pat. No. 5,023,243. The preparation of borano phosphate oligoribonucleotide is described in U.S. Pat. Nos. 5,130,302 and 5,177,198. The preparation of 3'-Deoxy-3'-amino phosphoramidate oligoribonucleotides is described in U.S. Pat. No. 5,476,925. 3'-Deoxy-3'-methylenephosphonate oligoribonucleotides is described in An, H, et al. J. Org. Chem. 2001, 66, 2789-2801. Preparation of sulfur bridged nucleotides is described 15 in Sproat et al. Nucleosides Nucleotides 1988, 7,651 and Crosstick et al. Tetrahedron Lett. 1989, 30, 4693. Sugar Group References Modifications to the 2' modifications can be found in Verma, S. et al. Annu. Rev. Biochem. 1998, 67, 99-134 and all references therein. Specific modifications to the ribose can be 20 found in the following references: 2'-fluoro (Kawasaki et. al., J Med. Chem., 1993, 36, 831 841), 2'-MOE (Martin, P. Helv. Chim. Acta 1996, 79, 1930-1938), "LNA" (Wengel, J. Acc. Chem. Res. 1999, 32, 301-310). Replacement of the Phosphate Group References Methylenemethylimino linked oligoribonucleosides, also identified herein as MMI linked 25 oligoribonucleosides, methylenedimethyhydrazo linked oligoribonucleosides, also identified herein as MDH linked oligoribonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified herein as amide-3 linked oligoribonucleosides, and 39 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 methyleneaminocarbonyl linked oligonucleosides, also identified herein as amide-4 linked oligoribonucleosides as well as mixed backbone compounds having, as for instance, alternating MMI and PO or PS linkages can be prepared as is described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677 and in published PCT applications PCT/US92/04294 and 5 PCT/US92/04305 (published as WO 92/20822 WO and 92/20823, respectively). Formacetal and thioformacetal linked oligoribonucleosides can be prepared as is described in U.S. Pat. Nos. 5,264,562 and 5,264,564. Ethylene oxide linked oligoribonucleosides can be prepared as is described in U.S. Pat. No. 5,223,618. Siloxane replacements are described in CormierJ.F. et al. Nucleic Acids Res. 1988, 16, 4583. Carbonate replacements are described in Tittensor, J.R. J 10 Chem. Soc. C 1971, 1933. Carboxymethyl replacements are described in Edge, M.D. et al. J Chem. Soc. Perkin Trans. 1 1972, 1991. Carbamate replacements are described in Stirchak, E.P. Nucleic Acids Res. 1989, 17, 6129. Replacement of the Phosphate-Ribose Backbone References Cyclobutyl sugar surrogate compounds can be prepared as is described in U.S. Pat. No. 15 5,359,044. Pyrrolidine sugar surrogate can be prepared as is described in U.S. Pat. No. 5,519,134. Morpholino sugar surrogates can be prepared as is described in U.S. Pat. Nos. 5,142,047 and 5,235,033, and other related patent disclosures. Peptide Nucleic Acids (PNAs) are known per se and can be prepared in accordance with any of the various procedures referred to in Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications, Bioorganic & 20 Medicinal Chemistry, 1996, 4, 5-23. They may also be prepared in accordance with U.S. Pat. No. 5,539,083. Terminal Modification References Terminal modifications are described in Manoharan, M. et al. Antisense and Nucleic Acid Drug Development 12, 103-128 (2002) and references therein. 25 Bases References N-2 substitued purine nucleoside amidites can be prepared as is described in U.S. Pat. No. 5,459,255. 3-Deaza purine nucleoside amidites can be prepared as is described in U.S. Pat. No. 5,457,191. 5,6-Substituted pyrimidine nucleoside amidites can be prepared as is described in 40 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 U.S. Pat. No. 5,614,617. 5-Propynyl pyrimidine nucleoside amidites can be prepared as is described in U.S. Pat. No. 5,484,908. Additional references can be disclosed in the above section on base modifications. 41 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Preferred iRNA Agents Preferred RNA agents have the following structure (see Formula 2 below):

A

1 R1 0

R

7 A R 5 0 R3 Ry

A

4

R

6 FORMULA 2 5 Referring to Formula 2 above, R 1 , R 2 , and R 3 are each, independently, H, (i.e. abasic nucleotides), adenine, guanine, cytosine and uracil, inosine, thymine, xanthine, hypoxanthine, nubularine, tubercidine, isoguanisine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil 10 (pseudouracil), 4-thiouracil, 5-halouracil, 5-(2-aminopropyl)uracil, 5-amino allyl uracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5 42 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, dihydrouracil, 3-deaza-5 azacytosine, 2-aminopurine, 5-alkyluracil, 7-alkylguanine, 5-alkyl cytosine,7-deazaadenine, 7 5 deazaguanine, N6, N6-dimethyladenine, 2,6-diaminopurine, 5-amino-allyl-uracil, N3 methyluracil, substituted 1,2,4-triazoles, 2-pyridinone, 5-nitroindole, 3-nitropyrrole, 5 methoxyuracil, uracil-5-oxyacetic acid, 5-methoxycarbonylmethyluracil, 5-methyl-2-thiouracil, 5-methoxycarbonylmethyl-2-thiouracil, 5-methylaminomethyl-2-thiouracil, 3-(3-amino 3carboxypropyl)uracil, 3-methylcytosine, 5-methylcytosine, N4-acetyl cytosine, 2-thiocytosine, 10 N6-methyladenine, N6-isopentyladenine, 2-methylthio-N6-isopentenyladenine, N methylguanines, or O-alkylated bases.

R

4 , R 5 , and R 6 are each, independently, OR 8 , O(CH 2

CH

2 O)mCH 2

CH

2 OR; O(CH 2 )nR 9 ;

O(CH

2 )nOR 9 , H; halo; NH 2 ; NHR 8 ; N(R) 2 ; NH(CH 2

CH

2 NH)mCH 2

CH

2

NIIR

9 ; NHC(O)R 8 ; cyano; mercapto, SR 8 ; alkyl-thio-alkyl; alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, alkenyl, 15 alkynyl, each of which may be optionally substituted with halo, hydroxy, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, diheteroaryl amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, or 20 ureido; or R, R5, or R6 together combine with R 7 to form an [-O-CH 2 -] covalently bound bridge between the sugar 2' and 4' carbons. 43 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 A' is: W1 X -P- Y1 W1 Z1 X1- P---Y1 or X1==P--Y1 W1 Z I Z1 _ or I I x=P-Y 1 x1 P- Y X 1 P- Y1 I II Z1 Z 1 Z1 5 ; H; OH; OCH 3 ; W1; an abasic nucleotide; or absent; (a preferred Al , especially with regard to anti-sense strands, is chosen from 5' monophosphate ((HO) 2 (O)P-0-5'), 5'-diphosphate ((HO) 2 (O)P-0-P(HO)(O)-0-5'), 5' triphosphate ((HO) 2 (O)P-O-(HO)(O)P-0-P(HO)(O)-0-5'), 5'-guanosine cap (7-methylated or non-methylated) (7m-G-O-5'-(HO)(O)P-O-(HO)(O)P-0-P(HO)(O)-O-5'), 5'-adenosine cap 10 (Appp), and any modified or unmodified nucleotide cap structure (N-0-5'-(HO)(O)P-O (HO)(O)P-0-P(HO)(O)-O-5'), 5'-monothiophosphate (phosphorothioate; (HO) 2 (S)P-O-5'), 5' monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-O-5'), 5'-phosphorothiolate

((HO)

2 (O)P-S-5'); any additional combination of oxgen/sulfur replaced monophosphate, diphosphate and triphosphates (e.g. 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 15 5'-phosphoramidates ((HO) 2 (O)P-NH-5', (HO)(NH 2 )(O)P-0-5'),~5'-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-0-5'-, (OH) 2 (O)P-5'-CH 2 -), 5' 44 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g. RP(OH)(O)-O-5'-)).

A

2 is:

X

2 -P -Y 2 Z2

A

3 is: 3 Z3 ; and 45 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

A

4 is:

X

4 =P- Y 4 Z1 Z, X4=P- Y4 or X4---P---Y4 4 Aor,

X

4 P- Y 4

X

4 P- Y 4

X

4 - P----Y 4 Z4 Z4 5 ; H; Z 4 ; an inverted nucleotide; an abasic nucleotide; or absent. W' is OH, (CH 2 )nRl", (CH 2 )nNHR'", (CH 2 )n OR' 0 , (CH 2 )n SR' 0 ; O(CH 2 )nR' 0 ;

O(CH

2 )nOR' 0 , O(CH 2 )nNR' 0 , O(CH 2 )nSR 10 ; O(CH 2 )nSS(CH 2 )nOR' 0 , O(CH 2 )nC(O)OR' 0 ,

NH(CH

2 )nR' 0 ; NH(CH 2 )nNR1 0

;NH(CH

2 )nOR' 0 , NH(CH 2 )n SR' 0 ; S(CH 2 )nRl 0 , S(CH 2 )nNR' 0 ,

S(CH

2 )nOR' 0 , S(CH 2

),SR'

0

O(CH

2

CH

2 O)mCH 2

CH

2

OR'

0 ; O(CH 2

CH

2 O)mCH 2

CH

2

NHR'

0 , 10 NH(CH 2

CH

2 NH)mCH 2

CH

2 NHR1 0 ; Q-R 0 , O-Q-Rl 0

N-Q-R

0 , S-Q-R 10 or -0-. W 4 is 0, CH 2 , NH, or S. XI, X 2 , X 3 , and X 4 are each, independently, 0 or S. Yl, Y 2 , y 3 , and Y 4 are each, independently, OH, 0-, OR', S, Se, BH3~, H, NHR 9 , N(R) 2 alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl, each of which may be optionally substituted. 15 Z1, Z 2 , and Z 3 are each independently 0, CH 2 , NH, or S. Z 4 is OH, (CH 2 )nR 10 ,

(CH

2 )nNHR', (CH 2 )n OR' 0 , (CH 2 )n SR'"; O(CH 2 )nR1 0 ; O(CH 2 )nOR' 0 , O(CH 2 )nNR 0 , 46 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

O(CH

2 )nSR' 0 , O(CH 2 )nSS(CH 2 )nOR", O(CH 2 )nC(O)OR' 0 ; NH(CH 2 )nRo; NH(CH 2 )nNR 0

;NH(CH

2 )nOR' 0 , NH(CH 2 )nSRI 0 ; S(CH 2 )nR 0 , S(CH 2 )nNR 0 , S(CH 2 )nOR 0 , S(CH 2 )nSR 10

O(CH

2

CH

2 O)mCH 2

CH

2

OR

1 0 , O(CH 2

CH

2 0)mCH 2

CH

2

NHR'

0 ,

NH(CH

2

CH

2 NH)mCH 2

CH

2 NHRI; Q-R' 0 , O-Q-R' 0

N-Q-R

10 , S-Q-R1 0 . 5 x is 5-100, chosen to comply with a length for an RNA agent described herein. R7 is H; or is together combined with R 4 , R, or R 6 to form an [-O-CH 2 -] covalently bound bridge between the sugar 2' and 4' carbons. R8 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, amino acid, or sugar; R9 is

NH

2 , alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino, 10 diheteroaryl amino, or amino acid; and R1 0 is H; fluorophore (pyrene, TAMRA, fluorescein, Cy3 or Cy5 dyes); sulfur, silicon, boron or ester protecting group; intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4,texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipohilic carriers (cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric 15 acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid,myristic acid,03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine)and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polyamino; alkyl, cycloalkyl, aryl, aralkyl, 20 heteroaryl; radiolabelled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles); or an RNA agent. m is 0-1,000,000, and n is 0-20. Q is a spacer selected from the group consisting of abasic sugar, amide, carboxy, oxyamine, oxyimine, thioether, 25 disulfide, thiourea, sulfonamide, or morpholino, biotin or fluorescein reagents. 47 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072WO1 Preferred RNA agents in which the entire phosphate group has been replaced have the following structure (see Formula 3 below):

A

1 0 0 R70 x x0 R40 R20 0

R

70

A

30

R

50 R30

A

40

R

60 FORMULA 3 5 Referring to Formula 3, A10-A40 is L-G-L; A" and/or A 4 0 may be absent, in which L is a linker, wherein one or both L may be present or absent and is selected from the group consisting of CH 2

(CH

2 )g; N(CH2)g; O(CH2)g; S(CH2)g. G is a functional group selected from the group consisting of siloxane, carbonate, carboxymethyl, carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, 10 methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino. 48 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 R', R 20 , and R 30 are each, independently, H, (i.e. abasic nucleotides), adenine, guanine, cytosine and uracil, inosine, thymine, xanthine, hypoxanthine, nubularine, tubercidine, isoguanisine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2 propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl 5 uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 5 halouracil, 5-(2-aminopropyl)uracil, 5-amino allyl uracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5 substituted uracils and cytosines, 7-methylguanine, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil 10 and 5-propynylcytosine, dihydrouracil, 3-deaza-5-azacytosine, 2-aminopurine, 5-alkyluracil, 7 alkylguanine, 5-alkyl cytosine,7-deazaadenine, 7-deazaguanine, N6, N6-dimethyladenine, 2,6 diaminopurine, 5-amino-allyl-uracil, N3-methyluracil substituted 1,2,4-triazoles, 2-pyridinone, 5-nitroindole, 3-nitropyrrole, 5-methoxyuracil, uracil-5-oxyacetic acid, 5 methoxycarbonylmethyluracil, 5-methyl-2-thiouracil, 5-methoxycarbonylmethyl-2-thiouracil, 5 15 methylaminomethyl-2-thiouracil, 3-(3-amino-3carboxypropyl)uracil, 3-methylcytosine, 5 methylcytosine, N 4 -acetyl cytosine, 2-thiocytosine, N6-methyladenine, N6-isopentyladenine, 2 methylthio-N6-isopentenyladenine, N-methylguanines, or O-alkylated bases. R4, R, and R 60 are each, independently, OR 8 , O(CH 2

CH

2 O)mCH 2

CH

2 OR; O(CH 2 )nR 9 ;

O(CH

2 )nOR 9 , H; halo; NH 2 ; NHRe; N(R) 2 ; NH(CH 2

CH

2 NH)mCH 2

CH

2

R

9 ; NHC(O)R;; cyano; 20 mercapto, SR 7 ; alkyl-thio-alkyl; alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, each of which may be optionally substituted with halo, hydroxy, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, diheteroaryl amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, alkanesulfonamido, 25 arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups; or R4, R50, or R60 together combine with R 70 to form an [-O-CH 2 -] covalently bound bridge between the sugar 2' and 4' carbons. x is 5-100 or chosen to comply with a length for an RNA agent described herein. 49 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

R

70 is H; or is together combined with R 40 , R 50 , or R 60 to form an [-O-CH 2 -] covalently bound bridge between the sugar 2' and 4' carbons.

R

8 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, amino acid, or sugar; and

R

9 is NH 2 , alkylamino, dialkylamino, heterocyclyl, arylamino, diary amino, heteroaryl amino, 5 diheteroaryl amino, or amino acid. m is 0-1,000,000, n is 0-20, and g is 0-2. Preferred nucleoside surrogates have the following structure (see Formula 4 below): SLR 00

-(M-SLR

2 o)x-M-SLR 300 FORMULA 4 10 S is a nucleoside surrogate selected from the group consisting of mophilino, cyclobutyl, pyrrolidine and peptide nucleic acid. L is a linker and is selected from the group consisting of

CH

2

(CH

2 )g; N(CH2)g; O(CH2)g; S(CH 2 )g; -C(O)(CH 2 )-or may be absent. M is an amide bond; sulfonamide; sulfinate; phosphate group; modified phosphate group as described herein; or may be absent. 15 R1 00 , R200, and R 3 oo are each, independently, H (i.e., abasic nucleotides), adenine, guanine, cytosine and uracil, inosine, thymine, xanthine, hypoxanthine, nubularine, tubercidine, isoguanisine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2 propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 5 20 halouracil, 5-(2-aminopropyl)uracil, 5-amino allyl uracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5 substituted uracils and cytosines, 7-methylguanine, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, dihydrouracil, 3-deaza-5-azacytosine, 2-aminopurine, 5-alkyluracil, 7 25 alkylguanine, 5-alkyl cytosine,7-deazaadenine, 7-deazaguanine, N6, N6-dimethyladenine, 2,6 diaminopurine, 5-amino-allyl-uracil, N3-methyluracil substituted 1, 2, 4,-triazoles, 2 pyridinones, 5-nitroindole, 3-nitropyrrole, 5-methoxyuracil, uracil-5-oxyacetic acid, 5 50 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 methoxycarbonylmethyluracil, 5-methyl-2-thiouracil, 5-methoxycarbonylmethyl-2-thiouracil, 5 methylaminomethyl-2-thiouracil, 3 -(3-amino-3carboxypropyl)uracil, 3-methylcytosine, 5 methyleytosine, N 4 -acetyl cytosine, 2-thiocytosine, N6-methyladenine, N6-isopentyladenine, 2 methylthio-N6-isopentenyladenine, N-methylguanines, or O-alkylated bases. 5 x is 5-100, or chosen to comply with a length for an RNA agent described herein; and g is 0-2. Nuclease resistant monomers An RNA, e.g., an iRNA agent, can incorporate a nuclease resistant monomer (NRM), such as those described herein and those described in copending, co-owned United States 10 Provisional Application Serial No. 60/469,612, filed on May 9, 2003, and International Application No. PCT/USO4/07070, both of which are hereby incorporated by reference. In addition, the invention includes iRNA agents having an NRM and another element described herein. E.g., the invention includes an iRNA agent described herein, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which 15 targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an architecture or structure described herein, an iRNA associated with an amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates an NRM. 20 An iRNA agent can include monomers which have been modifed so as to inhibit degradation, e.g., by nucleases, e.g., endonucleases or exonucleases, found in the body of a subject. These monomers are referred to herein as NRMs, or nuclease resistance promoting monomers or modifications. In many cases these modifications will modulate other properties of the iRNA agent as well, e.g., the ability to interact with a protein, e.g., a transport protein, e.g., 25 serum albumin, or a member of the RISC (RNA-induced Silencing Complex), or the ability of the first and second sequences to form a duplex with one another or to form a duplex with another sequence, e.g., a target molecule. 51 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 While not wishing to be bound by theory, it is believed that modifications of the sugar, base, and/or phosphate backbone in an iRNA agent can enhance endonuclease and exonuclease resistance, and can enhance interactions with transporter proteins and one or more of the functional components of the RISC complex. Preferred modifications are those that increase 5 exonuclease and endonuclease resistance and thus prolong the half-life of the iRNA agent prior to interaction with the RISC complex, but at the same time do not render the iRNA agent resistant to endonuclease activity in the RISC complex. Again, while not wishing to be bound by any theory, it is believed that placement of the modifications at or near the 3' and/or 5' end of antisense strands can result in iRNA agents that meet the preferred nuclease resistance criteria 10 delineated above. Again, still while not wishing to be bound by any theory, it is believed that placement of the modifications at e.g., the middle of a sense strand can result in iRNA agents that are relatively less likely to undergo off-targeting. Modifications described herein can be incorporated into any double-stranded RNA and RNA-like molecule described herein, e.g., an iRNA agent. An iRNA agent may include a duplex 15 comprising a hybridized sense and antisense strand, in which the antisense strand and/or the sense strand may include one or more of the modifications described herein. The anti sense strand may include modifications at the 3' end and/or the 5' end and/or at one or more positions that occur 1-6 (e.g., 1-5, 1-4, 1-3, 1-2) nucleotides from either end of the strand. The sense strand may include modifications at the 3' end and/or the 5' end and/or at any one of the 20 intervening positions between the two ends of the strand. The iRNA agent may also include a duplex comprising two hybridized antisense strands. The first and/or the second antisense strand may include one or more of the modifications described herein. Thus, one and/or both antisense strands may include modifications at the 3' end and/or the 5' end and/or at one or more positions that occur 1-6 (e.g., 1-5, 1-4, 1-3, 1-2) nucleotides from either end of the strand. Particular 25 configurations are discussed below. Modifications that can be useful for producing iRNA agents that meet the preferred nuclease resistance criteria delineated above can include one or more of the following chemical and/or stereochemical modifications of the sugar, base, and/or phosphate backbone: 52 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (i) chiral (Sp) thioates. Thus, preferred NRMs include nucleotide dimers with an enriched or pure for a particular chiral form of a modified phosphate group containing a heteroatom at the nonbridging position, e.g., Sp or Rp, at the position X, where this is the position normally occupied by the oxygen. The atom at X can also be S, Se, Nr 2 , or Br 3 . When X is S, enriched or 5 chirally pure Sp linkage is preferred. Enriched means at least 70, 80, 90, 95, or 99% of the preferred form. Such NRMs are discussed in more detail below; (ii) attachment of one or more cationic groups to the sugar, base, and/or the phosphorus atom of a phosphate or modified phosphate backbone moiety. Thus, preferred NRMs include monomers at the terminal position derivatized at a cationic group. As the 5' end of an antisense 10 sequence should have a terminal -OH or phosphate group this NRM is preferably not used at the 5' end of an anti-sense sequence. The group should be attached at a position on the base which minimizes interference with H bond formation and hybridization, e.g., away form the face which interacts with the complementary base on the other strand, e.g, at the 5' position of a pyrimidine or a 7-position of a purine. These are discussed in more detail below; 15 (iii) nonphosphate linkages at the termini. Thus, preferred NRMs include Non-phosphate linkages, e.g., a linkage of 4 atoms which confers greater resistance to cleavage than does a phosphate bond. Examples include 3' CH2-NCH 3 -O-CH2-5' and 3' CH2-NH-(O=)-CH2-5'.; (iv) 3'-bridging thiophosphates and 5'-bridging thiophosphates. Thus, preferred NRM's can included these structures; 20 (v) L-RNA, 2'-5' linkages, inverted linkages, a-nucleosides. Thus, other preferred NRM's include: L nucleosides and dimeric nucleotides derived from L-nucleosides; 2'-5' phosphate, non-phosphate and modified phosphate linkages (e.g., thiophosphates, phosphoramidates and boronophosphates); dimers having inverted linkages, e.g., 3'-3' or 5'-5' linkages; monomers having an alpha linkage at the 1' site on the sugar, e.g., the structures 25 described herein having an alpha linkage; (vi) conjugate groups. Thus, preferred NRM's can include e.g., a targeting moiety or a conjugated ligand described herein conjugated with the monomer, e.g., through the sugar, base, or backbone; 53 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (vi) abasic linkages. Thus, preferred NRM's can include an abasic monomer, e.g., an abasic monomer as described herein (e.g., a nucleobaseless monomer); an aromatic or heterocyclic or polyheterocyclic aromatic monomer as described herein.; and (vii) 5'-phosphonates and 5'-phosphate prodrugs. Thus, preferred NRM's include 5 monomers, preferably at the terminal position, e.g., the 5' position, in which one or more atoms of the phosphate group is derivatized with a protecting group, which protecting group or groups, are removed as a result of the action of a component in the subject's body, e.g, a carboxyesterase or an enzyme present in the subject's body. E.g., a phosphate prodrug in which a carboxy esterase cleaves the protected molecule resulting in the production of a thioate anion which 10 attacks a carbon adjacent to the 0 of a phosphate and resulting in the production of an unprotected phosphate. One or more different NRM modifications can be introduced into an iRNA agent or into a sequence of an iRNA agent. An NRM modification can be used more than once in a sequence or in an iRNA agent. As some NRM's interfere with hybridization the total number 15 incorporated, should be such that acceptable levels of iRNA agent duplex formation are maintained. In some embodiments NRM modifications are introduced into the terminal the cleavage site or in the cleavage region of a sequence (a sense strand or sequence) which does not target a desired sequence or gene in the subject. This can reduce off-target silencing. 20 Chiral Sp Thioates A modification can include the alteration, e.g., replacement, of one or both of the non linking (X and Y) phosphate oxygens and/or of one or more of the linking (W and Z) phosphate oxygens. Formula X below depicts a phosphate moiety linking two sugar/sugar surrogate-base moieties, SB 1 and SB 2 . 54 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

WSB

1 Z_

SB

2 FORMULA X In certain embodiments, one of the non-linking phosphate oxygens in the phosphate 5 backbone moiety (X and Y) can be replaced by any one of the following: S, Se, BR 3 (R is hydrogen, alkyl, aryl, etc.), C (i.e., an alkyl group, an aryl group, etc.), H, NR 2 (R is hydrogen, alkyl, aryl, etc.), or OR (R is alkyl or aryl). The phosphorus atom in an unmodified phosphate group is achiral. However, replacement of one of the non-linking oxygens with one of the above atoms or groups of atoms renders the phosphorus atom chiral; in other words a phosphorus atom 10 in a phosphate group modified in this way is a stereogenic center. The stereogenic phosphorus atom can possess either the "R" configuration (herein Rp) or the "S" configuration (herein Sp). Thus if 60% of a population of stereogenic phosphorus atoms have the Rp configuration, then the remaining 40% of the population of stereogenic phosphorus atoms have the Sp configuration. In some embodiments, iRNA agents, having phosphate groups in which a phosphate non 15 linking oxygen has been replaced by another atom or group of atoms, may contain a population of stereogenic phosphorus atoms in which at least about 50% of these atoms (e.g., at least about 60% of these atoms, at least about 70% of these atoms, at least about 80% of these atoms, at least about 90% of these atoms, at least about 95% of these atoms, at least about 98% of these atoms, at least about 99% of these atoms) have the Sp configuration. Alternatively, iRNA agents having 20 phosphate groups in which a phosphate non-linking oxygen has been replaced by another atom or group of atoms may contain a population of stereogenic phosphorus atoms in which at least about 50% of these atoms (e.g., at least about 60% of these atoms, at least about 70% of these 55 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 atoms, at least about 80% of these atoms, at least about 90% of these atoms, at least about 95% of these atoms, at least about 98% of these atoms, at least about 99% of these atoms) have the Rp configuration. In other embodiments, the population of stereogenic phosphorus atoms may have the Sp configuration and may be substantially free of stereogenic phosphorus atoms having the 5 Rp configuration. In still other embodiments, the population of stereogenic phosphorus atoms may have the Rp configuration and may be substantially free of stereogenic phosphorus atoms having the Sp configuration. As used herein, the phrase "substantially free of stereogenic phosphorus atoms having the Rp configuration" means that moieties containing stereogenic phosphorus atoms having the Rr configuration cannot be detected by conventional methods 10 known in the art (chiral HPLC, 1H NMR analysis using chiral shift reagents, etc.). As used herein, the phrase "substantially free of stereogenic phosphorus atoms having the Sp configuration" means that moieties containing stereogenic phosphorus atoms having the Sp configuration cannot be detected by conventional methods known in the art (chiral HIPLC, 1H NMR analysis using chiral shift reagents, etc.). 15 In a preferred embodiment, modified iRNA agents contain a phosphorothioate group, i.e., a phosphate groups in which a phosphate non-linking oxygen has been replaced by a sulfur atom. In an especially preferred embodiment, the population of phosphorothioate stereogenic phosphorus atoms may have the Sp configuration and be substantially free of stereogenic phosphorus atoms having the Rr configuration., 20 Phosphorothioates may be incorporated into iRNA agents using dimers e.g., formulas X 1 and X-2. The former can be used to introduce phosphorothioate 56 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 DMTO DMTO o BASE O BASE R21 R2' I I S-P-Y S P-y Z Z o BASE o BASE O R2' O R2' I NC 0 solid phase reagent p 0 N(ipr) 2 X-1 X-2 at the 3' end of a strand, while the latter can be used to introduce this modification at the 5' end or at a position that occurs e.g., 1, 2, 3, 4, 5, or 6 nucleotides from either end of the strand. In the 5 above formulas, Y can be 2-cyanoethoxy, W and Z can be 0, R 2 , can be, e.g., a substituent that can impart the C-3 endo configuration to the sugar (e.g., OH, F, OCH 3 ), DMT is dimethoxytrityl, and "BASE" can be a natural, unusual, or a universal base. X-1 and X-2 can be prepared using chiral reagents or directing groups that can result in phosphorothioate-containing dimers having a population of stereogenic phosphorus atoms 10 having essentially only the Rp configuration (i.e., being substantially free of the Sp configuration) or only the Sp configuration (i.e., being substantially free of the Rp configuration). Alternatively, dimers can be prepared having a population of stereogenic phosphorus atoms in which about 57 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 50% of the atoms have the Rp configuration and about 50% of the atoms have the Sp configuration. Dimers having stereogenic phosphorus atoms with the Rp configuration can be identified and separated from dimers having stereogenic phosphorus atoms with the Sp configuration using e.g., enzymatic degradation and/or conventional chromatography techniques. 5 Cationic Groups Modifications can also include attachment of one or more cationic groups to the sugar, base, and/or the phosphorus atom of a phosphate or modified phosphate backbone moiety. A cationic group can be attached to any atom capable of substitution on a natural, unusual or universal base. A preferred position is one that does not interfere with hybridization, i.e., does 10 not interfere with the hydrogen bonding interactions needed for base pairing. A cationic group can be attached e.g., through the C2' position of a sugar or analogous position in a cyclic or acyclic sugar surrogate. Cationic groups can include e.g., protonated amino groups, derived from e.g., 0-AMINE (AMINE = NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, or diheteroaryl amino, ethylene diamine, polyamino); aminoalkoxy, 15 e.g., O(CH 2 )nAMINE, (e.g., AMINE = NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, or diheteroaryl amino, ethylene diamine, polyamino); amino (e.g. NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, diheteroaryl amino, or amino acid); or NH(CH 2

CH

2 NH)nCH 2

CH

2 -AMINE (AMINE =NH 2 ; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino,or 20 diheteroaryl amino). Nonphosphate Linkages Modifications can also include the incorporation of nonphosphate linkages at the 5' and/or 3' end of a strand. Examples of nonphosphate linkages which can replace the phosphate group include methyl phosphonate, hydroxylamino, siloxane, carbonate, carboxymethyl, 25 carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino. Preferred replacements include the methyl phosphonate and hydroxylamino groups. 58 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 3'-bridging thiophosphates and 5 '-bridging thiophosphates; locked-RNA, 2 '-5' likages, inverted linkages, a-nucleosides; conjugate groups; abasic linkages; and 5'-phosphonates and 5 '-phosphate prodrugs Referring to formula X above, modifications can include replacement of one of the 5 bridging or linking phosphate oxygens in the phosphate backbone moiety (W and Z). Unlike the situation where only one of X or Y is altered, the phosphorus center in the phosphorodithioates is achiral which precludes the formation of iRNA agents containing a stereogenic phosphorus atom. Modifications can also include linking two sugars via a phosphate or modified phosphate 10 group through the 2' position of a first sugar and the 5' position of a second sugar. Also contemplated are inverted linkages in which both a first and second sugar are eached linked through the respective3' positions. Modified RNA's can also include "abasic" sugars, which lack a nucleobase at C-i'. The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a 15 modified iRNA agent can include nucleotides containing e.g., arabinose, as the sugar. In another subset of this modification, the natural, unusual, or universal base may have the a-configuration. Modifcations can also include L-RNA. Modifications can also include 5'-phosphonates, e.g., P(O)(0-) 2

-X-C

5 -sugar (X= CH2, CF2, CHF and 5'-phosphate prodrugs, e.g., P(O)[OCH2CH2SC(O)R] 2

CH

2

C

5 -sugar. In the 20 latter case, the prodrug groups may be decomposed via reaction first with carboxy esterases. The remaining ethyl thiolate group via intramolecular SN2 displacement can depart as episulfide to afford the underivatized phosphate group. Modification can also include the addition of conjugating groups described elsewhere herein, which are prefereably attached to an iRNA agent through any amino group available for 25 conjugation. Nuclease resistant modifications include some which can be placed only at the terminus and others which can go at any position. Generally the modifications that can inhibit hybridization so it is preferably to use them only in terminal regions, and preferrable to not use 59 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 them at the cleavage site or in the cleavage region of an sequence which targets a subject sequence or gene.. The can be used anywhere in a sense sequence, provided that sufficient hybridization between the two sequences of the iRNA agent is maintained. In some embodiments it is desirabable to put the NRM at the cleavage site or in the cleavage region of a 5 sequence which does not target a subject sequence or gene,as it can minimize off-target silencing. In addition, an iRNA agent described herein can have an overhang which does not form a duplex structure with the other sequence of the iRNA agent-it is an overhang, but it does hybridize, either with itself, or with another nucleic acid, other than the other sequence of the 10 iRNA agent. In most cases, the nuclease-resistance promoting modifications will be distributed differently depending on whether the sequence will target a sequence in the subject (often referred to as an anti-sense sequence) or will not target a sequence in the subject (often referred to as a sense sequence). If a sequence is to target a sequence in the subject, modifications which 15 interfer with or inhibit endonuclease cleavage should not be inserted in the region which is subject to RISC mediated cleavage, e.g., the cleavage site or the cleavage region (As described in Elbashir et al., 2001, Genes and Dev. 15: 188, hereby incorporated by reference, cleavage of the target occurs about in the middle of a 20 or 21 nt guide RNA, or about 10 or 11 nucleotides upstream of the first nucleotide which is complementary to the guide sequence. As used herein 20 cleavage site refers to the nucleotide on either side of the cleavage site, on the target or on the iRNA agent strand which hybridizes to it. Cleavage region means an nucleotide with 1, 2, or 3 nucletides of the cleave site, in either direction.) Such modifications can be introduced into the terminal regions, e.g., at the terminal position or with 2, 3, 4, or 5 positions of the terminus, of a sequence which targets or a sequence 25 which does not target a sequence in the subject. An iRNA agent can have a first and a second strand chosen from the following: a first strand which does not target a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end; 60 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 a first strand which does not target a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end; a first strand which does not target a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end and which has a NRM modification at or 5 within 1, 2, 3, 4, 5 , or 6 positions from the 5' end; a first strand which does not target a sequence and which has an NRM modification at the cleavage site or in the cleavage region; a first strand which does not target a sequence and which has an NRM modification at the cleavage site or in the cleavage region and one or more of an NRM modification at or within 1, 10 2, 3, 4, 5 , or 6 positions from the 3' end, a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end, or NRM modifications at or within 1, 2, 3, 4, 5 , or 6 positions from both the 3' and the 5' end; and a second strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end; 15 a second strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end (5' end NRM modifications are preferentially not at the terminus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense strand); a second strand which targets a sequence and which has an NRM modification at or 20 within 1, 2, 3, 4, 5 , or 6 positions from the 3' end and which has a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end; a second strand which targets a sequence and which preferably does not have an an NRM modification at the cleavage site or in the cleavage region; a second strand which targets a sequence and which does not have an NRM modification 25 at the cleavage site or in the cleavage region and one or more of an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end, a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end, or NRM modifications at or within 1, 2, 3, 4, 5 , or 6 positions 61 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 from both the 3' and the 5' end(5' end NRM modifications are preferentially not at the terminus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense strand). An iRNA agent can also target two sequences and can have a first and second strand chosen from: 5 a first strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end; a first strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end (5' end NRM modifications are preferentially not at the terminus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense 10 strand); a first strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end and which has a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end; a first strand which targets a sequence and which preferably does not have an an NRM 15 modification at the cleavage site or in the cleavage region; a first strand which targets a sequence and which dose not have an NRM modification at the cleavage site or in the cleavage region and one or more of an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end, a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end, or NRM modifications at or within 1, 2, 3, 4, 5 , or 6 positions from 20 both the 3' and the 5' end(5' end NRM modifications are preferentially not at the terminus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense strand) and a second strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end; a second strand which targets a sequence and which has an NRM modification at or 25 within 1, 2, 3, 4, 5 , or 6 positions from the 5' end (5' end NRM modifications are preferentially not at the terminus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense strand); 62 a second strand which targets a sequence and which has an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end and which has a NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 5' end; a second strand which targets a sequence and which preferably does not have an an NRM 5 modification at the cleavage site or in the cleavage region; a second strand which targets a sequence and which dose not have an NRM modification at the cleavage site or in the cleavage region and one or more of an NRM modification at or within 1, 2, 3, 4, 5 , or 6 positions from the 3' end, a NRM modification at or within 1, 2, 3, 4, 5, or 6 positions from the 5' end, or NRM modifications at or within 1, 2, 3, 4, 5 , or 6 positions 10 from both the 3' and the 5' end(5' end NRM modifications are preferentially not at the tenninus but rather at a position 1, 2, 3, 4, 5 , or 6 away from the 5' terminus of an antisense strand). Ribose Mimics An RNA, e.g., an iRNA agent, can incorporate a ribose mimic, such as those described herein and those described in copending co-owned United States Provisional Application Serial 15 No. 60/454,962, filed on March 13, 2003, and International Application No. PCT/US04/07070, both of which are hereby incorporated by reference. Described herein are iRNA agents having a ribose mimic and another element described herein. E.g., described herein is an iRNA agent described herein, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which 20 targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an architecture or structure described herein, an iRNA associated with an amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates a ribose mimic. 25 .Thus, described herein is an iRNA agent that includes a secondary hydroxyl group, which can increase efficacy and/or confer nuclease resistance to the agent. Nucleases, e.g., cellular nucleases, can hydrolyze nucleic acid phosphodiester bonds, resulting in partial or complete degradation of the nucleic acid. The secondary hydroxy group confers 63 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 I nuclease resistance to an iRNA agent by rendering the iRNA agent less prone to nuclease degradation relative to an iRNA which lacks the modification. While not wishing to be bound by theory, it is believed that the presence of a secondary hydroxyl group on the iRNA agent can act as a structural mimic of a 3' ribose hydroxyl group, thereby causing it to be less susceptible 5 to degradation. The secondary hydroxyl group refers to an "OH" radical that is attached to a carbon atom substituted by two other carbons and a hydrogen. The secondary hydroxyl group that confers nuclease resistance as described above can be part of any acyclic carbon-containing group. The hydroxyl may also be part of any cyclic carbon-containing group, and preferably one or more of 10 the following conditions is met (1) there is no ribose moiety between the hydroxyl group and the terminal phosphate group or (2) the hydroxyl group is not on a sugar moiety which is coupled to a base.. The hydroxyl group is located at least two bonds (e.g., at least three bonds away, at least four bonds away, at least five bonds away, at least six bonds away, at least seven bonds away, at least eight bonds away, at least nine bonds away, at least ten bonds away, etc.) from the terminal 15 phosphate group phosphorus of the iRNA agent. In preferred embodiments, there are five intervening bonds between the terminal phosphate group phosphorus and the secondary hydroxyl group. Preferred iRNA agent delivery modules with five intervening bonds between the terminal phosphate group phosphorus and the secondary hydroxyl group have the following structure (see 20 formula Y below): A X 'CH2 R3 R4 RNHT R2

R

5

OR

7 R6 64 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (Y) Referring to formula Y, A is an iRNA agent, including any iRNA agent described herein. The iRNA agent may be connected directly or indirectly (e.g., through a spacer or linker) to "W" 5 of the phosphate group. These spacers or linkers can include e.g., -(CH 2 )n-, -(CH 2 )nN-, (CH 2 )nO-, -(CH 2 )nS-, O(CH 2

CH

2 0) 0

CH

2

CH

2 OH (e.g., n = 3 or 6), abasic sugars, amide, carboxy, amine, oxyamine, oxyimine, thioether, disulfide, thiourea, sulfonamide, or morpholino, or biotin and fluorescein reagents. The iRNA agents can have a terminal phosphate group that is unmodified (e.g., W, X, Y, 10 and Z are 0) or modified. In a modified phosphate group, W and Z can be independently NH, 0, or S; and X and Y can be independently S, Se, BHf, C 1

-C

6 alkyl, C 6

-C

1 0 aryl, H, 0, 0-, alkoxy or amino (including alkylamino, arylamino, etc.). Preferably, W, X and Z are 0 and Y is S.

R

1 and R 3 are each, independently, hydrogen; or CI-C 100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, 0, S, 15 alkenyl or alkynyl.

R

2 is hydrogen; C 1

-C

100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, 0, S, alkenyl or alkynyl; or, when n is 1, R 2 may be taken together with with R 4 or R 6 to form a ring of 5-12 atoms.

R

4 is hydrogen; C 1

-C

100 alkyl, optionally substituted with hydroxyl, amino, halo, 20 phosphate or sulfate and/or may be optionally inserted with N, 0, S, alkenyl or alkynyl; or, when n is 1, R 4 may be taken together with with R 2 or R 5 to form a ring of 5-12 atoms.

R

5 is hydrogen, C 1

-C

1 oo alkyl optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, 0, S, alkenyl or alkynyl; or, when n is 1, R 5 may be taken together with with R 4 to form a ring of 5-12 atoms. 25 R 6 is hydrogen, C 1

-C

1 oo alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, 0, S, alkenyl or alkynyl, or, when n is 1, R 6 may be taken together with with R 2 to form a ring of 6-10 atoms; 65 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1

R

7 is hydrogen, C 1 -C1 00 alkyl, or C(O)(CH 2 )qC(O)NHR 9 ; T is hydrogen or a functional group; n and q are each independently 1-100; R 8 is C 1 -C10 alkyl or C 6

-C

10 aryl; and R 9 is hydrogen, Cl-C10 alkyl, C6-C1O aryl or a solid support agent. Preferred embodiments may include one of more of the following subsets of iRNA agent 5 delivery modules. In one subset of RNAi agent delivery modules, A can be connected directly or indirectly through a terminal 3' or 5' ribose sugar carbon of the RNA agent. In another subset of RNAi agent delivery modules, X, W, and Z are 0 and Y is S. In still yet another subset of RNAi agent delivery modules, n is 1, and R 2 and R 6 are 10 taken together to form a ring containing six atoms and R 4 and R 5 are taken together to form a ring containing six atoms. Preferably, the ring system is a trans-decalin. For example, the RNAi agent delivery module of this subset can include a compound of Formula (Y-1): A I NHT S O0

-

HO The functional group can be, for example, a targeting group (e.g., a steroid or a 15 carbohydrate), a reporter group (e.g., a fluorophore), or a label (an isotopically labelled moiety). The targeting group can further include protein binding agents, endothelial cell targeting groups (e.g., RGD peptides and mimetics), cancer cell targeting groups (e.g., folate Vitamin B12, Biotin), bone cell targeting groups (e.g., bisphosphonates, polyglutamates, polyaspartates), multivalent mannose (for e.g., macrophage testing), lactose, galactose, N-acetyl-galactosamine, 20 monoclonal antibodies, glycoproteins, lectins, melanotropin, or thyrotropin. 66 As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. 5 Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic RTansformations, VCH Publishers (1989); T.W. Greene and P.GM. 10 Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagentsfor Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia ofReagentsfor Organic Synthesis,, John Wiley and Sons (1995), and subsequent editions thereof. Ribose Replacement Monomer Subunits 15 iRNA agents can be modified in a number of ways which can optimize one or more characteristics of the iRNA agent. An RNA agent, e.g., an iRNA agent can include a ribose replacement monomer subunit (RRMS), such as those described herein and those described in one or more of United States Provisional Application Serial No. 60/493,986, filed on August 8, 2003, which is hereby incorporated by reference; United States Provisional 20 Application Serial No. 60/494,597, filed on August 11, 2003, which is hereby incorporated by reference; United States Provisional Application Serial No. 60/506,341, filed on September 26, 2003, which is hereby incorporated by reference; United States Provisional Application Serial No. 60/158,453, filed on November 7, 2003, which is hereby incorporated by reference; and International Application No. PCT/USO4/07070, filed March 8, 2004, which is hereby 25 incorporated by reference. In addition, described herein are iRNA agents having a RRMS and another element described herein. E.g., described here is an iRNA agent described herein, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an 67 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 architecture or structure described herein, an iRNA associated with an amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates a RRMS. 5 The ribose sugar of one or more ribonucleotide subunits of an iRNA agent can be replaced with another moiety, e.g., a non-carbohydrate (preferably cyclic) carrier. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred to herein as a ribose replacement modification subunit (RRMS). A cyclic carrier may be a carbocyclic ring system, i.e., all ring atoms are carbon atoms, or a heterocyclic ring system, i.e., 10 one or more ring atoms may be a heteroatom, e.g., nitrogen, oxygen, sulfur. The cyclic carrier may be a monocyclic ring system, or may contain two or more rings, e.g. fused rings. The cyclic carrier may be a fully saturated ring system, or it may contain one or more double bonds. The carriers further include (i) at least two "backbone attachment points" and (ii) at least one "tethering attachment point." A "backbone attachment point" as used herein refers to a 15 functional group, e.g. a hydroxyl group, or generally, a bond available for, and that is suitable for incorporation of the carrier into the backbone, e.g., the phosphate, or modified phosphate, e.g., sulfur containing, backbone, of a ribonucleic acid. A "tethering attachment point" as used herein refers to a constituent ring atom of the cyclic carrier, e.g., a carbon atom or a heteroatom (distinct from an atom which provides a backbone attachment point), that connects a selected moiety. 20 The moiety can be, e.g., a ligand, e.g., a targeting or delivery moiety, or a moiety which alters a physical property, e.g., lipophilicity, of an iRNA agent. Optionally, the selected moiety is connected by an intervening tether to the cyclic carrier. Thus, it will include a functional group, e.g., an amino group, or generally, provide a bond, that is suitable for incorporation or tethering of another chemical entity, e.g., a ligand to the constituent ring. 25 Incorporation of one or more RRMSs described herein into an RNA agent, e.g., an iRNA agent, particularly when tethered to an appropriate entity, can confer one or more new properties to the RNA agent and/or alter, enhance or modulate one or more existing properties in the RNA molecule. E.g., it can alter one or more of lipophilicity or nuclease resistance. Incorporation of one or more RRMSs described herein into an iRNA agent can, particularly when the RRMS is 68 tethered to an appropriate entity, modulate, e.g., increase, binding affinity of an iRNA agent to a target mRNA, change the geometry of the duplex form of the iRNA agent, alter distribution or target the iRNA agent to a particular part of the body, or modify the interaction with nucleic acid binding proteins (e.g., during RISC formation and strand separation). 5 Accordingly, described herein is an iRNA agent preferably comprising a first strand and a second strand, wherein at least one subunit having a formula (R-1) is incorporated into at least one of said strands. R IR6 R2 R5 R3 z .R4 (R-1) 10 Referring to formula (R-1), X is N(CO)R 7 , NR 7 or CH 2 ; Y is NR 8 , 0, S, CR 9 R', or absent; and Z is CR 11

RI

2 or absent. Each of R1, R 2 , R 3 , R 4 , R 9 , and R1 0 is, independently, H, ORa, ORb, (CH 2 )nORa, or

(CH

2 )nORe, provided that at least one of RI, R 2 , R 3 , R 4 , R 9 , and R' 0 is OR or ORb and that at least one of R1, R 2 , R 3 , R 4 , R, and R' 0 is (CH 2 )nORa, or (CH 2 )nOR (when the RRMS is terminal, 15 one of R1, R 2 , RW, R 4 , R?, and R 10 will include Ra and one will include Rb; when the RRMS is internal, two of R 1 , R 2 , R 3 , R 4 , R9, and R' 0 will each include an Rb); further provided that preferably ORa may only be present with (CH 2 )nORb and (CH 2 )nORa may only be present with ORb. Each of R5, R, R", and R 1 2 is, independently, H, C-C 6 alkyl optionally substituted with 20 1-3 R 3 , or C(O)NHR 7 ; or R 5 and R" together are C 3 -C& cycloalkyl optionally substituted with

R'

4 . 69 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1

R

7 is Cr-C 20 alkyl substituted with NRcRd; RI is C 1 -C, alkyl; R' 3 is hydroxy, C-C 4 alkoxy, or halo; and R 1 4 is NOR 7 . 5 Rais: A -P--B C and 10 Rb is: A In P-O-Strand C Each of A and C is, independently, 0 or S. B is OH, 0, or 70 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 O 0 O-P-0-P-OH Rc is H or Cl-C6 alkyl; Rd is H or a ligand; and n is 1-4. In a preferred embodiment the ribose is replaced with a pyrroline scaffold, and X is 5 N(CO)R or NR 7 , Y is CR 9

R'

0 , and Z is absent. In other preferred embodiments the ribose is replaced with a piperidine scaffold, and X is

N(CO)R

7 or NR 7 , Y is CR 9

R

1 0 , and Z is CR"R'. In other preferred embodiments the ribose is replaced with a piperazine scaffold, and X is N(CO)R orNR, Y is NR', and Z is CR"R . 10 In other preferred embodiments the ribose is replaced with a morpholino scaffold, and X is N(CO)R 7 or NR 7 , Y is 0, and Z is CR" ' 2 . In other preferred embodiments the ribose is replaced with a decalin scaffold, and X isCH 2 ; Y is CR 9 R1 0 ; and Z is CR"R 1 2 ; and Rs and R" together are C 6 cycloalkyl. In other preferred embodiments the ribose is replaced with a decalin/indane scafold and, 15 and X is CH 2 ; Y is CR 9

R

10 ; and Z is CR"R 1 2 ; and R5 and R" together are C 5 cycloalkyl. In other preferred embodiments, the ribose is replaced with a hydroxyproline scaffold. RRMSs described herein may be incorporated into any double-stranded RNA-like molecule described herein, e.g., an iRNA agent. An iRNA agent may include a duplex comprising a hybridized sense and antisense strand, in which the antisense strand and/or the 20 sense strand may include one or more of the RRMSs described herein. An RRMS can be introduced at one or more points in one or both strands of a double-stranded iRNA agent. An 71 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 RRMS can be placed at or near (within 1, 2, or 3 positions) of the 3' or 5' end of the sense strand or at near (within 2 or 3 positions of) the 3' end of the antisense strand. In some embodiments it is preferred to not have an RRMS at or near (within 1, 2, or 3 positions of) the 5' end of the antisense strand. An RRMS can be internal, and will preferably be positioned in regions not 5 critical for antisense binding to the target. In an embodiment, an iRNA agent may have an RRMS at (or within 1, 2, or 3 positions of) the 3' end of the antisense strand. In an embodiment, an iRNA agent may have an RRMS at (or within 1, 2, or 3 positions of) the 3' end of the antisense strand and at (or within 1, 2, or 3 positions of) the 3' end of the sense strand. In an embodiment, an iRNA agent may have an 10 RRMS at (or within 1, 2, or 3 positions of) the 3' end of the antisense strand and an RRMS at the 5' end of the sense strand, in which both ligands are located at the same end of the iRNA agent. In certain embodiments, two ligands are tethered, preferably, one on each strand and are hydrophobic moieties. While not wishing to be bound by theory, it is believed that pairing of the hydrophobic ligands can stabilize the iRNA agent via intermolecular van der Waals interactions. 15 In an embodiment, an iRNA agent may have an RRMS at (or within 1, 2, or 3 positions of) the 3' end of the antisense strand and an RRMS at the 5' end of the sense strand, in which both RRMSs may share the same ligand (e.g., cholic acid) via connection of their individual tethers to separate positions on the ligand. A ligand shared between two proximal RRMSs is referred to herein as a "hairpin ligand." 20 In other embodiments, an iRNA agent may have an RRMS at the 3' end of the sense strand and an RRMS at an internal position of the sense strand. An iRNA agent may have an RRMS at an internal position of the sense strand; or may have an RRMS at an internal position of the antisense strand; or may have an RRMS at an internal position of the sense strand and an RRMS at an internal position of the antisense strand. 25 In preferred embodiments the iRNA agent includes a first and second sequences, which are preferably two separate molecules as opposed to two sequences located on the same strand, have sufficient complementarity to each other to hybridize (and thereby form a duplex region), 72 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO 1 e.g., under physiological conditions, e.g., under physiological conditions but not in contact with a helicase or other unwinding enzyme. It is preferred that the first and second sequences be chosen such that the ds iRNA agent includes a single strand or unpaired region at one or both ends of the molecule. Thus, a ds iRNA 5 agent contains first and second sequences, preferable paired to contain an overhang, e.g., one or two 5' or 3' overhangs but preferably a 3' overhang of 2-3 nucleotides. Most embodiments will have a 3' overhang. Preferred sRNA agents will have single-stranded overhangs, preferably 3' overhangs, of 1 or preferably 2 or 3 nucleotides in length at each end. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length 10 being staggered.. 5' ends are preferably phosphorylated. An RNA agent, e.g., an iRNA agent, containing a preferred, but nonlimiting RRMS is presented as formula (R-2) in FIG. 4. The carrier includes two "backbone attachment points" (hydroxyl groups), a "tethering attachment point," and a ligand, which is connected indirectly to the carrier via an intervening tether. The RRMS may be the 5' or 3' terminal subunit of the RNA 15 molecule, i.e., one of the two "W" groups may be a hydroxyl group, and the other "W" group may be a chain of two or more unmodified or modified ribonucleotides. Alternatively, the RRMS may occupy an internal position, and both "W" groups may be one or more unmodified or modified ribonucleotides. More than one RRMS may be present in a RNA molecule, e.g., an iRNA agent. 20 The modified RNA molecule of formula (R-2) can be obtained using oligonucleotide synthetic methods known in the art. In a preferred embodiment, the modified RNA molecule of formula (II) can be prepared by incorporating one or more of the corresponding RRMS monomer compounds (RRMS monomers, see, e.g., A, B, and C in FIG 4) into a growing sense or antisense strand, utilizing, e.g., phosphoramidite or H-phosphonate coupling strategies. 25 The RRMS monomers generally include two differently functionalized hydroxyl groups

(OFG

1 and OFG 2 above), which are linked to the carrier molecule (see A in FIG 4), and a tethering attachment point. As used herein, the term "functionalized hydroxyl group" means that the hydroxyl proton has been replaced by another substituent. As shown in representative structures B and C, one hydroxyl group (OFG') on the carrier is functionalized with a protecting 73 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 group (PG). The other hydroxyl group (OFG 2 ) can be functionalized with either (1) a liquid or solid phase synthesis support reagent (solid circle) directly or indirectly through a linker, L, as in B, or (2) a phosphorus-containing moiety, e.g., a phosphoramidite as in C. The tethering attachment point may be connected to a hydrogen atom, a tether, or a tethered ligand at the time 5 that the monomer is incorporated into the growing sense or antisense strand (see R in Scheme 1). Thus, the tethered ligand can be, but need not be attached to the monomer at the time that the monomer is incorporated into the growing strand. In certain embodiments, the tether, the ligand or the tethered ligand may be linked to a "precursor" RRMS after a "precursor" RRMS monomer has been incorporated into the strand. 10 The (OFG 1 ) protecting group maybe selected as desired, e.g., from T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991). The protecting group is preferably stable under amidite synthesis conditions, storage conditions, and oligonucleotide synthesis conditions. Hydroxyl groups, -OH, are nucleophilic groups (i.e., Lewis bases), which react through the oxygen with electrophiles (i.e., Lewis acids). Hydroxyl 15 groups in which the hydrogen has been replaced with a protecting group, e.g., a triaryhnethyl group or a trialkylsilyl group, are essentially unreactive as nucleophiles in displacement reactions. Thus, the protected hydroxyl group is useful in preventing e.g., homocoupling of compounds exemplified by structure C during oligonucleotide synthesis. A preferred protecting group is the dimethoxytrityl group. 20 When the OFG2 in B includes a linker, e.g., a long organic linker, connected to a soluble or insoluble support reagent, solution or solid phase synthesis techniques can be employed to build up a chain of natural and/or modified ribonucleotides once OFG 1 is deprotected and free to react as a nucleophile with another nucleoside or monomer containing an electrophilic group (e.g., an amidite group). Alternatively, a natural or modified ribonucleotide or 25 oligoribonucleotide chain can be coupled to monomer C via an amidite group or H-phosphonate group at OFG 2 . Subsequent to this operation, OFG 1 can be deblocked, and the restored nucleophilic hydroxyl group can react with another nucleoside or monomer containing an electrophilic group (see FIG. 1). R' can be substituted or unsubstituted alkyl or alkenyl. In preferred embodiments, R' is methyl, allyl or 2-cyanoethyl. R" may a C-Cio alkyl group, 30 preferably it is a branched group containing three or more carbons, e.g., isopropyl. 74 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

OFG

2 in B can be hydroxyl functionalized with a linker, which in turn contains a liquid or solid phase synthesis support reagent at the other linker terminus. The support reagent can be any support medium that can support the monomers described herein. The monomer can be attached to an insoluble support via a linker, L, which allows the monomer (and the growing 5 chain) to be solubilized in the solvent in which the support is placed. The solubilized, yet immobilized, monomer can react with reagents in the surrounding solvent; unreacted reagents and soluble by-products can be readily washed away from the solid support to which the monomer or monomer-derived products is attached. Alternatively, the monomer can be attached to a soluble support moiety, e.g., polyethylene glycol (PEG) and liquid phase synthesis 10 techniques can be used to build up the chain. Linker and support medium selection is within skill of the art. Generally the linker may be -C(O)(CH2)qC(O)-, or -C(O)(CH2)qS-, preferably, it is oxalyl, succinyl or thioglycolyl. Standard control pore glass solid phase synthesis supports can not be used in conjunction with fluoride labile 5' silyl protecting groups because the glass is degraded by fluoride with a significant reduction in the amount of full-length product. Fluoride 15 stable polystyrene based supports or PEG are preferred. Preferred carriers have the general formula (R-3) provided below. (In that structure preferred backbone attachment points can be chosen from Ri or R2; R or R; or R 9 and R1 0 if Y is CR 9 Rl" (two positions are chosen to give two backbone attachment points, e.g., R 1 and R, or

R

4 and R9. Preferred tethering attachment points include R 7 ; R 5 or R6 when X is CH 2 . The 20 carriers are described below as an entity, which can be incorporated into a strand. Thus, it is understood that the structures also encompass the situations wherein one (in the case of a terminal position) or two (in the case of an internal position) of the attachment points, e.g., Ri or R2; R or R4; or R? or R 1 0 (when Y is CR 9

R

10 ), is connected to the phosphate, or modified phosphate, e.g., sulfur containing, backbone. E.g., one of the above-named R groups can be 25 CH2-, wherein one bond is connected to the carrier and one to a backbone atom, e.g., a linking oxygen or a central phosphorus atom.) 75 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1

R

1 R R 2 R5 RR (R-3) X is N(CO)R 7 , NR 7 or CH 2 ; Y is NR 8 , 0, S, CR 9

R

1 0 ; and Z is CRR 1 2 or absent. 5 Each of R', R 2 , R 3 , R 4 , R 9 , and RIO is, independently, H, ORa, or (CH 2 )nOR, provided that at least two of R 1 , R2 , RE, R, and R 1 0 are ORa and/or (CH 2

)

0 OR. Each of R 5 , R 6 , R", and R 12 is, independently, a ligand, H, C 1

-C

6 alkyl optionally substituted with 1-3 R 1 3 , or C(O)NHR 7 ; or R 5 and R" together are C 3 -Cs cycloalkyl optionally substituted with R 1 4 . 10 R is H, a ligand, or C 1

-C

20 alkyl substituted with NRcRd; R 5 is H or C 1

-C

6 alkyl; R 13 is hydroxy, C 1

-C

4 alkoxy, or halo; R 1 4 is NRR 7 ; R 15 is C 1

-C

6 alkyl optionally substituted with cyano, or C 2

-C

6 alkenyl; R1 6 is C 1

-C

1 0 alkyl; and R 17 is a liquid or solid phase support reagent. L is -C(O)(CH 2 )qC(O)-, or -C(O)(CH 2 )qS-; Ra is CAr 3 ; Rb is P(O)(O~)H, P(OR 15

)N(R

16

)

2 or L-R1 7 ; Rc is H or C 1

-C

6 alkyl; and Rd is H or a ligand. 15 Each Ar is, independently, C 6

-C

10 aryl optionally substituted with C 1

-C

4 alkoxy; n is 1-4; and q is 0-4. Exemplary carriers include those in which, e.g., X is N(CO)R 7 or NR 7 , Y is CR 9

R

1 0 , and Z is absent; or X is N(CO)R or NR, Y is CR 9

R

10 , and Z is CR 1 R1 2 ; or X is N(CO)R or NR!, Y is NR', and Z is CR R ; or X is N(CO)R 7 or NR, Y is 0, and Z is CR 1

"R

12 ; or X is CH 2 ; Y is 20 CR 9 R1 0 ; Z is CR"RE, and R' and R 11 together form C 6 cycloalkyl (H, z = 2), or the indane ring 76 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 system, e.g., X is CH 2 ; Y is CR 9

R

0 ; Z is CR"R , and Rs and R" together form C 5 cycloalkyl (H, z = 1). In certain embodiments, the carrier may be based on the pyrroline ring system or the 3 hydroxyproline ring system, e.g., X is N(CO)R 7 or NR, Y is CR 9

R

10 , and Z is absent (D). OFG' 5 is preferably attached to a primary carbon, e.g., an exocyclic alkylene

OFG

2 C C CH 2 0FG 1 C2 LIGAND D group, e.g., a methylene group, connected to one of the carbons in the five-membered ring (

CH

2 OFG' in D). OFG 2 is preferably attached directly to one of the carbons in the five membered ring (-OFG2 in D). For the pyrroline-based carriers, -CH 2 OFG' may be attached to C 10 2 and OFG 2 may be attached to C-3; or -CH 2

OFG

1 may be attached to C-3 and OFG 2 may be attached to C-4. . In certain embodiments, CH 2 OFG' and OFG 2 may be geminally substituted to one of the above-referenced carbons.For the 3-hydroxyproline-based carriers, -CH 2 OFG may be attached to C-2 and OFG 2 may be attached to C-4. The pyrroline- and 3-hydroxyproline-based monomers may therefore contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is 15 restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, CH 2 OFGI and OFG2 may be cis or trans with respect to one another in any of the pairings delineated above Accordingly, all cis/trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric 77 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 forms of the monomers are expressly included. The tethering attachment point is preferably nitrogen. In certain embodiments, the carrier may be based on the piperidine ring system (E), e.g., X is N(CO)R 7 or NR, Y is CRR", and Z is CR 1

R

12 . OFG 1 is preferably

OFG

2 C4/ C3 1 (CH2)nOFG4 NU2 LIGAND E 5 attached to a primary carbon, e.g., an exocyclic alkylene group, e.g., a methylene group (n=1) or ethylene group (n=2), connected to one of the carbons in the six-membered ring [-(CH 2 )nOFG' in E]. OFG 2 is preferably attached directly to one of the carbons in the six-membered ring (-OFG 2 in E). -(CH 2 )nOFG' and OFG 2 may be disposed in a geminal manner on the ring, i.e., both 10 groups may be attached to the same carbon, e.g., at C-2, C-3, or C-4. Alternatively, (CH 2 )nOFG' and OFG 2 may be disposed in a vicinal manner on the ring, i.e., both groups may be attached to adjacent ring carbon atoms, e.g., -(CH 2 )nOFG may be attached to C-2 and OFG 2 may be attached to C-3; -(CH 2 )nOFG may be attached to C-3 and OFG 2 may be attached to C-2;

-(CH

2 )nOFG may be attached to C-3 and OFG 2 may be attached to C-4; or -(CH 2 )nOFG may be 15 attached to C-4 and OFG2 may be attached to C-3. The piperidine-based monomers may therefore contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, -(CH 2 )nOFG' and OFG 2 may be cis or trans with respect to one another in any of the pairings delineated above. Accordingly, all cis/trans isomers are expressly included. The monomers may also 78 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. The tethering attachment point is preferably nitrogen. 5 In certain embodiments, the carrier may be based on the piperazine ring system (F), e.g., X is N(CO)R 7 or NR 7 , Y is NR, and Z is CR"R , or the morpholine ring system (G), e.g., X is N(CO)R or KR 7 , Y is 0, and Z is CR"R". OFG' is preferably R"' I OFG 2

OFG

2 N 0 3 C3 C3 -r-CH 2 OFG CH 2 OFG C2 /C2 LIGAND LIGAND F G attached to a primary carbon, e.g., an exocyclic alkylene group, e.g., a methylene group, 10 connected to one of the carbons in the six-membered ring (-CH 2 OFG in F or G). OFG 2 is preferably attached directly to one of the carbons in the six-membered rings (-OFG 2 in F or G). For both F and G, -CH 2 0FG' may be attached to C-2 and OFG 2 may be attached to C-3; or vice versa. In certain embodiments, CH 2

OFG

1 and OFG 2 may be geminally substituted to one of the above-referenced carbons.The piperazine- and morpholine-based monomers may therefore 15 contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, CH 2

OFG

1 and

OFG

2 may be cis or trans with respect to one another in any of the pairings delineated above. Accordingly, all cis/trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single 79 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. R"' can be, e.g., C 1

-C

6 alkyl, preferably CH 3 . The tethering attachment point is preferably nitrogen in both F and G. In certain embodiments, the carrier may be based on the decalin ring system, e.g., X is 5 CH 2 ; Y is CR 9 R'(; Z is CR 11

R

12 , and R and R" together form C 6 cycloalkyl (H, z = 2), or the indane ring system, e.g., X is CH 2 ; Y is CR 9

R

1 "; Z is CR"R , and Rs and R 11 together form C 5 cycloalkyl (H, z = 1). OFG' is preferably attached to a primary carbon,

OFG

2 C7 C 4 z(16C (CH2)nOFG1 C, C3 C 2 H e.g., an exocyclic methylene group (n=1) or ethylene group (n=2) connected to one of C-2, C-3, 10 C-4, or C-5 [-(CH 2 )nOFG' in H]. OFG 2 is preferably attached directly to one of C-2, C-3, C-4, or C-5 (-OFG 2 in H). -(CH 2 )nOFG and OFG 2 may be disposed in a geminal manner on the ring, i.e., both groups may be attached to the same carbon, e.g., at C-2, C-3, C-4, or C-5. Alternatively, -(CH 2 )nOFG' and OFG 2 may be disposed in a vicinal manner on the ring, i.e., both groups may be attached to adjacent ring carbon atoms, e.g., -(CH 2 )nOFG' may be attached to C-2 15 and OFG 2 may be attached to C-3; -(CH 2 )nOFG may be attached to C-3 and OFG 2 may be attached to C-2; -(CH 2 )nOFG may be attached to C-3 and OFG 2 may be attached to C-4; or (CH 2 )nOFG may be attached to C-4 and OFG 2 may be attached to C-3; -(CH 2 )nOFG may be attached to C-4 and OFG 2 may be attached to C-5; or -(CH 2 )nOFG may be attached to C-5 and

OFG

2 may be attached to C-4. The decalin or indane-based monomers may therefore contain 20 linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, -(CH 2 )nOFG 1 and OFG 2 may be cis or trans with respect to one another in any of the pairings delineated above. Accordingly, all cis/trans isomers are expressly included. The monomers may also contain one or more 80 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. In a preferred embodiment, the substituents at C-1 and C-6 are trans with respect to one another. The tethering attachment point is preferably C-6 or C-7. 5 Other carriers may include those based on 3-hydroxyproline (J). Thus, -(CH 2 )nOFG' and

OFG

2 may be cis or trans with respect to one another. Accordingly, all cis/trans isomers are expressly included. The monomers may also contain one or more asymmetric centers 2 GFO(CH2), N OFG 1 LIGAND J and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers 10 and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. The tethering attachment point is preferably nitrogen., Representative carriers are shown in FIG. 5. In certain embodiments, a moiety, e.g., a ligand may be connected indirectly to the carrier via the intermediacy of an intervening tether. Tethers are connected to the carrier at the tethering 15 attachment point (TAP) and may include any C 1

-C

100 carbon-containing moiety, (e.g. C 1

-C

75 , C 1 C 50 , C-C 20 , C-C 10 , CrC 6 ), preferably having at least one nitrogen atom. In preferred embodiments, the nitrogen atom forms part of a terminal amino group on the tether, which may serve as a connection point for the ligand. Preferred tethers (underlined) include TAP (CHz),NH__' TAP-C(O)(CH,)Nll; or TAP-NR""(CHZ),Ni, in which n is 1-6 and R"" is C 20 C 6 alkyl. and Rd is hydrogen or a ligand. In other embodiments, the nitrogen may form part of a terminal oxyamino group, e.g., -ONH 2 , or hydrazino group, -NHNH 2 . The tether may optionally 81 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 be substituted, e.g., with hydroxy, alkoxy, perhaloalkyl, and/or optionally inserted with one or more additional heteroatoms, e.g., N, 0, or S. Preferred tethered ligands may include, e.g., TAP,-(CH7l NH(LIGAND), TAP-C(O)(CH?)NH(LIGAND), or TAP-NR"" (CHJ)NH(LIGAND); 5 TAP-(CH ONH(LIGAND), TAP-C(O)(CH )ONH(LIGAND) or TAP-NR""..(CH2),ONH(LIGAND); TAP-{CH2 2NN~(LIGAND), TAP-C(O)(CH?),Ni (LIGAND), or TAP-NR""(CHz)NHNH(LIGAND). In other embodiments the tether may include an electrophilic moiety, preferably at the terminal position of the tether. Preferred electrophilic moieties include, e.g., an aldehyde, alkyl 10 halide, mesylate, tosylate, nosylate, or brosylate, or an activated carboxylic acid ester, e.g. an NHS ester, or a pentafluorophenyl ester. Preferred tethers (underlined) include TAP (CH2)CHO; TAP-C(Q)( ,CHO; or TAP-NR""(CH -CHO, in which n is 1-6 and R"" is

C

1

-C

6 alkyl; or TAP-(CH2),C(O)ONHS; TAP-C(O)(CH)OC(O)ONHS; or TAP-NR""(CH2) C(O)ONHS, in which n is 1-6 and R"" is C 1

-C

6 alkyl; 15 TAP-(CH2 _C(O)OCF 5 ; TAP-C(O)(CH2).JC(O) OC F ; or TAP-NR""(CH2) C(O) OC 6

F

5 , in which n is 1-6 and R"" is CI-C 6 alkyl; or -(CH2),_CHLG; TAP-C(0(CH)CHLG; or TAP NR""(CH2),1aLG, in which n is 1-6 and R"" is C-C 6 alkyl (LG can be a leaving group, e.g., halide, mesylate, tosylate, nosylate, brosylate). Tethering can be carried out by coupling a nucleophilic group of a ligand, e.g., a thiol or amino group with an electrophilic group on the 20 tether. Tethered Entities A wide variety of entities can be tethered to an iRNA agent, e.g., to the carrier of an RRMS. Examples are described below in the context of an RRMS but that is only preferred, entities can be coupled at other points to an iRNA agent. Preferred entities are those which 25 target to the liver. 82 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 Preferred moieties are ligands, which are coupled, preferably covalently, either directly or indirectly via an intervening tether, to the RRMS carrier. In preferred embodiments, the ligand is attached to the carrier via an intervening tether. As discussed above, the ligand or tethered ligand may be present on the RRMS monomer when the RRMS monomer is incorporated into 5 the growing strand. In some embodiments, the ligand may be incorporated into a "precursor" RRMS after a "precursor" RRMS monomer has been incorporated into the growing strand. For example, an RRMS monomer having, e.g., an amino-terminated tether (i.e., having no associated ligand), e.g., TAP-(CH 2 )nNH 2 may be incorporated into a growing sense or antisense strand. In a subsequent operation, i.e., after incorporation of the precursor monomer into the strand, a ligand 10 having an electrophilic group, e.g., a pentafluorophenyl ester or aldehyde group, can subsequently be attached to the precursor RRMS by coupling the electrophilic group of the ligand with the terminal nucleophilic group of the precursor RRMS tether. In preferred embodiments, a ligand alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated. In preferred embodiments a ligand provides an 15 enhanced affinity for a selected target, e.g, molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a species absent such a ligand. Preferred ligands will not take part in duplex pairing in a duplexed nucleic acid. Preferred ligands can improve transport, hybridization, and specificity properties and may 20 also improve nuclease resistance of the resultant natural or modified oligoribonucleotide, or a polymeric molecule comprising any combination of monomers described herein and/or natural or modified ribonucleotides. Ligands in general can include therapeutic modifiers, e.g., for enhancing uptake; diagnostic compounds or reporter groups e.g., for monitoring distribution; cross-linking agents; 25 and nuclease-resistance conferring moieties. General examples include lipids, steroids, vitamins, sugars, proteins, peptides, polyamines, and peptide mimics. Ligands can include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid); or a lipid. The ligand may 83 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2 5 hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, 10 quaternary salt of a polyamine, or an alpha helical peptide. Ligands can also include targeting groups, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a liver cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl 15 galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, or an RGD peptide or RGD peptide mimetic. Other examples of ligands include dyes, intercalating agents (e.g. acridines), cross-linkers 20 (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic molecules, e.g, cholesterol, cholic acid, adamantane acetic acid, 1 -pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,03 25 (oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine)and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, bisimidazole, histamine, 84 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 I imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles), dinitrophenyl, HRP, or AP. Ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as 5 a cancer cell, endothelial cell, or bone cell. Ligands may also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl gulucosamine multivalent mannose, or multivalent fucose. The ligand can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF-KB. 10 The ligand can be a substance, e.g, a drug, which can increase the uptake of the iRNA agent into the cell, for example, by disrupting the cell's cytoskeleton, e.g., by disrupting the cell's microtubules, microfilaments, and/or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. 15 The ligand can increase the uptake of the iRNA agent into the cell by activating an inflammatory response, for example. Exemplary ligands that would have such an effect include tumor necrosis factor alpha (TNFalpha), interleukin-1 beta, or gamma interferon. In one aspect, the ligand is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferably binds a serum protein, e.g., human serum albumin (HSA). An HSA binding 20 ligand allows for distribution of the conjugate to a target tissue, e.g., a non-liver target tissue of the body. Preferably, the target tissue is the liver, preferably parenchymal cells of the liver. Other molecules that can bind HSA can also be used as ligands. For example, neproxin or aspirin can be used. A lipid or lipid-based ligand can (a) increase resistance to degradation of the conjugate, (b) increase targeting or transport into a target cell or cell membrane, and/or (c) can be 25 used to adjust binding to a serum protein, e.g., HSA. A lipid based ligand can be used to modulate, e.g., control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA more strongly will be less likely to be targeted to the liver and therefore less likely to be cleared from the body. 85 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In a preferred embodiment, the lipid based ligand binds HSA. Preferably, it binds HSA with a sufficient affinity such that the conjugate will be preferably distributed to a non-kidney tissue. However, it is preferred that the affinity not be so strong that the HSA-ligand binding cannot be reversed. 5 In another aspect, the ligand is a moiety, e.g., a vitamin, which is taken up by a target cell, e.g., a proliferating cell. These are particularly useful for treating disorders characterized by unwanted cell proliferation, e.g., of the malignant or non-malignant type, e.g., cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins include are B vitamin, e.g., folic acid, B12, riboflavin, biotin, pyridoxal or other vitamins or nutrients taken up 10 by cancer cells. Also included are HSA and low density lipoprotein (LDL). In another aspect, the ligand is a cell-permeation agent, preferably a helical cell permeation agent. Preferably, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennopedia. If the agent is a peptide, it can be modified, including a peptidylmimetic, invertomers, non-peptide or pseudo-peptide linkages, and use of D-amino acids. The helical 15 agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. The ligand can be a peptide or peptidomimetic. A peptidomimetic (also referred to herein as an oligopeptidomimetic) is a molecule capable of folding into a defined three dimensional structure similar to a natural peptide. The attachment of peptide and 20 peptidomimetics to iRNA agents can affect pharmacokinetic distribution of the iRNA, such as by enhancing cellular recognition and absorption. The peptide or peptidomimetic moiety can be about 5-50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long (see Table 2, for example). 86 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Table 2. Exemplary Cell Permeation Peptides Cell Amino acid Sequence Reference Permeation Peptide Penetratin RQIKIWFQNRRMKWKK (SEQ ID NO:6700) Derossi et al., J. Biol. Chem. 269:10444, 1994 Tat fragment GRKKRRQRRRPPQC (SEQ ID NO:6701) Vives et al., J. Biol. (48-60) Chem., 272:16010, 1997 Signal GALFLGWLGAAGSTMGAWSQPKKKRKV Chaloin et al., Sequence- (SEQ ID NO:6702) Biochem. Biophys. based peptide Res. Commun., 243:601, 1998 PVEC LLIILRRRIRKQAHAHSK (SEQ ID NO:6703) Elmquist et al., Exp. Cell Res., 269:237, 2001 Transportan GWTLNSAGYLLKINLKALAALAKKIL Pooga et al., FASEB (SEQ ID NO:6704) J., 12:67, 1998 87 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Amphiphilic KLALKLALKALKAALKLA (SEQ ID Oehlke et al., Mol. model peptide NO:6705) Ther., 2:339, 2000 Arg 9 RRRRRRRRR (SEQ ID NO:6706) Mitchell et al., J. Pept. Res., 56:318, 2000 Bacterial cell KFFKFFKFFK (SEQ ID NO:6707) wall permeating LL-37 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRN LVPRTES (SEQ ID NO:6708) Cecropin P1 SWLSKTAKKLENSAKKRISEGIAIAIQGGP R (SEQ ID NO:6709) a-defensin ACYCRIPACIAGERRYGTCIYQGRLWAFC C (SEQIDNO:6710) b-defensin DHYNCVSSGGQCLYSACPIFTKIQGTCYR GKAKCCK (SEQ IDNO:6711) Bactenecin RKCRIVVIRVCR (SEQ ID NO:6712) PR-39 RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPP RFPPRFPGKR-NH2 (SEQ ID NO:6713) Indolicidin ILPWKWPWWPWRR-NH2 (SEQ ID NO:6714) A peptide or peptidomimetic can be, for example, a cell permeation peptide, cationic peptide, amphipathic peptide, or hydrophobic peptide (e.g., consisting primarily of Tyr, Trp or Phe). The peptide moiety can be a dendrimer peptide, constrained peptide or crosslinked 5 peptide. The peptide moiety can be an L-peptide or D-peptide. In another alternative, the 88 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 peptide moiety can include a hydrophobic membrane translocation sequence (MTS). An exemplary hydrophobic MTS-containing peptide is RFGF having the amino acid sequence AAVALLPAVLLALLAP (SEQ ID NO:6715). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO:6716)) containing a hydrophobic MTS can also be a targeting 5 moiety. The peptide moiety can be a "delivery" peptide, which can carry large polar molecules including peptides, oligonucleotides, and protein across cell membranes. For example, sequences from the HIV Tat protein (GRKKRRQRRRPPQ (SEQ ID NO:6717)) and the Drosophila Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO:6718)) have been found to be capable of functioning as delivery peptides. A peptide or peptidomimetic can be 10 encoded by a random sequence of DNA, such as a peptide identified from a phage-display library, or one-bead-one-compound (OBOC) combinatorial library (Lam et al., Nature, 354:82 84, 1991). Preferably the peptide or peptidomimetic tethered to an iRNA agent via an incorporated monomer unit is a cell targeting peptide such as an arginine-glycine-aspartic acid (RGD)-peptide, or RGD mimic. A peptide moiety can range in length from about 5 amino acids 15 to about 40 amino acids. The peptide moieties can have a structural modification, such as to increase stability or direct conformational properties. Any of the structural modifications described below can be utilized. An RGD peptide moiety can be used to target a tumor cell, such as an endothelial tumor cell or a breast cancer tumor cell (Zitzmann et al., Cancer Res., 62:5139-43, 2002). An RGD 20 peptide can facilitate targeting of an iRNA agent to tumors of a variety of other tissues, including the lung, kidney, spleen, or liver (Aoki et al., Cancer Gene Therapy 8:783-787, 2001). The RGD peptide can be linear or cyclic, and can be modified, e.g., glycosylated or methylated to facilitate targeting to specific tissues. For example, a glycosylated RGD peptide can deliver an iRNA agent to a tumor cell expressing uVB 3 (Haubner et al., Jour. Nucl. Med., 42:326-336, 25 2001). Peptides that target markers enriched in proliferating cells can be used. E.g., RGD containing peptides and peptidomimetics can target cancer cells, in particular cells that exhibit an a0s3 integrin. Thus, one could use RGD peptides, cyclic peptides containing RGD, RGD peptides that include D-amino acids, as well as synthetic RGD mimics. In addition to RGD, one 30 can use other moieties that target the ay-P3 integrin ligand. Generally, such ligands can be used 89 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 to control proliferating cells and angiogeneis. Preferred conjugates of this type include an iRNA agent that targets PECAM-1, VEGF, or other cancer gene, e.g., a cancer gene described herein. A "cell permeation peptide" is capable of permeating a cell, e.g., a microbial cell, such as a bacterial or fungal cell, or a mammalian cell, such as a human cell. A microbial cell 5 permeating peptide can be, for example, an a-helical linear peptide (e.g., LL-37 or Ceropin Pl), a disulfide bond-containing peptide (e.g., a -defensin, fl-defensin or bactenecin), or a peptide containing only one or two dominating amino acids (e.g., PR-39 or indolicidin). A cell permeation peptide can also include a nuclear localization signal (NLS). For example, a cell permeation peptide can be a bipartite amphipathic peptide, such as MPG, which is derived from 10 the fusion peptide domain of HIV-1 gp4l and the NLS of SV40 large T antigen (Simeoni et al., Nucl. Acids Res. 31:2717-2724, 2003). In one embodiment, a targeting peptide tethered to an RRMS can be an amphipathic a helical peptide. Exemplary amphipathic a-helical peptides include, but are not limited to, cecropins, lycotoxins, paradaxins, buforin, CPF, bombinin-like peptide (BLP), cathelicidins, 15 ceratotoxins, S. clava peptides, hagfish intestinal antimicrobial peptides (HFIAPs), magainines, brevinins-2, dermaseptins, melittins, pleurocidin, H 2 A peptides, Xenopus peptides, esculentinis 1, and caerins. A number of factors will preferably be considered to maintain the integrity of helix stability. For example, a maximum number of helix stabilization residues will be utilized (e.g., leu, ala, or lys), and a minimum number helix destabilization residues will be utilized (e.g., 20 proline, or cyclic monomeric units. The capping residue will be considered (for example Gly is an exemplary N-capping residue and/or C-terminal amidation can be used to provide an extra H bond to stabilize the helix. Formation of salt bridges between residues with opposite charges, separated by i 3, or i ± 4 positions can provide stability. For example, cationic residues such as lysine, arginine, homo-arginine, ornithine or histidine can form salt bridges with the anionic 25 residues glutamate or aspartate. Peptide and petidomimetic ligands include those having naturally occurring or modified peptides, e.g., D or L peptides; a, P, or y peptides; N-methyl peptides; azapeptides; peptides having one or more amide, i.e., peptide, linkages replaced with one or more urea, thiourea, carbamate, or sulfonyl urea linkages; or cyclic peptides. 90 Methods for making iRNA agents iRNA agents can include modified or non-naturally occuring bases, e.g., bases described in copending and coowned United States Provisional Application Serial No. 60/463,772, filed on April 17, 2003, which is hereby incorporated by reference and/or in copending and coowned 5 United States Provisional Application Serial No. 60/465,802, filed on April 25, 2003, which is hereby incorporated by reference. Monomers and iRNA agents which include such bases can be made by the methods found in United States Provisional Application Serial No. 60/463,772, filed on April 17, 2003, and/or in United States Provisional Application Serial No. 60/465,802, filed on April 25, 2003. 10 In addition, described herein are iRNA agents having a modified or non-naturally occurring base and another element described herein. E.g., described herein is an iRNA agent described herein, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an architecture or structure described herein, an iRNA associated with an 15 amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates a modified or non-naturally occuring base. The synthesis and purification of oligonucleotide peptide conjugates can be performed by established methods. See, for example, Trufert et al., Tetrahedron, 52:3005, 1996; and 20 Manoharan, "Oligonucleotide Conjugates in Antisense Technology," in Antisense Drug Technology, ed. S.T. Crooke, Marcel Dekker, Inc., 2001. In one embodiment,, a peptidomimetic can be modified to create a constrained peptide that adopts a distinct and specific preferred conformation, which can increase the potency and selectivity of the peptide. For example, the constrained peptide can be 25 an azapeptide (Gante, Synthesis, 405-413, 1989). An azapeptide is synthesized by replacing the ca-carbon of an amino acid with a nitrogen atom without changing the structure of the amino acid side chain. For example, the azapeptide can be synthesized by using hydrazine in traditional peptide synthesis coupling methods, such as by reacting hydrazine with a "carbonyl donor," e.g., phenylchloroformate. 91 In one embodiment, a peptide or peptidomimetic (e.g., a peptide or peptidomimetic tethered to an RRMS) can be an N-methyl peptide. N-methyl peptides are composed of N-methyl amino acids, which provide an additional methyl group in the peptide backbone, thereby potentially providing additional means of resistance to proteolytic cleavage. 5 N-methyl peptides can by synthesized by methods known in the art (see, for example, Lindgren et al., Trends Pharmacol. Sci. 21:99, 2000; Cell Penetrating Peptides: Processes and Applications. Langel, ed., CRC Press, Boca Raton, FL, 2002; Fische et al., Bioconjugate. Chem. 12: 825, 2001; Wander et al., J. Am. Chem. Soc., 124:13382, 2002). For example, an Ant or Tat peptide can be an N-methyl peptide. 10 In one embodiment, peptide or peptidomimetic (e.g., a peptide or peptidomimetic tethered to an RRMS) can be a #-peptide. #-peptides form stable secondary structures such as helices, pleated sheets, turns and hairpins in solutions. Their cyclic derivatives can fold into nanotubes in the solid state. f-peptides are resistant to degradation by proteolytic enzymes. #-peptides can be synthesized by methods known in the art. For example, an Ant or 15 Tat peptide can be a 0-peptide. In one embodiment, a peptide or peptidomimetic (e.g., a peptide or peptidomimetic tethered to an RRMS) can be a oligocarbamate. Oligocarbamate peptides are internalized into a cell by a transport pathway facilitated by carbamate transporters. For example, an Ant or Tat peptide can be an oligocarbamate. 20 In one embodiment, peptide or peptidomimetic (e.g., a peptide or peptidomimetic tethered to an RRMS) can be an oligourea conjugate (or an oligothiourea conjugate), in which the amide bond of a peptidomimetic is replaced with a urea moiety. Replacement of the amide bond provides increased resistance to degradation by proteolytic enzymes, e.g., proteolytic enzymes in the gastrointestinal tract. In one embodiment, an oligourea 25 conjugate is tethered to an iRNA agent for use in oral delivery. The backbone in each repeating unit of an oligourea peptidomimetic can be extended by one carbon atom in comparison with the natural amino acid. The single carbon atom extension can increase peptide stability and lipophilicity, for example. An oligourea peptide can therefore be advantageous when an iRNA agent is directed for passage through a bacterial cell wall, or when an iRNA agent must traverse 92 the blood-brain barrier, such as for the treatment of a neurological disorder. In one embodiment, a hydrogen bonding unit is conjugated to the oligourea peptide, such as to create an increased affinity with a receptor. For example, an Ant or Tat peptide can be an oligourea conjugate (or an oligothiourea conjugate). 5 The siRNA peptide conjugates described herein .- Gan be affiliated with, e.g., tethered to, RRMSs occurring at various positions on an iRNA agent. For example, a peptide can be terminally conjugated, on either the sense or the antisense strand, or a peptide can be bisconjugated (one peptide tethered to each end, one conjugated to the sense strand, and one conjugated to the antisense strand). In another option, the peptide can be internally conjugated, 10 such as in the loop of a short hairpin iRNA agent. In yet another option, the peptide can be affiliated with a complex, such as a peptide-carrier complex. A peptide-carrier complex consists of at least a carrier molecule, which can encapsulate one or more iRNA agents (such as for delivery to a biological system and/or a cell), and a peptide moiety tethered to the outside of the carrier molecule, such as for targeting the carrier 15 complex to a particular tissue or cell type. A carrier complex can carry additional targeting molecules on the exterior of the complex, or fusogenic agents to aid in cell delivery. The one or more iRNA agents encapsulated within the carrier can be conjugated to lipophilic molecules, which can aid in the delivery of the agents to the interior of the carrier. A carrier molecule or structure can be, for example, a micelle, a liposome (e.g., a cationic 20 liposome), a nanoparticle, a microsphere, or a biodegradable polymer. A peptide moiety can be tethered to the carrier molecule by a variety of linkages, such as a disulfide linkage, an acid labile linkage, a peptide-based linkage, an oxyamino linkage or a hydrazine linkage. For example, a peptide-based linkage can be a GFLG peptide. Certain linkages will have particular advantages, and the advantages (or disadvantages) can be considered depending on the tissue 25 target or intended use. For example, peptide based linkages are stable in the blood stream but are susceptible to enzymatic cleavage in the lysosomes. 93 Targeting The iRNA agents described herein are particularly useful when targeted to the liver. An iRNA agent can be targeted to the liver by incorporation of an RRMS containing a ligand that targets the liver. For example, a liver-targeting agent can be a lipophilic moiety. Preferred 5 lipophilic moieties include lipids, cholesterols, oleyl, retinyl, or cholesteryl residues. Other lipophilic moieties that can function as liver-targeting agents include cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, 10 dimethoxytrityl, or phenoxazine. An iRNA agent can also be targeted to the liver by association with a low-density lipoprotein (LDL), such as lactosylated LDL. Polymeric carriers complexed with sugar residues can also function to target iRNA agents to the liver. A targeting agent that incorporates a sugar, e.g., galactose and/or analogues thereof, is 15 particularly useful. These agents target, in particular, the parenchymal cells of the liver. For example, a targeting moiety can include more than one or preferably two or three galactose moieties, spaced about 15 angstroms from each other. The targeting moiety can alternatively be lactose (e.g., three lactose moieties), which is glucose coupled to a galactose. The targeting moiety can also be N-Acetyl-Galactosamine, N-Ac-Glucosamine. A mannose or mannose-6 20 phosphate targeting moiety can be used for macrophage targeting. Conjugation of an iRNA agent with a serum albumin (SA), such as human serum albumin, can also be used to target the iRNA agent to a non-kidney tissue, such as the liver. An iRNA agent targeted to the liver by an RRMS targeting moiety described herein can target a gene expressed in the liver. 25 An iRNA agent targeted to the liver by an RRMS targeting moiety described herein can target a gene expressed in the liver. For example, the iRNA agent can target p21(WAF1/DIP 1), P27(KIP 1), the a-fetoprotein gene, beta-catenin, or c-MET, such as for treating a cancer of the liver. In another embodiment, the iRNA agent can target apoB-100, such as for the treatment of 94 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 an HDL/LDL cholesterol imbalance; dyslipidemias, e.g., familial combined hyperlipidemia (FCHL), or acquired hyperlipidemia; hypercholesterolemia; statin-resistant hypercholesterolemia; coronary artery disease (CAD); coronary heart disease (CHD); or atherosclerosis. In another embodiment, the iRNA agent can target forkhead homologue in 5 rhabdomyosarcoma (FKHR); glucagon; glucagon receptor; glycogen phosphorylase; PPAR Gamma Coactivator (PGC-1); fructose-1,6-bisphosphatase; glucose-6-phosphatase; glucose-6 phosphate translocator; glucokinase inhibitory regulatory protein; or phosphoenolpyruvate carboxykinase (PEPCK), such as to inhibit hepatic glucose production in a mammal, such as a human, such as for the treatment of diabetes. In another embodiment, an iRNA agent targeted to 10 the liver can target Factor V, e.g., the Leiden Factor V allele, such as to reduce the tendency to form a blood clot. An iRNA agent targeted to the liver can include a sequence which targets hepatitis virus (e.g., Hepatitis A, B, C, D, E, F, G, or H). For example, an iRNA agent of the invention can target any one of the nonstructural proteins of HCV: NS3, 4A, 4B, 5A, or 5B. For the treatment of hepatitis B, an iRNA agent can target the protein X (HBx) gene, for example. 15 Preferred ligands on RRMSs include folic acid, glucose, cholesterol, cholic acid, Vitamin E, Vitamin K, or Vitamin A. Definitions The term 'halo" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched 20 chain, containing the indicated number of carbon atoms. For example, C-C 12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). Alkyl and haloalkyl groups may be optionally inserted with 0, N, or S. The terms "aralkyl" refers to an 25 alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "aralkyl" include benzyl, 9-fluorenyl, benzhydryl, and trityl groups. 95 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-8 carbon atoms and characterized in having one or more double bonds. Examples of a typical alkenyl include, but not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-8 carbon 5 atoms and characterized in having one or more triple bonds. Some examples of a typical alkynyl are ethynyl, 2-propynyl, and 3-methylbutynyl, and propargyl. The sp 2 and sp 3 carbons may optionally serve as the point of attachment of the alkenyl and alkynyl groups, respectively. The term "alkoxy" refers to an -0-alkyl radical. The term "aminoalkyl" refers to an alkyl substituted with an aminoThe term "mercapto" refers to an -SH radical. The term "thioalkoxy" 10 refers to an -S-alkyl radical. The term "alkylene" refers to a divalent alkyl (i.e., -R-), e.g., -CH 2 -, -CH 2

CH

2 -, and CH 2

CH

2

CH

2 -. The term "alkylenedioxo" refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene. The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring 15 system, wherein any ring atom capable of substitution can be substituted by a substituent. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic,or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution can be substituted by a substituent. The cycloalkyl groups herein described may also 20 contain fused rings. Fused rings are rings that share a common carbon-carbon bond. Examples of cycloalkyl moieties include, but are not limited to, cyclohexyl, adamantyl, and norbornyl. The term "heterocyclyl" refers to a nonaromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms 25 selected from 0, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein any ring atom capable of substitution can be substituted by a substituent. The heterocyclyl groups herein described may also contain fused rings. Fused rings are rings that share a common carbon-carbon bond. Examples of 96 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 heterocyclyl include, but are not limited to tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl and pyrrolidinyl. The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 5 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein any ring atom capable of substitution can be substituted by a substituent. The term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to 10 carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur. The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents. The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, alkenyl, 15 alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation, alkyl, alkenyl, alkynyl, alkoxy, halo, hydroxy, cyano, nitro, amino, S03H, sulfate, phosphate, perfluoroalkyl, perfluoroalkoxy, methylenedioxy, ethylenedioxy, carboxyl, oxo, thioxo, imino (alkyl, aryl, aralkyl), S(O),alkyl (where n is:0-2), S(O), aryl (where n is 0-2), S(O)n heteroaryl (where n is 0-2), S(O)n 20 heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof), unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl, and unsubstituted cycloalkyl. In one aspect, the substituents on a group are 25 independently any one single, or any subset of the aforementioned substituents. The terms "adeninyl, cytosinyl, guaninyl, thyminyl, and uracilyl" and the like refer to radicals of adenine, cytosine, guanine, thymine, and uracil. As used herein, an "unusual" nucleobase can include any one of the following: 97 WO 2004/091515 PCT/US2004/01 1255 Attorney's Docket No.: 14174-072W01I 2-methyladeninyl, N6-methyladeninyl, 2-methylthio-N6-methyladeninyl, N6-isopentenyladeninyl, 5 2-methylthio-N6-isopentenyladeninyl, N6-(cis-hydroxyisopentenyl)adeninyl, 2-methylthio-N6-(cis-hydroxyisopentenyl) adeninyl, N6-glycinylcarbamoyladeninyl, N6-threonylcarbamoyladeninyl, 10 2-methylthio-N6-threonyl carbamoyladeninyl, N6-methyl-N6-threonylcarbamoyladeninyl, N6-hydroxynorvalylcarbamoyladeninyl, 2-methylthio-N6-hydroxynorvalyl carbarnoyladeninyl, N6,N6-dimethyladeninyl, 15 3-methylcytosinyl, 5-methylcytosinyl, 2-thiocytosinyl, 5-formylcytosinyl, NH COOHN

H

2 N) N' N. H ~'98 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 N4-methylcytosinyl, 5-hydroxymethylcytosinyl, 1-methylguaninyl, N2-methylguaninyl, 5 7-methylguaninyl, N2,N2-dimethylguaninyl,

NHCOOCH

3

NHCOOCH

3

NHCOOCH

3

H

3 COOC H 3 COOC OH H 3 COOC OOH O 0 O / N N, ;I N

H

3 C N H 3 C NH3C N N N N N <N N

OH

3 H 3 OH 3

NH

2 HOOC OH 0 H 3 0 O 0_IN N 3'N N N H 3 C H 3 C \> H3CN N ' N N N N , H 3

CH

3

CH

3 99 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01I HN N H 3 C, OH NH HN H

H

2 N N N H 2 N z'N N HO HO beta-galactosyl 0o> beta-mannosyl 0 0HN H O NH 0 NH 0 N 2 ' HN HN HN

H

2 N N N

H

2 2N N2,7-dirmethylgaaninyl, N2,N2,7-trimethylguaninyl, 1 -methylguaninyl, 5 7-cyano-7-deazaguaflifyl, 7-aminornethyl-7-deazaguaninyl, pseudouracilyl, dihydrouracilyl, 5-methyluracilyl, 10 1 -methyipseudouracilyl, 2-thiouracilyl, 4-thiouracilyl, 100 WO 2004/091515 PCT/US2004/01 1255 Attorney's Docket No.: 14174-072W01 2-thiothymi-nyl 5-methyl-2-thiouracilyl, 3-(3 -amino-.3-carboxypropyl)uracilyl, 5-hydroxyuracilyl, 5 5-methoxyuracilyl, uracilyl 5-oxyacetic acid, uracilyl 5-oxyacetic acid methyl ester, 5-(carboxyhydroxymethyl)uracilyl, 5-(carboxyhydroxymethyl)uracily methyl ester, 10 5-methoxycarbonylmethyluracilyl, 5-methoxycarbonylmethyl-2-thiouracilyl, 5-amtinomethyl-2-thiouracilyl, 5-methylaminomethyluracilyl, 5-methylamninomethyl-2-thiouracilyl, 15 5-methylaminomethyl-2-selenouracilyl, 5-carbamoylmethyluracilyl, 5-carboxymethylaminoinethyluracilyl, 5.-carboxymethylaminomethyl-2-thiouracilyl, 3-methyluracilyl, 20 1 -methyl-3-(3 -amino-3-carboxypropyl) pseudouracilyl, 101 5-carboxymethyluracilyl, 5-methyldihydrouracilyl, or 3-methylpseudouracilyl. Palindromes An RNA, e.g., an iRNA agent, can have a palindrome structure as described herein and 5 those described in one or more of United States Provisional Application Serial No. 60/452,682, filed March 7, 2003; United States Provisional Application Serial No. 60/462,894, filed April 14, 2003; and International Application No. PCT/USO4/07070, filed March 8, 2004, all of which are hereby incorporated by reference. The iRNA agents described herein can target more than 10 one RNA region. For example, an iRNA agent can include a first and second sequence that are sufficiently complementary to each other to hybridize. The first sequence can be complementary to a first target RNA region and the second sequence can be complementary to a second target RNA region. The first and second sequences of the iRNA agent can be on different RNA strands, and the mismatch between the first and second sequences can be less than 50%, 40%, 15 30%, 20%, 10%, 5%, or 1%. The first and second sequences of the iRNA agent are on the same RNA strand, and in a related embodiment more than 50%, 60%, 70%, 80%, 90%, 95%, or'l% of the iRNA agent can be in bimolecular form. The first and second sequences of the iRNA agent can be fully complementary to each other. The first target RNA region can be encoded by a first gene and the second target RNA 20 region can encoded by a second gene, or the first and second target RNA regions can be different regions of an RNA from a single gene. The first and second sequences can differ by at least 1 nucleotide. The first and second target RNA regions can be on transcripts encoded by first and second sequence variants, e.g., first and second alleles, of a gene. The sequence variants can be 25 mutations, or polymorphisms, for example. The first target RNA region can include a nucleotide substitution, insertion, or deletion relative to the second target RNA region, or the second target RNA region can a mutant or variant of the first target region. 102 The first and second target RNA regions can comprise viral or human RNA regions. The first and second target RNA regions can also be on variant transcripts of an oncogene or include different mutations of a tumor suppressor gene transcript. In addition, the first and second target RNA regions can corresnond to hot-snots for genetic variation. 5 The composition described herein can include mixtures of iRNA agent molecules. For example, one iRNA agent can contain a first sequence and a second sequence sufficiently complementary to each other to hybridize, and in addition the first sequence is complementary to a first target RNA region and the second sequence is complementary to a second target RNA region. The mixture can also include at least one additional iRNA agent variety that includes a 10 third sequence and a fourth sequence sufficiently complementary to each other to hybridize, and where the third sequence is complementary to a third target RNA region and the fourth sequence is complementary to a fourth target RNA region. In addition, the first or second sequence can be sufficiently complementary to the third or fourth sequence to be capable of hybridizing to each other. The first and second sequences can be on the same or different RNA strands, and the third 15 and fourth sequences can be on the same or different RNA strands. The target RNA regions can be variant sequences of a viral or human RNA, and in certain embodiments, at least two of the target RNA regions can be on variant transcripts of an oncogene or tumor suppressor gene. The target RNA regions can correspond to genetic hot spots. 20 Methods of making an iRNA agent composition can include obtaining or providing information about a region of an RNA of a target gene (e.g., a viral or human gene, or an oncogene or tumor suppressor, e.g., p53), where the region has high variability or mutational frequency (e.g., in humans). In addition, information about a plurality of RNA targets within the region can be obtained or provided, where each RNA target corresponds to a different variant or 25 mutant of the gene (e.g., a region including the codon encoding p53 248Q and/or p53 249S). The iRNA agent can be constructed such that a first sequence is complementary to a first of the plurality of variant RNA targets (e.g., encoding 249Q) and a second sequence is complementary to a second of the plurality of variant RNA targets (e.g., encoding 249S), and the first and second sequences can be sufficiently complementary to hybridize. 103 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Sequence analysis, e.g., to identify common mutants in the target gene, can be used to identify a region of the target gene that has high variability or mutational frequency. A region of the target gene having high variability or mutational frequency can be identified by obtaining or providing genotype information about the target gene from a population. 5 Expression of a target gene can be modulated, e.g., downregulated or silenced, by providing an iRNA agent that has a first sequence and a second sequence sufficiently complementary to each other to hybridize. In addition, the first sequence can be complementary to a first target RNA region and the second sequence can be complementary to a second target RNA region. 10 An iRNA agent can include a first sequence complementary to a first variant RNA target region and a second sequence complementary to a second variant RNA target region. The first and second variant RNA target regions can correspond to first and second variants or mutants of a target gene, e.g., viral gene, tumor suppressor or oncogene. The first and second variant target RNA regions can include allelic variants, mutations (e.g., point mutations), or polymorphisms of 15 the target gene. The first and second variant RNA target regions can correspond to genetic hot spots. A plurality of iRNA agents (e.g., a panel or bank) can be provided. Other than Canonical Watson-Crick Duplex Structures An RNA, e.g., an iRNA agent can include monomers which can form other than a 20 canonical Watson-Crick pairing with another monomer, e.g., a monomer on another strand, such as those described herein and those described in United States Provisional Application Serial No. 60/465,665, filed April 25, 2003, and International Application No. PCT/US04/07070, filed March 8, 2004, both of which are hereby incorporated by reference. The use of "other than canonical Watson-Crick pairing" between monomers of a duplex 25 can be used to control, often to promote, melting of all or part of a duplex. The iRNA agent can include a monomer at a selected or constrained position that results in a first level of stability in the iRNA agent duplex (e.g., between the two separate molecules of a double stranded iRNA agent) and a second level of stability in a duplex between a sequence of an iRNA agent and 104 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 another sequence molecule, e.g., a target or off-target sequence in a subject. In some cases the second duplex has a relatively greater level of stability, e.g., in a duplex between an anti-sense sequence of an iRNA agent and a target mRNA. In this case one or more of the monomers, the position of the monomers in the iRNA agent, and the target sequence (sometimes referred to 5 herein as the selection or constraint parameters), are selected such that the iRNA agent duplex is has a comparatively lower free energy of association (which while not wishing to be bound by mechanism or theory, is believed to contribute to efficacy by promoting disassociation of the duplex iRNA agent in the context of the RISC) while the duplex formed between an anti-sense targeting sequence and its target sequence, has a relatively higher free energy of association 10 (which while not wishing to be bound by mechanism or theory, is believed to contribute to efficacy by promoting association of the anti-sense sequence and the target RNA). In other cases the second duplex has a relatively lower level of stability, e.g.; in a duplex between a sense sequence of an iRNA agent and an off-target mRNA. In this case one or more of the monomers, the position of the monomers in the iRNA agent, and an off-target sequence, 15 are selected such that the iRNA agent duplex is has a comparatively higher free energy of association while the duplex formed between a sense targeting sequence and its off-target sequence, has a relatively lower free energy of association (which while not wishing to be bound by mechanism or theory, is believed to reduce the level of off-target silencing by contribute to efficacy by promoting disassociation of the duplex formed by the sense strand and the off-target 20 sequence). Thus, inherent in the structure of the iRNA agent is the property of having a first stability for the intra-iRNA agent duplex and a second stability for a duplex formed between a sequence from the iRNA agent and another RNA, e.g., a target mRNA. As discussed above, this can be accomplished by judicious selection of one or more of the monomers at a selected or constrained 25 position, the selection of the position in the duplex to place the selected or constrained position, and selection of the sequence of a target sequence (e.g., the particular region of a target gene which is to be targeted). The iRNA agent sequences which satisfy these requirements are sometimes referred herein as constrained sequences. Exercise of the constraint or selection parameters can e, e.g., by inspection, or by computer assisted methods. Exercise of the 105 parameters can result in selection of a target sequence and of particular monomers to give a desired result in terms of the stability, or relative stability, of a duplex. Thus, described herein is an iRNA agent which includes: a first sequence which targets a first target region and a second sequence which targets a second target 5 region. The first and second sequences have sufficient complementarity to each other to hybridize, e.g., under physiological conditions, e.g., under physiological conditions but not in contact with a helicase or other unwinding enzyme. In a duplex region of the iRNA agent, at a selected or constrained position, the first target region has a first monomer, and the second target region has a second monomer. The first and second monomers occupy complementary or 10 corresponding positions. One, and preferably both monomers are selected such that the stability of the pairing of the monomers contribute to a duplex between the first and second sequence will differ form the stability of the pairing between the first or second sequence with a target sequence. Usually, the monomers will be selected (selection of the target sequence may be required 15 as well) such that they form a pairing in the iRNA agent duplex which has a lower free energy of dissociation, and a lower Tm, than will be possessed by the paring of the monomer with its complementary monomer in a duplex between the iRNA agent sequence and a target RNA. duplex. The constraint placed upon the monomers can be applied at a selected site or at more 20 than one selected site. By way of example, the constraint can be applied at more than 1, but less than 3, 4, 5, 6, or 7 sites in an iRNA agent duplex. A constrained or selected site can be present at a number of positions in the iRNA agent duplex. E.g., a constrained or selected site can be present within 3, 4, 5, or 6 positions from either end, 3' or 5' of a duplexed sequence. A constrained or selected site can be present in the 25 middle of the duplex region, e.g., it can be more than 3, 4, 5, or 6, positions from the end of a duplexed region. In some embodiment the duplex region of the iRNA agent will have, mismatches, in addition to the selected or constrained site or sites. Preferably it will have no more than 1, 2, 3, 106 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 4, or 5 bases, which do not form canonical Watson-Crick pairs or which do not hybridize. Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The first and second iRNA agent 5 sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. The monomers can be selected such that: first and second monomers are naturally occurring ribonuceotides, or modified ribonucleotides having naturally occurring bases, and when occupying complemetary sites either do not pair and have no substantial level of H 10 bonding, or form a non canonical Watson-Crick pairing and form a non-canonical pattern of H bonding, which usually have a lower free energy of dissociation than seen in a canonical Watson-Crick pairing, or otherwise pair to give a free energy of association which is less than that of a preselected value or is less, e.g., than that of a canonical pairing. When one (or both) of the iRNA agent sequences duplexes with a target, the first (or second) monomer forms a 15 canonical Watson-Crick pairing with the base in the complemetary position on the target, or forms a non canonical Watson-Crick pairing having a higher free energy of dissociation and a higher Tm than seen in the paring in the iRNA agent. The classical Watson-Crick parings are as follows: A-T, G-C, and A-U. Non-canonical Watson-Crick pairings are known in the art and can include, U-U, G-G, G-Atrans, G-Aci,, and GU. 20 The monomer in one or both of the sequences is selected such that, it does not pair, or forms a pair with its corresponding monomer in the other sequence which minimizes stability (e.g., the H bonding formed between the monomer at the selected site in the one sequence and its monomer at the corresponding site in the other sequence are less stable than the H bonds formed by the monomer one (or both) of the sequences with the respective target sequence. The 25 monomer is one or both strands is also chosen to promote stability in one or both of the duplexes made by a strand and its target sequence. E.g., one or more of the monomers and the target sequences are selected such that at the selected or constrained position, there is are no H bonds formed, or a non canonical pairing is formed in the iRNA agent duplex, or otherwise they otherwise pair to give a free energy of association which is less than that of a preselected value 30 or is less, e.g., than that of a canonical pairing, but when one ( or both) sequences form a duplex 107 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 with the respective target, the pairing at the selected or constrained site is a canonical Watson Crick paring. The inclusion of such a monomers will have one or more of the following effects: it will destabilize the iRNA agent duplex, it will destabilize interactions between the sense sequence 5 and unintended target sequences, sometimes referred to as off-target sequences, and duplex interactions between the a sequence and the intended target will not be destabilized. By way of example: The monomer at the selected site in the first sequence includes an A (or a modified base which pairs with T), and the monomer in at the selected position in the second sequence is 10 chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., G. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. 15 The monomer at the selected site in the first sequence includes U (or a modified base which pairs with A), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., U or G. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful 20 wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. The monomer at the selected site in the first sequence includes a G (or a modified base which pairs with C), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., G, 25 Acis, Atrans, or U. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target sequence for the second strand has a monomer which 108 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. The monomer at the selected site in the first sequence includes a C (or a modified base which pairs with G), and the monomer in at the selected position in the second sequence is 5 chosen a monomer which will not pair or which will form a non-canonical pairing. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. 10 A non-naturally occurring or modified monomer or monomers can be chosen such that when a non-naturally occurring or modified monomer occupies a positions at the selected or constrained position in an iRNA agent they exhibit a first free energy of dissociation and when one (or both) of them pairs with a naturally occurring monomer, the pair exhibits a second free energy of dissociation, which is usually higher than that of the pairing of the first and second 15 monomers. E.g., when the first and second monomers occupy complementary positions they either do not pair and have no substantial level of H-bonding, or form a weaker bond than one of them would form with a naturally occurring monomer, and reduce the stability of that duplex, but when the duplex dissociates at least one of the strands will forn a duplex with a target in which the selected monomer will promote stability, e.g., the monomer will form a more stable pair with 20 a naturally occurring monomer in the target sequence than the pairing it formed in the iRNA agent. An example of such a pairing is 2-amino A and either of a 2-thio pyrimidine analog of U or T. When placed in complementary positions of the iRNA agent these monomers will pair 25 very poorly and will minimize stability. However, a duplex is formed between 2 amino A and the U of a naturally occurring target, or a duplex is between 2-thio U and the A of a naturally occurring target or 2-thio T and the A of a naturally occurring target will have a relatively higher free energy of dissociation and be more stable. This is shown in the FIG. 1. 109 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 The pair shown in FIG. 1 (the 2-amino A and the 2-s U and T) is exemplary. In another embodiment, the monomer at the selected position in the sense strand can be a universal pairing moiety. A universal pairing agent will form some level of H bonding with more than one and preferably all other naturally occurring monomers. An examples of a universal pairing moiety is 5 a monomer which includes 3-nitro pyrrole. (Examples of other candidate universal base analogs can be found in the art, e.g., in Loakes, 2001, NAR 29: 2437-2447, hereby incorporated by reference. Examples can also be found in the section on Universal Bases below.) In these cases the monomer at the corresponding position of the anti-sense strand can be chosen for its ability to form a duplex with the target and can include, e.g., A, U, G, or C. 10 iRNA agents of the invention can include: A sense sequence, which preferably does not target a sequence in a subject, and an anti sense sequence, which targets a target gene in a subject. The sense and anti-sense sequences have sufficient complementarity to each other to hybridize hybridize, e.g., under physiological conditions, e.g., under physiological conditions but not in contact with a helicase or other 15 unwinding enzyme. In a duplex region of the iRNA agent, at a selected or constrained position, the monomers are selected such that: The monomer in the sense sequence is selected such that, it does not pair, or forms a pair with its corresponding monomer in the anti-sense strand which minimizes stability (e.g., the H bonding formed between the monomer at the selected site in the sense strand and its monomer at 20 the corresponding site in the anti-sense strand are less stable than the H bonds formed by the monomer of the anti-sense sequence and its canonical Watson-Crick partner or, if the monomer in the anti-sense strand includes a modified base, the natural analog of the modified base and its canonical Watson-Crick partner); The monomer is in the corresponding position in the anti-sense strand is selected such 25 that it maximizes the stability of a duplex it forms with the target sequence, e.g., it forms a canonical Watson-Crick paring with the monomer in the corresponding position on the target stand; 110 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Optionally, the monomer in the sense sequence is selected such that, it does not pair, or forms a pair with its corresponding monomer in the anti-sense strand which minimizes stability with an off-target sequence. The inclusion of such a monomers will have one or more of the following effects: it will 5 destabilize the iRNA agent duplex, it will destabilize interactions between the sense sequence and unintended target sequences, sometimes referred to as off-target sequences, and duplex interactions between the anti-sense strand and the intended target will not be destabilized. The constraint placed upon the monomers can be applied at a selected site or at more than one selected site. By way of example, the constraint can be applied at more than 1, but less 10 than 3, 4, 5, 6, or 7 sites in an iRNA agent duplex. A constrained or selected site can be present at a number of positions in the iRNA agent duplex. E.g., a constrained or selected site can be present within 3, 4, 5, or 6 positions from either end, 3' or 5' of a duplexed sequence. A constrained or selected site can be present in the middle of the duplex region, e.g., it can be more than 3, 4, 5, or 6, positions from the end of a 15 duplexed region. In some embodiment the duplex region of the iRNA agent will have, mismatches, in addition to the selected or constrained site or sites. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, which do not form canonical Watson-Crick pairs or which do not hybridize. Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in 20 length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. The monomers can be selected such that: first and second monomers are naturally 25 occurring ribonuceotides, or modified ribonucleotides having naturally occurring bases, and when occupying complemetary sites either do not pair and have no substantial level of H bonding, or form a non canonical Watson-Crick pairing and form a non-canonical pattern of H bonding, which usually have a lower free energy of dissociation than seen in a canonical 111 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Watson-Crick pairing, or otherwise pair to give a free energy of association which is less than that of a preselected value or is less, e.g., than that of a canonical pairing. When one (or both) of the iRNA agent sequences duplexes with a target, the first (or second) monomer forms a canonical Watson-Crick pairing with the base in the complemetary position on the target, or 5 forms a non canonical Watson-Crick pairing having a higher free energy of dissociation and a higher Tm than seen in the paring in the iRNA agent. The classical Watson-Crick parings are as follows: A-T, G-C, and A-U. Non-canonical Watson-Crick pairings are known in the art and can include, U-U, G-G, G-Aims, G-Acis, and GU. The monomer in one or both of the sequences is selected such that, it does not pair, or 10 forms a pair with its corresponding monomer in the other sequence which minimizes stability (e.g., the H bonding formed between the monomer at the selected site in the one sequence and its monomer at the corresponding site in the other sequence are less stable than the H bonds formed by the monomer one (or both) of the sequences with the respective target sequence. The monomer is one or both strands is also chosen to promote stability in one or both of the duplexes 15 made by a strand and its target sequence. E.g., one or more of the monomers and the target sequences-are selected such that at the selected or constrained position, there is are no H bonds formed, or a non canonical pairing is formed in the iRNA agent duplex, or otherwise they otherwise pair to give a free energy of association which is less than that of a preselected value or is less, e.g., than that of a canonical pairing, but when one (or both) sequences form a duplex 20 with the respective target, the pairing at the selected or constrained site is a canonical Watson Crick paring. The inclusion of such a monomers will have one or more of the following effects: it will destabilize the iRNA agent duplex, it will destabilize interactions between the sense sequence and unintended target sequences, sometimes referred to as off-target sequences, and duplex 25 interactions between the a sequence and the intended target will not be destabilized. By way of example: The monomer at the selected site in the first sequence includes an A (or a modified base which pairs with T), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., G. 112 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. 5 The monomer at the selected site in the first sequence includes U (or a modified base which pairs with A), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., U or G. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful 10 wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. The monomer at the selected site in the first sequence includes a G (or a modified base which pairs with C), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., G, 15 Acs, Atrans, or U. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. 20 The monomer at the selected site in the first sequence includes a C (or a modified base which pairs with G), and the monomer in at the selected position in the second sequence is chosen a monomer which will not pair or which will form a non-canonical pairing. These will be useful in applications wherein the target sequence for the first sequence has a T at the selected position. In embodiments where both target duplexes are stabilized it is useful wherein the target 25 sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand. A non-naturally occurring or modified monomer or monomers can be chosen such that when a non-naturally occurring or modified monomer occupies a positions at the selected or constrained position in an iRNA agent they exhibit a first free energy of dissociation and when 113 one (or both) of them pairs with a naturally occurring monomer, the pair exhibits a second free energy of dissociation, which is usually higher than that of the pairing of the first and second monomers. E.g., when the first and second monomers occupy complementary positions they either do not pair and have no substantial level of H-bonding, or form a weaker bond than one of 5 them would form with a naturally occurring monomer, and reduce the stability of that duplex, but when the duplex dissociates at least one of the strands will form a duplex with a target in which the selected monomer will promote stability, e.g., the monomer will form a more stable pair with a naturally occurring monomer in the target sequence than the pairing it formed in the iRNA agent. 10 An example of such a pairing is 2-amino A and either of a 2-thio pyrimidine analog of U or T. When placed in complementary positions of the iRNA agent these monomers will pair very poorly and will minimize stability. However, a duplex is formed between 2 amino A and the U of a naturally occurring target, or a duplex is between 2-thio U and the A of a naturally 15 occurring target or 2-thio T and the A of a naturally occurring target will have a relatively higher free energy of dissociation and be more stable. The monomer at the selected position in the sense strand can be a universal pairing moiety. A universal pairing agent will form some level of H bonding with more than one and preferably all other naturally occurring monomers. An examples of a universal pairing moiety is 20 a monomer which includes 3-nitro pyrrole. (Examples of other candidate universal base analogs can be found in the art, e.g., in Loakes, 2001, NAR 29: 2437-2447, hereby incorporated by reference. Examples can also be found in the section on Universal Bases below.) In these cases the monomer at the corresponding position of the anti-sense strand can be chosen for its ability to form a duplex with the target and can include, e.g., A, U, G, or C. 25 iRNA agents described herein can include: A sense sequence, which preferably does not target a sequence in a subject, and an anti sense sequence, which targets a target gene in a subject. The sense and anti-sense sequences have sufficient complementarity to each other to hybridize hybridize, e.g., under physiological 114 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 conditions, e.g., under physiological conditions but not in contact with a helicase or other unwinding enzyme. In a duplex region of the iRNA agent, at a selected or constrained position, the monomers are selected such that: The monomer in the sense sequence is selected such that, it does not pair, or forms a pair 5 with its corresponding monomer in the anti-sense strand which minimizes stability (e.g., the H bonding formed between the monomer at the selected site in the sense strand and its monomer at the corresponding site in the anti-sense strand are less stable than the H bonds formed- by the monomer of the anti-sense sequence and its canonical Watson-Crick partner or, if the monomer in the anti-sense strand includes a modified base, the natural analog of the modified base and its 10 canonical Watson-Crick partner); The monomer is in the corresponding position in the anti-sense strand is selected such that it maximizes the stability of a duplex it forms with the target sequence, e.g., it forms a canonical Watson-Crick paring with the monomer in the corresponding position on the target stand; 15 Optionally, the monomer in the sense sequence is selected such that, it does not pair, or forms a pair with its corresponding monomer in the anti-sense strand which minimizes stability with an off-target sequence. The inclusion of such a monomers will have one or more of the following effects: it will destabilize the iRNA agent duplex, it will destabilize interactions between the sense sequence 20 and unintended target sequences, sometimes referred to as off-target sequences, and duplex interactions between the anti-sense strand and the intended target will not be destabilized. The constraint placed upon the monomers can be applied at a selected site or at more than one selected site. By way of example, the constraint can be applied at more than 1, but less than 3, 4, 5, 6, or 7 sites in an iRNA agent duplex. 25 A constrained or selected site can be present at a number of positions in the iRNA agent duplex. E.g., a constrained or selected site can be present within 3, 4, 5, or 6 positions from either end, 3' or 5' of a duplexed sequence. A constrained or selected site can be present in the 115 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 middle of the duplex region, e.g., it can be more than 3, 4, 5, or 6, positions from the end of a duplexed region. The iRNA agent can be selected to target a broad spectrum of genes, including any of the genes described herein. 5 In a preferred embodiment the iRNA agent has an architecture (architecture refers to one or more of overall length, length of a duplex region, the presence, number, location, or length of overhangs, sing strand versus double strand form) described herein. E.g., the iRNA agent can be less than 30 nucleotides in length, e.g., 21-23 nucleotides. Preferably, the iRNA is 21 nucleotides in length and there is a duplex region of about 19 pairs. 10 In one embodiment, the iRNA is 21 nucleotides in length, and the duplex region of the iRNA is 19 nucleotides. In another embodiment, the iRNA is greater than 30 nucleotides in length. In some embodiment the duplex region of the iRNA agent will have, mismatches, in addition to the selected or constrained site or sites. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, which do not form canonical Watson-Crick pairs or which do not hybridize. 15 Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence. The first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. 20 One or more selection or constraint parameters can be exercised such that: monomers at the selected site in the sense and anti-sense sequences are both naturally occurring ribonucleotides, or modified ribonucleotides having naturally occurring bases, and when occupying complementary sites in the iRNA agent duplex either do not pair and have no substantial level of H-bonding, or form a non-canonical Watson-Crick pairing and thus form a 25 non-canonical pattern of H bonding, which generally have a lower free energy of dissociation than seen in a Watson-Crick pairing, or otherwise pair to give a free energy of association which is less than that of a preselected value or is less, e.g., than that of a canonical pairing. When one, usually the anti-sense sequence of the iRNA agent sequences forms a duplex with another 116 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 sequence, generally a sequence in the subject, and generally a target sequence, the monomer forms a classic Watson-Crick pairing with the base in the complementary position on the target, or forms a non-canonical Watson-Crick pairing having a higher free energy of dissociation and a higher Tm than seen in the paring in the iRNA agent. Optionally, when the other sequence of the 5 iRNA agent, usually the sense sequences forms a duplex with another sequence, generally a sequence in the subject, and generally an off-target sequence, the monomer fails to forms a canonical Watson-Crick pairing with the base in the complementary position on the off target sequence, e.g., it forms or forms a non-canonical Watson-Crick pairing having a lower free energy of dissociation and a lower Tm. 10 By way of example: the monomer at the selected site in the anti-sense stand includes an A (or a modified base which pairs with T), the corresponding monomer in the target is a T, and the sense strand is chosen from a base which will not pair or which will form a noncanonical pair, e.g., G; the monomer at the selected site in the anti-sense stand includes a U (or a modified base 15 which pairs with A), the corresponding monomer in the target is an A, and the sense strand is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., U or G; the monomer at the selected site in the anti-sense stand includes a C (or a modified base which pairs with G), the corresponding monomer in the target is a G, and the sense strand is 20 chosen a monomer which will not pair or which will form a non-canonical pairing, e.g., G, Acis, Atrans, or U; or the monomer at the selected site in the anti-sense stand includes a G (or a modified base which pairs with C), the corresponding monomer in the target is a C, and the sense strand is chosen from a monomer which will not pair or which will form a non-canonical pairing. 25 In another embodiment a non-naturally occurring or modified monomer or monomers is chosen such that when it occupies complementary a position in an iRNA agent they exhibit a first free energy of dissociation and when one (or both) of them pairs with a naturally occurring monomer, the pair exhibits a second free energy of dissociation, which is usually higher than that 117 of the pairing of the first and second monomers. E.g., when the first and second monomers occupy complementary positions they either do not pair and have no substantial level of H bonding, or form a weaker bond than one of them would form with a naturally occurring monomer, and reduce the stability of that duplex, but when the duplex dissociates at least one of 5 the strands will form a duplex with a target in which the selected monomer will promote stability, e.g., the monomer will form a more stable pair with a naturally occurring monomer in the target sequence than the pairing it formed in the iRNA agent. An example of such a pairing is 2-amino A and either of a 2-thio pyrimidine analog of U or T. As is discussed above, when placed in complementary positions of the iRNA agent these 10 monomers will pair very poorly and will minimize stability. However, a duplex is formed between 2 amino A and the U of a naturally occurring target, or a duplex is formed between 2 thio U and the A of a naturally occurring target or 2-thio T and the A of a naturally occurring target will have a relatively higher free energy of dissociation and be more stable. The monomer at the selected position in the sense strand can be a universal pairing 15 moiety. A universal pairing agent will form some level of H bonding with more than one and preferably all other naturally occurring monomers. An examples of a universal pairing moiety is a monomer which includes 3-nitro pyrrole. Examples of other candidate universal base analogs can be found in the art, e.g., in Loakes, 2001, NAR 29: 2437-2447, hereby incorporated by reference. In these cases the monomer at the corresponding position of the anti-sense strand can 20 be chosen for its ability to form a duplex with the target and can include, e.g., A, U, G, or C. Also described herein is an iRNA agent which includes: a sense sequence, which preferably does not target a sequence in a subject, and an anti sense sequence, which targets a plurality of target sequences in a subject, wherein the targets differ in sequence at only 1 or a small number, e.g., no more than 5, 4, 3 or 2 positions. The 25 sense and anti-sense sequences have sufficient complementarity to each other to hybridize, e.g., under physiological conditions, e.g., under physiological conditions but not in contact with a helicase or other unwinding enzyme. In the sequence of the anti-sense strand of the iRNA agent is selected such that at one, some, or all of the positions which correspond to positions that differe in sequence between the target sequences, the anti-sense strand will include a monomer 118 which will form H-bonds with at least two different target sequences. In a preferred example the anti-sense sequence will include a universal or promiscuous monomer, e.g., a monomer which includes 5-nitro pyrrole, 2-amino A, 2-thio U or 2-thio T, or other universal base referred to herein. 5 In a preferred embodiment the iRNA agent targets repeated sequences (which differ at only one or a small number of positions from each other) in a single gene, a plurality of genes, or a viral genome, e.g., the HCV genome. An embodiment is illustrated in the FIGs. 2 and 3. . In another form, the disclosure features, determining, e.g., by measurement or 10 calculation, the stability of a pairing between monomers at a selected or constrained positoin in the iRNA agent duplex, and preferably determining the stability for the corresponding pairing in a duplex between a sequence form the iRNA agent and another RNA, e.g., a taret sequence. The determinations can be compared. An iRNA agent thus analysed can be used in the devolopement of a further modified iRNA agent or can be administered to a subject. This analysis can be 15 performed successively to refine or desing optimized iRNA agents. Also described herein is a kit which inlcudes one or more of the folowing an iRNA described herein, a sterile container in which the iRNA agent is discolsed, and instructions for use. Also described herein is an iRNA agent containing a constrained 20 sequence made by a method described herein. The iRNA agent can target one or more of the genes referred to herein. iRNA agents having constrained or selected sites, e.g., as described herein, can be used in any way described herein. Accordingly, they iRNA agents having constrained or selected sites, e.g., as described herein, can be used to silence a target, e.g., in any of the methods 25 described herein and to target any of the genes described herein or to treat any of the disorders described herein. iRNA agents having constrained or selected sites, e.g., as described herein, can be incorporated into any of the formulations or preparations, e.g., pharmaceutical or sterile 119 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 preparations described herein. iRNA agents having constrained or selected sites, e.g., as described herein, can be administered by any of the routes of administration described herein. The term "other than canonical Watson-Crick pairing" as used herein, refers to a pairing between a first monomer in a first sequence and a second monomer at the corresponding position 5 in a second sequence of a duplex in which one or more of the following is true: (1) there is essentially no pairing between the two, e.g., there is no significant level of H bonding between the monomers or binding between the monomers does not contribute in any significant way to the stability of the duplex; (2) the monomers are a non-canonical paring of monomers having a naturally occurring bases, i.e., they are other than A-T, A-U, or G-C, and they form monomer 10 monomer H bonds, although generally the H bonding pattern formed is less strong than the , bonds formed by a canonical pairing; or(3) at least one of the monomers includes a non-naturally occurring bases and the H bonds formed between the monomers is, preferably formed is less strong than the bonds formed by a canonical pairing, namely one or more of A-T, A-U, G-C. The term "off-target" as used herein, refers to as a sequence other than the sequence to be 15 silenced. Universal Bases: "wild-cards"; shape-based complementarity Bi-stranded, multisite replication of a base pair between difluorotoluene and adenine: confirmation by 'inverse' sequencing. Liu, D.; Moran, S.; Kool, E. T. Chem. Biol., 1997, 4, 919-926) F cH 3 Hc H H HO F HON 00 OH F OH z (Importance of terminal base pair hydrogen-bonding in 3'-end proofreading by the Klenow fragment of 20 DNA polymerase I. Morales, J. C.; Kool, E. T. Biochemistry, 2000, 39, 2626-2632) (Selective and stable DNA base pairing without hydrogen bonds. Matray, T, J.; Kool, E. T. J. Am. Chem. Soc., 1998, 120, 6191-6192) 120 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 F

H

3 C HO F 0 OH (Difluorotoluene, a nonpolar isostere for thymine, codes specifically and efficiently for adenine in DNA replication. Moran, S. Ren, R. X.-F.; Rumney IV, S.; Kool, E. T. J. Am. Chem. Soc., 1997, 119, 2056-2057) 5 (Structure and base pairing properties of a replicable nonpolar isostere for deoxyadenosine. Guckian, K. M.; Morales, J. C.; Kool, E. T. J Org. Chem., 1998, 63, 9652-9656) F CH, HO C N HO F HO N 0 O OH F OH z 121 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 N02 HO N OH 3-nitropyrrole HO N N OH 5-nitroindole N N O N 0 N 0 N 0 MICS PIM 5MICS (Universal bases for hybridization, replication and chain termination. Berger, M.; Wu. Y.; Ogawa, A. K.; 5 McMinn, D. L.; Schultz, P.G.; Romesberg, F. E. Nucleic Acids Res., 2000, 28, 2911-2914) 0 0 TM DM ~ src TMDMICS PICS -N N 2MN DMN 7A 2Np 3MN 122 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (1. Efforts toward the expansion of the genetic alphabet: Information storage and replication with unnatural hydrophobic base pairs. Ogawa, A. K.; Wu, Y.; McMinn, D. L.; Liu, J.; Schultz, P. G.; Romesberg, F. E. J. Am. ChIem. Soc., 2000, 122, 3274-3287. 2. Rational design of an unnatural base pair with increased kinetic selectivity. Ogawa, A. K.; Wu. Y.; Berger, M.; Schultz, P. G.; Romesberg, F. E. J. Am. Chem. Soc., 2000, 122, 5 8803-8804) S N 7Al (Efforts toward expansion of the genetic alphabet: replication of DNA with three base pairs. Tae, E. L.; 10 Wu, Y.; Xia, G.; Schultz, P. G.; Romesberg, F. E. J Am. Chem. Soc., 2001, 123, 7439-7440) N N HO 0 OH (1. Efforts toward expansion of the genetic alphabet: Optimization of interbase hydrophobic interactions. Wu, Y.; Ogawa, A. K.; Berger, M.; McMinn, D. L.; Schultz, P. G.; Romesberg, F. E. J. Am. Chem. Soc., 2000, 122, 7621-7632. 2. Efforts toward expansion of genetic alphabet: DNA polymerase recognition of a highly stable, self pairing hydrophobic base. McMinn, D. L.; Ogawa. A. K.; Wu, Y.; Liu, J.; Schultz, P. G.; Romesberg, F. E. J. Am. 15 Chem. Soc., 1999, 121, 11585-11586) (A stable DNA duplex containing a non-hydrogen-bonding and non-shape complementary base couple: Interstrand stacking as the stability determining factor. Brotschi, C.; Haberli, A.; Leumann, C, J. Angew. Chem. Int. Ed., 2001, 40, 3012-3014) (2,2'-Bipyridine Ligandoside: A novel building block for modifying DNA with intra-duplex metal 20 complexes. Weizman, H.; Tor, Y. J. Am. Chem. Soc., 2001, 123, 3375-3376) 123 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

NH

2

NH

2 NN N HO HO 0 OH OH d2APy d2APm (Minor groove hydration is critical to the stability of DNA duplexes. Lan, T.; McLaughlin, L. W. J. Am. Chem. Soc., 2000,122, 6512-13)

NO

2 HO N OH (Effect of the Universal base 3-nitropyrrole on the selectivity of neighboring natural bases. Oliver, J. S.; 5 Parker, K. A.; Suggs, J. W. Organic Lett., 2001, 3, 1977-1980. 2. Effect of the 1-(2'-deoxy-$-D-ribofuranosyl)-3 nitropyrrol residue on the stability of DNA duplexes and triplexes. Amosova, 0.; George J.; Fresco, J. R. Nucleic Acids Res., 1997, 25, 1930-1934. 3. Synthesis, structure and deoxyribonucleic acid sequencing with a universal nucleosides: 1-(2'-deoxy- -D-ribofuranosy1)-3-nitropyrrole. Bergstrom, D. E.; Zhang, P.; Toma, P. H.; Andrews, P. C.; Nichols, R. J. Aim. Chem. Soc., 1995, 117, 1201-1209) 10 ( OH H OH HO"- " O NO "Bu HO " H-N H HI O N H H HA H H N- O OH O 0 -Clb/. (Model studies directed toward a general triplex DNA recognition scheme: a novel DNA base that binds a CG base-pair in an organic solvent. Zimmerman, S. C.; Schmitt, P. J. Am. Chem. Soc., 1995, 117, 10769-10770) 124 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 0 DNA 0 0

NO

2 0 DNA (A universal, photocleavable DNA base: nitropiperonyl 2'-deoxyriboside. J. Org. Chem., 2001, 66, 2067 2071) R10 R2 / N N N H N H 5 (Recognition of a single guanine bulge by 2-acylanino-1,8-naphthyridine. Nakatani, K.; Sando, S.; Saito, I. J. Am. Chem. Soc., 2000, 122, 2172-2177. b. Specific binding of 2-amino-1,8-naphthyridine into single guanine bulge as evidenced by photooxidation of GC doublet, Nakatani, K.; Sando, S.; Yoshida, K.; Saito, I. Bioorg. Med. Chem. Lett., 2001, 11, 335-337) 0 Ns

N~H,,

0 N H / \ H-N O ~ N N N o "H-N >' O H o o o o 10 Other universal bases can have the following formulas: 125 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

R

53

R

54 R46 R 51 Q'Q Q 5 iv R55 v" \ R. \N Q N N R48 R R62 O R1 R63 N and R60-- 57 R 64 R 67 RR R59 R58 RS RS R 72 fly iv Q R 68 R R70 R 69 wherein: Q is N or CR 44 ; 5 Q' is N or CR 4 5 ; Q" is N or CR 47 ; 126 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Q." is N or CR 49 ; Q is N or

CR

50 ;

R

44 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHRb, or WR*, C1-C 6 alkyl, C 6

-C

1 0 aryl, C 6

-C

10 heteroaryl, C 3

-C

8 heterocyclyl, or when taken together with R 45 forms 5 -OCH 2 0-;

R

45 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR, or NRW, C 1

-C

6 alkyl, C 6 -Cio aryl, C 6

-C

1 o heteroaryl, C 3 -Cs heterocyclyl, or when taken together with R 44 or R 46 forms -OCH 2 0-;

R

46 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHIR, or NRbR", C 1-

C

6 10 alkyl, C 6 -CIO aryl, C 6 -C1o heteroaryl, C 3

-C

8 heterocyclyl, or when taken together with R 45 or R7 forms -OCH 2 0-;

R

47 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NIRb, or NReR, C 1

-C

6 alkyl, C 6

-C

10 aryl, C 6 -C1o heteroaryl, C 3

-C

8 heterocyclyl, or when taken together with R 46 or R4I forms -OCH20-; 15 R 8 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR , or N Re, C 1

-C

6 alkyl, C 6 -Cio aryl, C 6

-C

10 heteroaryl, C 3

-C

8 heterocyclyl, or when taken together with R 47 forms -OCH20-;

R

49

R

50 , R 51 , Rs 2 , Rs 3 , Rs 4 , R 7 , R 8 , R 9 , R 60 , R 61

,R

6 2 , R 63 , R 4 , R 5 , R 66 , R 6 7

,R

6 e, R 6 9 , R70, R!', and R72 are each independently selected from hydrogen, halo, hydroxy, nitro, protected 20 hydroxy, NH 2 , NN, or N R, C 1

-C

6 alkyl, C 2

-C

6 alkynyl, C 6

-C

1 O aryl, C 6

-C

1 o heteroaryl, C 3 C 8 heterocyclyl, NC(O)R 17 , or NC(O)R;

R

55 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR, or NRR*, C 1

-C

6 alkyl, C 2

-C

6 alkynyl, C 6 -Cio aryl, C 6

-C

10 heteroaryl, C 3

-C

8 heterocyclyl, NC(O)R' 7 , or NC(O)R, or when taken together with R 56 forms a fused aromatic ring which may be optionally 25 substituted; 127 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01

R

6 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR, or N R , C 1

-C

6 alkyl, C 2

-C

6 alkynyl, C 6

-C

10 aryl, C 6

-C

10 heteroaryl, C 3

-C

8 heterocyclyl, NC(O)R", or NC(O)R*, or when taken together with R 55 forms a fused aromatic ring which may be optionally substituted; 5 R 1 7 is halo, NH 2 , NHRb, or NkbRc; Rb is CI-C 6 alkyl or a nitrogen protecting group; R is C 1

-C

6 alkyl; and R' is alkyl optionally substituted with halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR , or WRW, C 1

-C

6 alkyl, C 2

-C

6 alkynyl, C 6

-C

10 aryl, C 6

-C

1 0 heteroaryl, C 3

-C

8 heterocyclyl, 10 NC(O)R 7 , or NC(O)R". 128 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 Examples of universal bases include: F CH 3

NH

2

NH

2 0 2 N

H

3 C NN NN 02 N0 2 0 0 ~ NNBuHN N N- 0 2 N H H CH O

CH

3 O O CH 3 NH N \ H N N \ H 3 C C - ~~ H 3 C ' H 3

CH

3

H

3 C

CH

3 N C', N N CCH 3 -q O

-

H

3 ,and N

CH

3 5 129 Asymmetrical Modifications An RNA, e.g., an iRNA agent, can be asymmetrically modified as described herein, and as described in International Application Serial No. PCT/USO4/07070, filed March 8, 2004, which is hereby incorporated by reference. 5 In addition, described herein are iRNA agents having asymmetrical modifications and another element described herein. E.g., described herein is an iRNA agent, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an architecture or structure described herein, an iRNA associated with an amphipathic delivery 10 agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates an asymmetrical modification. An asymmetrically modified iRNA agent is one in which a strand has a modification which is not present on the other strand. An asymmetrical modification is a modification found 15 on one strand but not on the other strand. Any modification, e.g., any modification described herein, can be present as an asymmetrical modification. An asymmetrical modification can confer any of the desired properties associated with a modification, e.g., those properties discussed herein. E.g., an asymmetrical modification can: confer resistance to degradation, an alteration in half life; target the iRNA agent to a particular target, e.g., to a particular tissue; 20 modulate, e.g., increase or decrease, the affinity of a strand for its complement or target sequence; or hinder or promote modification of a terminal moiety, e.g., modification by a kinase or other enzymes involved in the RISC mechanism pathway. The designation of a modification as having one property does not mean that it has no other property, e.g., a modification referred to as one which promotes stabilization might also enhance targeting. 25 While not wishing to be bound by theory or any particular mechanistic model, it is believed that asymmetrical modification allows an iRNA agent to be optimized in view of the different or "asymmetrical" functions of the sense and antisense strands. For example, both strands can be modified to increase nuclease resistance, however, since some changes can inhibit RISC activity, these changes can be chosen for the sense stand . In addition, since some 130 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 modifications, e.g., targeting moieties, can add large bulky groups that, e.g., can interfere with the cleavage activity of the RISC complex, such modifications are preferably placed on the sense strand. Thus, targeting moieties, especially bulky ones (e.g. cholesterol), are preferentially added to the sense strand. In one embodiment, an asymmetrical modification in which a phosphate of 5 the backbone is substituted with S, e.g., a phosphorothioate modification, is present in the antisense strand, and a 2' modification, e.g., 2' OMe is present in the sense strand. A targeting moiety can be present at either (or both) the 5' or 3' end of the sense strand of the iRNA agent. In a preferred example, a P of the backbone is replaced with S in the antisense strand, 2'OMe is present in the sense strand, and a targeting moiety is added to either the 5' or 3' end of the sense 10 strand of the iRNA agent. In a preferred embodiment an asynmnetrically modified iRNA agent has a modification on the sense strand which modification is not found on the antisense strand and the antisense strand has a modification which is not found on the sense strand. Each strand can include one or more asymmetrical modifications. By way of example: 15 one strand can include a first asymmetrical modification which confers a first property on the iRNA agent and the other strand can have a second asymmetrical modification which confers a second property on the iRNA. E.g., one strand, e.g., the sense strand can have a modification which targets the iRNA agent to a tissue, and the other strand, e.g., the antisense strand, has a modification which promotes hybridization with the target gene sequence. 20 In some embodiments both strands can be modified to optimize the same property, e.g., to increase resistance to nucleolytic degradation, but different modifications are chosen for the sense and the antisense strands, e.g., because the modifications affect other properties as well. E.g., since some changes can affect RISC activity these modifications are chosen for the sense strand. 25 In an embodiment one strand has an asymmetrical 2' modification, e.g., a 2' OMe modification, and the other strand has an asymmetrical modification of the phosphate backbone, e.g., a phosphorothioate modification. So, in one embodiment the antisense strand has an asymmetrical 2' OMe modification and the sense strand has an asymmetrical phosphorothioate modification (or vice versa). In a particularly preferred embodiment the RNAi agent will have 131 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 asymmetrical 2'-O alkyl, preferably, 2'-OMe modifications on the sense strand and asymmetrical backbone P modification, preferably a phosphothioate modification in the antisense strand. There can be one or multiple 2'-OMe modifications, e.g., at least 2, 3, 4, 5, or 6, of the subunits of the sense strand can be so modified. There can be one or multiple 5 phosphorothioate modifications, e.g., at least 2, 3, 4, 5, or 6, of the subunits of the antisense strand can be so modified. It is preferable to have an iRNA agent wherein there are multiple 2' OMe modifications on the sense strand and multiple phophorothioate modifications on the antisense strand. All of the subunits on one or both strands can be so modified. A particularly preferred embodiment of multiple asymmetric modification on both strands has a duplex region 10 about 20-21, and preferably 19, subunits in length and one or two 3' overhangs of about 2 subunits in length. Asymmetrical modifications are useful for promoting resistance to degradation by nucleases, e.g., endonucleases. iRNA agents can include one or more asymmetrical modifications which promote resistance to degradation. In preferred embodiments the 15 modification on the antisense strand is one which will not interfere with silencing of the target, e.g., one which will not interfere with cleavage of the target. Most if not all sites on a strand are vulnerable, to some degree, to degradation by endonucleases. One can determine sites which are relatively vulnerable and insert asymmetrical modifications which inhibit degradation. It is often desirable to provide asymmetrical modification of a UA site in an iRNA agent, and in some 20 cases it is desirable to provide the UA sequence on both strands with asymmetrical modification. Examples of modifications which inhibit endonucleolytic degradation can be found herein. Particularly favored modifications include: 2' modification, e.g., provision of a 2' OMe moiety on the U, especially on a sense strand; modification of the backbone, e.g., with the replacement of an 0 with an S, in the phosphate backbone, e.g., the provision of a phosphorothioate 25 modification, on the U or the A or both, especially on an antisense strand; replacement of the U with a C5 amino linker; replacement of the A with a G (sequence changes are preferred to be located on the sense strand and not the antisense strand); and modification of the at the 2', 6', 7', or 8' position. Preferred embodiments are those in which one or more of these modifications are present on the sense but not the antisense strand, or embodiments where the antisense strand has 30 fewer of such modifications. 132 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Asymmetrical modification can be used to inhibit degradation by exonucleases. Asymmetrical modifications can include those in which only one strand is modified as well as those in which both are modified. In preferred embodiments the modification on the antisense strand is one which will not interfere with silencing of the target, e.g., one which will not 5 interfere with cleavage of the target. Some embodiments will have an asymmetrical modification on the sense strand, e.g., in a 3' overhang, e.g., at the 3' terminus, and on the antisense strand, e.g., in a 3' overhang, e.g., at the 3' terminus. If the modifications introduce moieties of different size it is preferable that the larger be on the sense strand. If the modifications introduce moieties of different charge it is preferable that the one with greater 10 charge be on the sense strand. Examples of modifications which inhibit exonucleolytic degradation can be found herein. Particularly favored modifications include: 2' modification, e.g., provision of a F' OMe moiety in a 3' overhang, e.g., at the 3' terminus (3' terminus means at the 3' atom of the molecule or at the most 3' moiety, e.g., the most 3' P or 2' position, as indicated by the context); modification 15 of the backbone, e.g., with the replacement of a P with an S, e.g., the provision of a phosphorothioate modification, or the use of a methylated P in a 3' overhang, e.g., at the 3' terminus; combination of a 2' modification, e.g., provision of a 2' 0 Me moiety and modification of the backbone, e.g., with the replacement of a P with an S, e.g., the provision of a phosphorothioate modification, or the use of a methylated P, in a 3' overhang, e.g., at the 3' 20 terminus; modification with a 3' alkyl; modification with an abasic pyrolidine in a 3' overhang, e.g., at the 3' terminus; modification with naproxene, ibuprofen, or other moieties which inhibit degradation at the 3' terminus. Preferred embodiments are those in which one or more of these modifications are present on the sense but not the antisense strand, or embodiments where the antisense strand has fewer of such modifications. 25 Modifications, e.g., those described herein, which affect targeting can be provided as asymmetrical modifications. Targeting modifications which can inhibit silencing, e.g., by inhibiting cleavage of a target, can be provided as asymmetrical modifications of the sense strand. A biodistribution altering moiety, e.g., cholesterol, can be provided in one or more, e.g., two, asymmetrical modifications of the sense strand. Targeting modifications which introduce 30 moieties having a relatively large molecular weight, e.g., a molecular weight of more than 400, 133 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 500, or 1000 daltons, or which introduce a charged moiety (e.g., having more than one positive charge or one negative charge) can be placed on the sense strand. Modifications, e.g., those described herein, which modulate, e.g., increase or decrease, the affinity of a strand for its compliment or target, can be provided as asymmetrical 5 modifications. These include: 5 methyl U; 5 methyl C; pseudouridine, Locked nucleic acids ,2 thio U and 2-amino-A. In some embodiments one or more of these is provided on the antisense strand. iRNA agents have a defined structure, with a sense strand and an antisense strand, and in many cases short single strand overhangs, e.g., of 2 or 3 nucleotides are present at one or both 3' 10 ends. Asymmetrical modification can be used to optimize the activity of such a structure, e.g., by being placed selectively within the iRNA. E.g., the end region of the iRNA agent defined by the 5' end of the sense strand and the 3'end of the antisense strand is important for function. This region can include the terminal 2, 3, or 4 paired nucleotides and any 3' overhang. In preferred embodiments asymmetrical modifications which result in one or more of the following 15 are used: modifications of the 5' end of the sense strand which inhibit kinase activation of the sense strand, including, e.g., attachments of conjugates which target the molecule or the use modifications which protect against 5' exonucleolytic degradation; or modifications of either strand, but preferably the sense strand, which enhance binding between the sense and antisense strand and thereby promote a "tight" structure at this end of the molecule. 20 The end region of the iRNA agent defined by the 3' end of the sense strand and the 5'end of the antisense strand is also important for function. This region can include the terminal 2, 3, or 4 paired nucleotides and any 3' overhang. Preferred embodiments include asymmetrical modifications of either strand, but preferably the sense strand, which decrease binding between the sense and antisense strand and thereby promote an "open" structure at this end of the 25 molecule. Such modifications include placing conjugates which target the molecule or modifications which promote nuclease resistance on the sense strand in this region. Modification of the antisense strand which inhibit kinase activation are avoided in preferred embodiments. 134 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Exemplary modifications for asymmetrical placement in the sense strand include the following: (a) backbone modifications, e.g., modification of a backbone P, including replacement of 5 P with S, or P substituted with alkyl or allyl, e.g., Me, and dithioates (S-P=S); these modifications can be used to promote nuclease resistance; (b) 2'-O alkyl, e.g., 2'-OMe, 3'-O alkyl, e.g., 3'-OMe (at terminal and/or internal positions); these modifications can be used to promote nuclease resistance or to enhance binding of the sense to the antisense strand, the 3' modifications can be used at the 5' end of the sense 10 strand to avoid sense strand activation by RISC; (c) 2'-5' linkages (with 2'-H, 2'-OH and 2'-OMe and with P=O or P=S) these modifications can be used to promote nuclease resistance or to inhibit binding of the sense to the antisense strand, or can be used at the 5' end of the sense strand to avoid sense strand activation by RISC; 15 (d) L sugars (e.g., L ribose, L-arabinose with 2'-H, 2'-OH and 2'-OMe); these modifications can be used to promote nuclease resistance or to inhibit binding of the sense to the antisense strand, or can be used at the 5' end of the sense strand to avoid sense strand activation by RISC; (e) modified sugars (e.g., locked nucleic acids (LNA's), hexose nucleic acids (HNA's) 20 and cyclohexene nucleic acids (CeNA's)); these modifications can be used to promote nuclease resistance or to inhibit binding of the sense to the antisense strand, or can be used at the 5' end of the sense strand to avoid sense strand activation by RISC; (f) nucleobase modifications (e.g., C-5 modified pyrimidines, N-2 modified purines, N-7 modified purines, N-6 modified purines), these modifications can be used to promote nuclease 25 resistance or to enhance binding of the sense to the antisense strand; (g) cationic groups and Zwitterionic groups (preferably at a terminus), these modifications can be used to promote nuclease resistance; 135 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (h) conjugate groups (preferably at terminal positions), e,g., naproxen, biotin, cholesterol, ibuprofen, folic acid, peptides, and carbohydrates; these modifications can be used to promote nuclease resistance or to target the molecule, or can be used at the 5' end of the sense strand to avoid sense strand activation by RISC. 5 Exemplary modifications for asymmetrical placement in the antisense strand include the following: (a) backbone modifications, e.g., modification of a backbone P, including replacement of P with S, or P substituted with alkyl or allyl, e.g., Me, and dithioates (S-P=S); (b) 2'-O alkyl, e.g., 2'-OMe, (at terminal positions); 10 (c) 2'-5' linkages (with 2'-H, 2'-OH and 2'-OMe) e.g., terminal at the 3' end); e.g., with P=O or P=S preferably at the 3'-end, these modifications are preferably excluded from the 5' end region as they may interfere with RISC enzyme activity such as kinase activity; (d) L sugars (e.g, L ribose, L-arabinose with 2'-H, 2'-OH and 2'-OMe); e.g., terminal at the 3' end; e.g., with P=O or P=S preferably at the 3'-end, these modifications are preferably 15 excluded from the 5' end region as they may interfere with kinase activity; (e) modified sugars (e.g., LNA's, HNA's and CeNA's); these modifications are preferably excluded from the 5' end region as they may contribute to unwanted enhancements of paring between the sense and antisense strands, it is often preferred to have a "loose" structure in the 5' region, additionally, they may interfere with kinase activity; 20 (f) nucleobase modifications (e.g., C-5 modified pyrimidines, N-2 modified purines, N-7 modified purines, N-6 modified purines); (g) cationic groups and Zwitterionic groups (preferably at a terminus); cationic groups and Zwitterionic groups at 2'-position of sugar; 3'-position of the sugar; as nucleobase modifications (e.g., C-5 modified pyrimidines, N-2 modified purines, N-7 25 modified purines, N-6 modified purines); 136 conjugate groups (preferably at terminal positions), e,g., naproxen, biotin, cholesterol, ibuprofen, folic acid, peptides, and carbohydrates, but bulky groups or generally groups which inhibit RISC activity should are less preferred. The 5'-OH of the antisense strand should be kept free to promote activity. In some 5 preferred embodiments modifications that promote nuclease resistance should be included at the 3' end, particularly in the 3' overhang. Also described herein is ; a method of optimizing, e.g., stabilizing, an iRNA agent. The method includes selecting a sequence having activity, introducing one or more asymmetric modifications into the sequence, wherein the introduction of the asymmetric 10 modification optimizes a property of the iRNA agent but does not result in a decrease in activity. The decrease in activity can be less than a preselected level of decrease. In preferred embodiments decrease in activity means a decrease of less than 5, 10, 20, 40, or 50 % activity, as compared with an otherwise similar iRNA lacking the introduced modification. Activity can, e.g., be measured in vivo, or in vitro, with a result in either being sufficient to demonstrate the 15 required maintenance of activity. The optimized property can be any property described herein and in particular the properties discussed in the section on asymmetrical modifications provided herein. The modification can be any asymmetrical modification, e.g., an asymmetric modification described in the section on asymmetrical modifications described herein. Particularly preferred 20 asymmetric modifications are 2'-O alkyl modifications, e.g., 2'-OMe modifications, particularly in the sense sequence, and modifications of a backbone 0, particularly phosphorothioate modifications, in the antisense sequence. In a preferred embodiment a sense sequence is selected and provided with an asymmetrical modification, while in other embodiments an antisense sequence is selected and 25 provided with an asymmetrical modification. In some embodiments both sense and antisense sequences are selected and each provided with one or more asymmetrical modifications. 137 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Multiple asymmetric modifications can be introduced into either or both of the sense and antisense sequence. A sequence can have at least 2, 4, 6, 8, or more modifications and all or substantially all of the monomers of a sequence can be modified. Table 3 shows examples having strand I with a selected modification and strand II with a 5 selected modification. Table 3. Exemplary strand I- and strand II-modifications Strand I Strand II Nuclease Resistance (e.g., 2'-OMe) Biodistribution (e.g., P=S) Biodistribution conjugate Protein Binding Functionality (e.g., Lipophile) (e.g., Naproxen) Tissue Distribution Functionality Cell Targeting Functionality (e.g., Carbohydrates) (e.g., Folate for cancer cells) Tissue Distribution Functionality Fusogenic Functionality (e.g., liver Cell Targeting moieties) (e.g., Polyethylene imines) Cancer Cell Targeting Fusogenic Functionality (e.g., RGD peptides and imines) (e.g., peptides) Nuclease Resistance (e.g., 2'-OMe) Increase in binding Affinity (5-Me-C, 5-Me-U, 2 thio-U, 2-amino-A, G-clamp, LNA) Tissue Distribution Functionality RISC activity improving Functionality Helical conformation changing Tissue Distribution Functionality 138 Functionalities (P=S; lipophile, carbohydrates) Z-X-Y Architecture An RNA, e.g., an iRNA agent, can have a Z-X-Y architecture or structure such as those described herein and those described in copending, co-owned United States Provisional Application Serial No. 60/510,246, filed on October 9, 2003, which is hereby incorporated by 5 reference, copending, co-owned United States Provisional Application Serial No. 60/510,318, filed on October 10, 2003, which is hereby incorporated by reference, and copending, co-owned International Application No. PCT/USO4/07070, filed March 8, 2004. In addition, described herein are iRNA agents having a Z-X-Y structure and another element described herein. E.g., described herein is an iRNA agent, e.g., a 10 palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene described herein, e.g., a gene active in the liver, an iRNA associated with an amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates a Z-X-Y architecture. 15. Thus, an iRNA agent can have a first segment, the Z region, a second segment, the X region, and optionally a third region, the Y region: Z-X-Y. It may be desirable to modify subunits in one or both of Zand/or Y on one hand and X on the other hand. In some cases they will have the same modification or the same class of 20 modification but it will more often be the case that the modifications made in Z and/or Y will differ from those made in X. The Z region typically includes a terminus of an iRNA agent. The length of the Z region can vary, but will typi'callybe from 2-14, more preferably 2-10, subunits in length. It typically is single stranded, i.e., it will not base pair with bases of another strand, though it may in some 25 embodiments self associate, e.g., to form a loop structure. Such structures can be formed by the 139 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 end of a strand looping back and forming an intrastrand duplex. E.g., 2, 3, 4, 5 or more intra strand bases pairs can form, having a looped out or connecting region, typically of 2 or more subunits which do not pair. This can occur at one or both ends of a strand. A typical embodiment of a Z region is a single strand overhang, e.g., an over hang of the length described 5 elsewhere herein. The Z region can thus be or include a 3' or 5' terminal single strand. It can be sense or antisense strand but if it is antisense it is preferred that it is a 3- overhang. Typical inter-subunit bonds in the Z region include: P=O; P=S; S-P=S; P-NR 2 ; and P-BR 2 . Chiral P=X, where X is S, N, or B) inter-subunit bonds can also be present. (These inter-subunit bonds are discussed in more detail elsewhere herein.) Other preferred Z region subunit modifications (also 10 discussed elsewhere herein) can include: 3'-OR, 3'SR, 2'-OMe, 3'-OMe, and 2'OH modifications and moieties; alpha configuration bases; and 2' arabino modifications. The X region will in most cases be duplexed, in the case of a single strand iRNA agent, with a corresponding region of the single strand, or in the case of a double stranded iRNA agent, with the corresponding region of the other strand. The length of the X region can vary but will 15 typically be between 10-45 and more preferably between 15 and 35 subunits. Particularly preferred region X's will include 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs, though other suitable lengths are described elsewhere herein and can be used. Typical X region subunits include 2'-OH subunits. In typical embodiments phosphate inter-subunit bonds are preferred while phophorothioate or non-phosphate bonds are absent. Other modifications preferred in the 20 X region include: modifications to improve binding, e.g., nucleobase modifications; cationic nucleobase modifications; and C-5 modified pyrimidines, e.g., allylamines. Some embodiments have 4 or more consecutive 2'OH subunits. While the use of phosphorothioate is sometimes non preferred they can be used if they connect less than 4 consecutive 2'OH subunits. The Y region will generally conform to the the parameters set out for the Z regions. 25 However, the X and Z regions need not be the same, different types and numbers of modifications can be present, and infact, one will usually be a 3' overhang and one will usually be a 5' overhang. In a preferred embodiment the iRNA agent will have a Y and/or Z region each having ribonucleosides in which the 2'-OH is substituted, e.g., with 2'-OMe or other alkyl; and an X 140 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 region that includes at least four consecutive ribonucleoside subunits in which the 2'-OH remains unsubstituted. The subunit linkages (the linkages between subunits) of an iRNA agent can be modified, e.g., to promote resistance to degradation. Numerous examples of such modifications are 5 disclosed herein, one example of which is the phosphorothioate linkage. These modifications can be provided bewteen the subunits of any of the regions, Y, X, and Z. However, it is preferred that their occureceis minimized and in particular it is preferred that consecutive modified linkages be avoided. In a preferred embodiment the iRNA agent will have a Y and Z region each having 10 ribonucleosides in which the 2'-OH is substituted, e.g., with 2'-OMe; and an X region that includes at least four consecutive subunits, e.g., ribonucleoside subunits in which the 2'-OH remains unsubstituted. As mentioned above, the subunit linkages of an iRNA agent can be modified, e.g., to promote resistance to degradation. These modifications can be provided between the subunits of 15 any of the regions, Y, X, and Z. However, it is preferred that they are minimized and in particular it is preferred that consecutive modified linkages be avoided. Thus, in a preferred embodiment, not all of the subunit linkages of the iRNA agent are modified and more preferably the maximum number of consecutive subunits linked by other than a phospodiester bond will be 2, 3, or 4. Particulary preferred iRNA agents will not have four or 20 more consecutive subunits, e.g., 2'-hydroxyl ribonucleoside subunits, in which each subunits is joined by modified linkages - i.e. linkages that have been modified to stabilize them from degradation as compared to the phosphodiester linkages that naturally occur in RNA and DNA. It is particularly preferred to minimize the occurrence in region X. Thus, in preferred embodiments each of the nucleoside subunit linkages in X will be phosphodiester linkages, or if 25 subunit linkages in region X are modified, such modifications will be minimized. E.g., although the Y and/or Z regions can include inter subunit linkages which have been stabilized against degradation, such modifications will be minimized in the X region, and in particular consecutive modifications will be minimized. Thus, in preferred embodiments the maximum number of 141 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 consecutive subunits linked by other than a phospodiester bond will be 2, 3, or 4. Particulary preferred X regions will not have four or more consecutive subunits, e.g., 2'-hydroxyl ribonucleoside subunits, in which each subunits is joined by modified linkages - i.e. linkages that have been modified to stabilize them from degradation as compared to the phosphodiester 5 linkages that naturally occur in RNA and DNA. In a preferred embodiment Y and /or Z will be free of phosphorothioate linkages, though either or both may contain other modifications, e.g., other modifications of the subunit linkages. In a preferred embodiment region X, or in some cases, the entire iRNA agent, has no more than 3 or no more than 4 subunits having identical 2' moieties. 10 In a preferred embodiment region X, or in some cases, the entire iRNA agent, has no more than 3 or no more than 4 subunits having identical subunit linkages. In a preferred embodiment one or more phosphorothioate linkages (or other modifications of the subunit linkage) are present in Y and/or Z, but such modified linkages do not connect two adjacent subunits, e.g., nucleosides, having a 2' modification, e.g., a 2'-O-alkyl 15 moiety. E.g., any adjacent 2'-O-alkyl moieties in the Y and/or Z, are connected by a linkage other than a a phosphorothioate linkage. In a preferred embodiment each of Y and/or Z independently has only one phosphorothioate linkage between adjacent subunits, e.g., nucleosides, having a 2' modification, e.g., 2'-O-alkyl nucleosides. If there is a second set of adjacent subunits, e.g., nucleosides, 20 having a 2' modification, e.g., 2'-O-alkyl nucleosides, in Y and/or Z that second set is connected by a linkage other than a phosphorothioate linkage, e.g., a modified linkage other than a phosphorothioate linkage. In a prefered embodiment each of Y and/orZ independently has more than one phosphorothioate linkage connecting adjacent pairs of subunits, e.g., nucleosides, having a 2' 25 modification, e.g., 2'-O-alkyl nucleosides, but at least one pair of adjacent subunits, e.g., nucleosides, having a 2' modification, e.g., 2'-O-alkyl nucleosides, are be connected by a linkage other than a phosphorothioate linkage, e.g., a modified linkage other than a phosphorothioate linkage. 142 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In a prefered embodiment one of the above recited limitation on adjacent subunits in Y and or Z is combined with a limitation on the subunits in X. E.g., one or more phosphorothioate linkages (or other modifications of the subunit linkage) are present in Y and/or Z, but such modified linkages do not connect two adjacent subunits, e.g., nucleosides, having a 2' 5 modification, e.g., a 2'-0-alkyl moiety. E.g., any adjacent 2'-O-alkyl moieties in the Y and/or Z, are connected by a linkage other than a a phosporothioate linkage. In addition, the X region has no more than 3 or no more than 4 identical subunits, e.g., subunits having identical 2' moieties or the X region has no more than 3 or no more than 4 subunits having identical subunit linkages. A Y and/or Z region can include at least one, and preferably 2, 3 or 4 of a modification 10 disclosed herein. Such modifications can be chosen, independently, from any modification described herein, e.g., from nuclease resistant subunits, subunits with modified bases, subunits with modified intersubunit linkages, subunits with modified sugars, and subunits linked to another moiety, e.g., a targeting moiety. In a preferred embodiment more than 1 of such subunits can be present but in some emobodiments it is prefered that no more than 1, 2, 3, or 4 of such 15 modifications occur, or occur consecutively. In a preferred embodiment the frequency of the modification will differ between Yand /or Z and X, e.g., the modification will be present one of Y and/or Z or X and absent in the other. An X region can include at least one, and preferably 2, 3 or 4 of a modification disclosed herein. Such modifications can be chosen, independently, from any modification described 20 herein, e.g., from nuclease resistant subunits, subunits with modified bases, subunits with modified intersubunit linkages, subunits with modified sugars, and subunits linked to another moiety, e.g., a targeting moiety. In a preferred embodiment more than 1 of such subunits can b present but in some emobodiments it is prefered that no more than 1, 2, 3, or 4 of such modifications occur, or occur consecutively. 25 An RRMS (described elswhere herein) can be introduced at one or more points in one or both strands of a double-stranded iRNA agent. An RRMS can be placed in a Y and/or Z region, at or near (within 1, 2, or 3 positions) of the 3' or 5' end of the sense strand or at near (within 2 or 3 positions of) the 3' end of the antisense strand. In some embodiments it is preferred to not have an RRMS at or near (within 1, 2, or 3 positions of) the 5' end of the antisense strand. An 143 RRMS can be positioned in the X region, and will preferably be positioned in the sense strand or in an area of the antisense strand not critical for antisense binding to the target. Differential Modification of Terminal Duplex Stability Described herein is an iRNA agent which can have differential 5 modification of terminal duplex stability (DMTDS). In addition, described herein are iRNA agents having DMTDS and another element described herein. E.g., including an iRNA agent described herein, e.g., a palindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene described herein, e.g., a gene active in the liver, an iRNA agent having an 10 architecture or structure described herein, an iRNA associated with an amphipathic delivery agent described herein, an iRNA associated with a drug delivery module described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, which also incorporates DMTDS. iRNA agents can be optimized by increasing the propensity of the duplex to disassociate 15 or melt (decreasing the free energy of duplex association), in the region of the 5' end of the antisense strand duplex. This can be accomplished, e.g., by the inclusion of subunits which increase the propensity of the duplex to disassociate or melt in the region of the 5' end of the antisense strand. It can also be accomplished by the attachment of a ligand that increases the propensity of the duplex to disassociate of melt in the region of the 5'end. While not wishing to 20 be bound by theory, the effect may be due to promoting the effect of an enzyme such as helicase, for example, promoting the effect of the enzyme in the proximity of the 5' end of the antisense strand. The inventors have also discovered that iRNA agents can be optimized by decreasing the propensity of the duplex to disassociate or melt (increasing the free energy of duplex 25 association), in the region of the 3' end of the antisense strand duplex. This can be accomplished, e.g., by the inclusion of subunits which decrease the propensity of the duplex to disassociate or melt in the region of the 3' end of the antisense strand. It can also be 144 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 accomplished by the attachment of ligand that decreases the propensity of the duplex to disassociate of melt in the region of the 5'end. Modifications which increase the tendency of the 5' end of the duplex to dissociate can be used alone or in combination with other modifications described herein, e.g., with 5 modifications which decrease the tendency of the 3' end of the duplex to dissociate. Likewise, modifications which decrease the tendency of the 3' end of the duplex to dissociate can be used alone or in combination with other modifications described herein, e.g., with modifications which increase the tendency of the 5' end of the duplex to dissociate. Decreasing the stability of the AS 5' end of the duplex 10 Subunit pairs can be ranked on the basis of their propensity to promote dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, though next neighbor or similar analysis can also be used). In terms of promoting dissociation: A:U is preferred over G:C; 15 G:U is preferred over G:C; I:C is preferred over G:C (I=inosine); mismatches, e.g., non-canonical or other than canonical pairings (as described elsewhere herein) are preferred over canonical (A:T, A:U, G:C) pairings; pairings which include a universal base are preferred over canonical pairings. 20 A typical ds iRNA agent can be diagrammed as follows: S 5' R 1

N

1

N

2

N

3

N

4

N

5 [N] N..

5 N4 N.

3

N.

2

N.

1

R

2 3' AS 3' R 3

N

1

N

2

N

3

N

4

N

5 [N] N..

5

N.

4

N-

3

N.

2

N.

1

R

4 5' S:AS P 1

P

2

P

3

P

4 PS [N] P.

5

P.

4

P..

3

P-

2

P..

1 5' 145 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 S indicates the sense strand; AS indicates antisense strand; R 1 indicates an optional (and nonpreferred) 5' sense strand overhang; R 2 indicates an optional (though preferred) 3' sense overhang; R 3 indicates an optional (though preferred) 3' antisense sense overhang; R 4 indicates an optional (and nonpreferred) 5' antisense overhang; N indicates subunits; [N] indicates that 5 additional subunit pairs may be present; and P,, indicates a paring of sense Nx and antisense Nx. Overhangs are not shown in the P diagram. In some embodiments a 3' AS overhang corresponds to region Z, the duplex region corresponds to region X, and the 3' S strand overhang corresponds to region Y, as described elsewhere herein. (The diagram is not meant to imply maximum or minimum lengths, on which guidance is provided elsewhere herein.) 10 It is preferred that pairings which decrease the propensity to form a duplex are used at 1 or more of the positions in the duplex at the 5' end of the AS strand. The terminal pair (the most 5' pair in terms of the AS strand) is designated as P.

1 , and the subsequent pairing positions (going in the 3' direction in terms of the AS strand) in the duplex are designated, P..

2 , P- 3 , P-4, P- 5 , and so on. The preferred region in which to modify to modulate duplex formation is at P-5 15 through P..

1 , more preferably P- 4 through P.1 , more preferably P- 3 through P- 1 . Modification at P. 1, is particularly preferred, alone or with modification(s) other position(s), e.g., any of the positions just identified. It is preferred that at least 1, and more preferably 2, 3, 4, or 5 of the pairs of one of the recited regions be chosen independently from the group of: A:U 20 G:U I:C mismatched pairs, e.g., non-canonical or other than canonical pairings or pairings which include a universal base. In preferred embodiments the change in subunit needed to achieve a pairing which 25 promotes dissociation will be made in the sense strand, though in some embodiments the change will be made in the antisense strand. 146 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 In a preferred embodiment the at least 2, or 3, of the pairs in P.

1 , through P.

4 , are pairs which promote disociation. In a preferred embodiment the at least 2, or 3, of the pairs in P..

1 , through P.

4 , are A:U. In a preferred embodiment the at least 2, or 3, of the pairs in P.

1 , through P.

4 , are G:U. 5 In a preferred embodiment the at least 2, or 3, of the pairs in P.

1 , through P.

4 , are I:C. In a preferred embodiment the at least 2, or 3, of the pairs in P.

1 , through P.

4 , are mismatched pairs, e.g., non-canonical or other than canonical pairings pairings. In a preferred embodiment the at least 2, or 3, of the pairs in P..

1 , through P.

4 , are pairings which include a universal base. 10 Increasing the stability of the AS 3' end of the duplex Subunit pairs can be ranked on the basis of their propensity to promote stability and inhibit dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, though next neighbor or similar analysis can also be used). In terms of promoting duplex 15 stability: G:C is preferred over A:U Watson-Crick matches (A:T, A:U, G:C) are preferred over non-canonical or other than canonical pairings analogs that increase stability are preferred over Watson-Crick matches (A:T, A:U, 20 G:C) 2-amino-A:U is preferred over A:U 2-thio U or 5 Me-thio-U:A are preferred over U:A G-clamp (an analog of C having 4 hydrogen bonds):G is preferred over C:G 147 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 guanadinium-G-clamp:G is preferred over C:G psuedo uridine:A is preferred over U:A sugar modifications, e.g., 2' modifications, e.g., 2'F, ENA, or LNA, which enhance binding are preferred over non-modified moieties and can be present on one or both strands to 5 enhance stability of the duplex. It is preferred that pairings which increase the propensity to form a duplex are used at 1 or more of the positions in the duplex at the 3' end of the AS strand. The terminal pair (the most 3' pair in terms of the AS strand) is designated as P 1 , and the subsequent pairing positions (going in the 5' direction in terms of the AS strand) in the duplex are designated, P 2 , P 3 , P 4 , P 5 , and so on. The preferred region in which to modify to modulate .10 duplex formation is at P 5 through P 1 , more preferably P 4 through Pi , more preferably P 3 through

P

1 . Modification at P 1 , is particularly preferred, alone or with mdification(s) at other position(s), e.g.,any of the positions just identified. It is preferred that at least 1, and more preferably 2, 3, 4, or 5 of the pairs of the recited regions be chosen independently from the group of: 15 G:C a pair having an analog that increases stability over Watson-Crick matches (A:T, A:U, G:C) 2-amino-A:U 2-thio U or 5 Me-thio-U:A 20 G-clamp (an analog of C having 4 hydrogen bonds):G guanadinium-G-clamp:G psuedo uridine:A a pair in which one or both subunits has a sugar modification, e.g., a 2' modification, e.g., 2'F, ENA, or LNA, which enhance binding. 148 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 In a preferred embodiment the at least 2, or 3, of the pairs in P..

1 , through P- 4 , are pairs which promote duplex stability. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are G:C. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are a pair 5 having an analog that increases stability over Watson-Crick matches. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are 2-amino A:U. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are 2-thio U or 5 Me-thio-U:A. 10 In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are G clamp:G. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P4, are guanidinium-G-clamp:G. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are psuedo 15 uridine:A. In a preferred embodiment the at least 2, or 3, of the pairs in P 1 , through P 4 , are a pair in which one or both subunits has a sugar modification, e.g., a 2' modification, e.g., 2'F, ENA, or LNA, which enhances binding. G-clamps and guanidinium G-clamps are discussed in the following references: Holmes 20 and Gait, "The Synthesis of 2'-O-Methyl G-Clamp Containing Oligonucleotides and Their Inhibition of the HIV-1 Tat-TAR Interaction," Nucleosides, Nucleotides & Nucleic Acids, 22:1259-1262, 2003; Holmes et al., "Steric inhibition of human immunodeficiency virus type-1 Tat-dependent trans-activation in vitro and in cells by oligonucleotides containing 2'-O-methyl G-clamp ribonucleoside analogues," Nucleic Acids Research, 31:2759-2768, 2003; Wilds, et al., 25 "Structural basis for recognition of guanosine by a synthetic tricyclic cytosine analogue: Guanidinium G-clamp," Helvetica Chimica Acta, 86:966-978, 2003; Rajeev, et al., "High 149 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W01 Affinity Peptide Nucleic Acid Oligomers Containing Tricyclic Cytosine Analogues," Organic Letters, 4:4395-4398, 2002; Ausin, et al., "Synthesis of Amino- and Guanidino-G-Clamp PNA Monomers," Organic Letters, 4:4073-4075, 2002; Maier et al., "Nuclease resistance of oligonucleotides containing the tricyclic cytosine analogues phenoxazine and 9-(2 5 aminoethoxy)-phenoxazine ("G-clamp") and origins of their nuclease resistance properties," Biochemistry, 41:1323-7, 2002; Flanagan, et al., "A cytosine analog that confers enhanced potency to antisense oligonucleotides," Proceedings Of The National Academy Of Sciences Of The United States Of America, 96:3513-8, 1999. 150 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Simultaneously decreasing the stability of the AS 5'end of the duplex and increasing the stability of the AS 3' end of the duplex As is discussed above, an iRNA agent can be modified to both decrease the stability of the AS 5'end of the duplex and increase the stability of the AS 3' end of the duplex. This can be 5 effected by combining one or more of the stability decreasing modifications in the AS 5' end of the duplex with one or more of the stability increasing modifications in the AS 3' end of the duplex. Accordingly a preferred embodiment includes modification in P..

5 through P.

1 , more preferably P-4 through P..

1 and more preferably P- 3 through P- 1 . Modification at P- 1 , is particularly preferred, alone or with other position, e.g., the positions just identified. It is preferred that at 10 least 1, and more preferably 2, 3, 4, or 5 of the pairs of one of the recited regions of the AS 5' end of the duplex region be chosen independently from the group of: A:U G:U I:C 15 mismatched pairs, e.g., non-canonical or other than canonical pairings which include a universal base; and a modification in P 5 through P1, more preferably P 4 through P 1 and more preferably P 3 through P 1 . Modification at P 1 , is particularly preferred, alone or with other position, e.g., the positions just identified. It is preferred that at least 1, and more preferably 2, 3, 4, or 5 of the 20 pairs of one of the recited regions of the AS 3' end of the duplex region be chosen independently from the group of: G:C a pair having an analog that increases stability over Watson-Crick matches (A:T, A:U, G:C) 25 2-amino-A:U 151 2-thio U or 5 Me-thio-U:A G-clamp (an analog of C having 4 hydrogen bonds):G guanadinium-G-clamp:G psuedo uridine:A 5 a pair in which one or both subunits has a sugar modification, e.g., a 2' modification, e.g., 2'F, ENA, or LNA. which enhance binding. Described herein are methods of selecting and making iRNA agents having DMTDS. E.g., when screening a target sequence for candidate sequences for use as iRNA agents one can select sequences having a DMTDS property described herein or one which can be 10 modified, preferably with as few changes as possible, especially to the AS strand, to provide a desired level of DMTDS. The disclosure includes, providing a candidate iRNA agent sequence, and modifying at least one P in P-5 through P., and/or at least one P in P 5 through P 1 to provide a DMTDS iRNA agent. 15 DMTDS iRNA agents can be used in any method described herein, e.g., to silence any gene disclosed herein, to treat any disorder described herein, in any formulation described herein, and generally in and/or with the methods and compositions described elsewhere herein. DMTDS iRNA agents can incorporate other modifications described herein, e.g., the attachment of targeting agents or the inclusion of modifications which enhance stability, e.g., the inclusion of 20 nuclease resistant monomers or the inclusion of single strand overhangs (e.g., 3' AS overhangs and/or 3' S strand overhangs) which self associate to form intrastrand duplex structure. Preferably these iRNA agents will have an architecture described herein. Other Embodiments An RNA, e.g., an iRNA agent, can be produced in a cell in vivo, e.g., from exogenous 25 DNA templates that are delivered into the cell. For example, the DNA templates can be inserted 152 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470), or by stereotactic injection (see, e.g., Chen et al., Proc. Natl. A cad. Sci. USA 91:3054-3057, 1994). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in 5 an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. The DNA templates, for example, can include two transcription units, one that produces a transcript that includes the top strand of an iRNA agent and one that produces a transcript that includes the bottom strand of an iRNA agent. When the templates are transcribed, the iRNA agent is produced, and processed into sRNA agent fragments that mediate gene 10 silencing. In vivo Delivery An iRNA agent can be linked, e.g., noncovalently linked to a polymer for the efficient delivery of the iRNA agent to a subject, e.g., a mammal, such as a human. The iRNA agent can, for example, be complexed with cyclodextrin. Cyclodextrins have been used as delivery 15 vehicles of therapeutic compounds. Cyclodextrins can form inclusion complexes with drugs that are able to fit into the hydrophobic cavity of the cyclodextrin. In other examples, cyclodextrins form non-covalent associations with other biologically active molecules such as oligonucleotides and derivatives thereof. The use of cyclodextrins creates a water-soluble drug delivery complex, that can be modified with targeting or other functional groups. Cyclodextrin cellular delivery 20 system for oligonucleotides described in U.S. Pat. No. 5,691,316, which is hereby incorporated by reference, are suitable for use in methods of the invention. In this system, an oligonucleotide is noncovalently complexed with a cyclodextrin, or the oligonucleotide is covalently bound to adamantine which in turn is non-covalently associated with a cyclodextrin. The delivery molecule can include a linear cyclodextrin copolymer or a linear oxidized 25 cyclodextrin copolymer having at least one ligand bound to the cyclodextrin copolymer. Delivery systems , as described in U.S. Patent No. 6,509,323, herein incorporated by reference, are suitable for use in methods of the invention. An iRNA agent can be bound to the linear cyclodextrin copolymer and/or a linear oxidized cyclodextrin copolymer. Either or both of the 153 cyclodextrin or oxidized cyclodextrin copolymers can be crosslinked to another polymer and/or bound to a ligand. A composition for iRNA delivery can employ an "inclusion complex," a molecular compound having the characteristic structure of an adduct. In this structure, the "host 5 molecule" spatially encloses at least part of another compound in the delivery vehicle. The enclosed compound (the "guest molecule") is situated in the cavity of the host molecule without affecting the framework structure of the host. A "host" is preferably cyclodextrin, but can be any of the molecules suggested in U.S. Patent Publ. 2003/0008818, herein incorporated by reference. Cyclodextrins can interact with a variety of ionic and molecular species, and the resulting 10 inclusion compounds belong to the class of "host-guest" complexes. Within the host-guest relationship, the binding sites of the host and guest molecules should be complementary in the stereoelectronic sense. A composition described herein can contain at least one polymer and at least one therapeutic agent, generally in the form of a particulate composite of the polymer and therapeutic agent, e.g., the iRNA agent. The iRNA agent can contain one or more complexing 15 agents. At least one polymer of the particulate composite can interact with the complexing agent in a host-guest or a guest-host interaction to form an inclusion complex between the polymer and the complexing agent. The polymer and, more particularly, the complexing agent can be used to introduce functionality into the composition. For example, at least one polymer of the particulate composite has host functionality and forms an inclusion complex with a complexing agent 20 having guest functionality. Alternatively, at least one polymer of the particulate composite has guest functionality and forms an inclusion complex with a complexing agent having host functionality. A polymer of the particulate composite can also contain both host and guest functionalities and form inclusion complexes with guest complexing agents and host complexing agents. A polymer with functionality can, for example, facilitate cell targeting and/or cell 25 contact (e.g., targeting or contact to a liver cell), intercellular trafficking, and/or cell entry and release. Upon forming the particulate composite, the iRNA agent may or may not retain its biological or therapeutic activity. Upon release from the therapeutic composition, specifically, from the polymer of the particulate composite, the activity of the iRNA agent is restored. 154 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Accordingly, the particulate composite advantageously affords the iRNA agent protection against loss of activity due to, for example, degradation and offers enhanced bioavailability. Thus, a composition may be used to provide stability, particularly storage or solution stability, to an iRNA agent or any active chemical compound. The iRNA agent may be further modified 5 with a ligand prior to or after particulate composite or therapeutic composition formation. The ligand can provide further functionality. For example, the ligand can be a targeting moiety. Physiological Effects The iRNA agents described herein can be designed such that determining therapeutic toxicity is made easier by the complementarity of the iRNA agent with both a human and a non 10 human animal sequence. By these methods, an iRNA agent can consist of a sequence that is fully complementary to a nucleic acid sequence from a human and a nucleic acid sequence from at least one non-human animal, e.g., a non-human mammal, such as a rodent, ruminant or primate. For example, the non-human mammal can be a mouse, rat, dog, pig, goat, sheep, cow, monkey, Pan paniscus, Pan troglodytes, Macaca mulatto, or Cynomolgus monkey. The sequence 15 of the iRNA agent could be complementary to sequences within homologous genes, e.g., oncogenes or tumor suppressor genes, of the non-human mammal and the human. By determining the toxicity of the iRNA agent in the non-human mammal, one can extrapolate the toxicity of the iRNA agent in a human. For a more strenuous toxicity test, the iRNA agent can be complementary to a human and more than one, e.g., two or three or more, non-human 20 animals. The methods described herein can be used to correlate any physiological effect of an iRNA agent on a human, e.g., any unwanted effect, such as a toxic effect, or any positive, or desired effect. Delivery Module 25 An RNA, e.g., an iRNA agent described herein, can be used with a drug delivery conjugate or module, such as those described herein and those described in copending, co-owned United States Provisional Application Serial No. 60/454,265, filed on March 12, 2003, and 155 International Application Serial No. PCT/USO4/07070, filed March 8, 2004, both of which are hereby incorporated by reference. In addition, described herein are iRNA agents, e.g., apalindromic iRNA agent, an iRNA agent having a non canonical pairing, an iRNA agent which targets a gene 5 described herein, e.g., a gene active in the liver, an iRNA agent having a chemical modification described herein, e.g., a modification which enhances resistance to degradation, an iRNA agent having an architecture or structure described herein, an iRNA agent administered as described herein, or an iRNA agent formulated as described herein, combined with, associated with, and delivered by such a drug delivery conjugate or module. 10 The iRNA agents can be complexed to a delivery agent that features a modular complex. The complex can include a carrier agent linked to one or more of (preferably two or more, more preferably all three of): (a) a condensing agent (e.g., an agent capable of attracting, e.g., binding, a nucleic acid, e.g., through ionic or electrostatic interactions); (b) a fusogenic agent (e.g., an agent capable of fusing and/or being transported through a cell membrane, e.g., an endosome 15 membrane); and (c) a targeting group, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a liver cell. An iRNA agent, e.g., iRNA agent or sRNA agent described herein, can be linked, e.g., coupled or bound, to the modular complex. The iRNA agent can interact with the condensing 20 agent of the complex, and the complex can be used to deliver an iRNA agent to a cell, e.g., in vitro or in vivo. For example, the complex can be used to deliver an iRNA agent to a subject in need thereof, e.g., to deliver an iRNA agent to a subject having a disorder, e.g., a disorder described herein, such as a disease or disorder of the liver. The fusogenic agent and the condensing agent can be different agents or the one and the 25 same agent. For example, a polyamino chain, e.g., polyethyleneimine (PEI), can be the fusogenic and/or the condensing agent. The delivery agent can be a modular complex. For example, the complex can include a carrier agent linked to one or more of (preferably two or more, more preferably all three of): 156 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 (a) a condensing agent (e.g., an agent capable of attracting, e.g., binding, a nucleic acid, e.g., through ionic interaction), (b) a fusogenic agent (e.g., an agent capable of fusing and/or being transported through a cell membrane, e.g., an endosome membrane), and 5 (c) a targeting group, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a liver cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, 10 multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, Neproxin, or an RGD peptide or RGD peptide mimetic. Carrier agents The carrier agent of a modular complex described herein can be a substrate for 15 attachment of one or more of: a condensing agent, a fusogenic agent, and a targeting group. The carrier agent would preferably lack an endogenous enzymatic activity. The agent would preferably be a biological molecule, preferably a macromolecule. Polymeric biological carriers are preferred. It would also be preferred that the carrier molecule be biodegradable.. The carrier agent can be a naturally occurring substance, such as a protein (e.g., human 20 serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid); or lipid. The carrier molecule can also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L 25 lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2 hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Other useful carrier molecules can be identified by routine methods. 157 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 A carrier agent can be characterized by one or more of: (a) is at least 1 Da in size; (b) has at least 5 charged groups, preferably between 5 and 5000 charged groups; (c) is present in the complex at a ratio of at least 1:1 carrier agent to fusogenic agent; (d) is present in the complex at a ratio of at least 1:1 carrier agent to condensing agent; (e) is present in the complex at a ratio of 5 at least 1:1 carrier agent to targeting agent. Fusogenic agents A fusogenic agent of a modular complex described herein can be an agent that is responsive to, e.g., changes charge depending on, the pH environment. Upon encountering the pH of an endosome, it can cause a physical change, e.g., a change in osmotic properties which 10 disrupts or increases the permeability of the endosome membrane. Preferably, the fusogenic agent changes charge, e.g., becomes protonated, at pH lower than physiological range. For example, the fusogenic agent can become protonated at pH 4.5-6.5. The fusogenic agent can serve to release the iRNA agent into the cytoplasm of a cell after the complex is taken up, e.g., via endocytosis, by the cell, thereby increasing the cellular concentration of the iRNA agent in 15 the cell. In one embodiment, the fusogenic agent can have a moiety, e.g., an amino group, which, when exposed to a specified pH range, will undergo a change, e.g., in charge, e.g., protonation. The change in charge of the fusogenic agent can trigger a change, e.g., an osmotic change, in a vesicle, e.g., an endocytic vesicle, e.g., an endosome. For example, the fusogenic agent, upon 20 being exposed to the pH environment of an endosome, will cause a solubility or osmotic change substantial enough to increase the porosity of (preferably, to rupture) the endosomal membrane. The fusogenic agent can be a polymer, preferably a polyamino chain, e.g., polyethyleneimine (PEI). The PEI can be linear, branched, synthetic or natural. The PEI can be, e.g., alkyl substituted PEI, or lipid substituted PEI. 25 In other embodiments, the fusogenic agent can be polyhistidine, polyimidazole, polypyridine, polypropyleneimine, mellitin, or a polyacetal substance, e.g., a cationic polyacetal. In some embodiment, the fusogenic agent can have an alpha helical structure. The fusogenic agent can be a membrane disruptive agent, e.g., mellittin. 158 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 A fusogenic agent can have one or more of the following characteristics: (a) is at least IDa in size; (b) has at least 10 charged groups, preferably between 10 and 5000 charged groups, more preferably between 50 and 1000 charged groups; (c) is present in the complex at a ratio of at least 1:1 fusogenic agent to carrier agent; (d) is present in the complex at a ratio of at least 1:1 5 fusogenic agent to condensing agent; (e) is present in the complex at a ratio of at least 1:1 fusogenic agent to targeting agent. Other suitable fusogenic agents can be tested and identified by a skilled artisan. The ability of a compound to respond to, e.g., change charge depending on, the pH environment can be tested by routine methods, e.g., in a cellular assay. For example, a test compound is 10 combined or contacted with a cell, and the cell is allowed to take up the test compound, e.g., by endocytosis. An endosome preparation can then be made from the contacted cells and the endosome preparation compared to an endosome preparation from control cells. A change, e.g., a decrease, in the endosome fraction from the contacted cell vs. the control cell indicates that the test compound can function as a fusogenic agent. Alternatively, the contacted cell and control 15 cell can be evaluated, e.g., by microscopy, e.g., by light or electron microscopy, to determine a difference in endosome population in the cells. The test compound can be labeled. In another type of assay, a modular complex described herein is constructed using one or more testcor putative fusogenic agents. The modular complex can be constructed using a labeled nucleic acid instead of the iRNA. The ability of the fusogenic agent to respond to, e.g., change charge 20 depending on, the pH environment, once the modular complex is taken up by the cell, can be evaluated, e.g., by preparation of an endosome preparation, or by microscopy techniques, as described above. A two-step assay can also be performed, wherein a first assay evaluates the ability of a test compound alone to respond to, e.g., change charge depending on, the pH environment; and a second assay evaluates the ability of a modular complex that includes the test 25 compound to respond to, e.g., change charge depending on, the pH environment. Condensing agent The condensing agent of a modular complex described herein can interact with (e.g., attracts, holds, or binds to) an iRNA agent and act to (a) condense, e.g., reduce the size or charge of the iRNA agent and/or (b) protect the iRNA agent, e.g., protect the iRNA agent against 159 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072WO1 degradation. The condensing agent can include a moiety, e.g., a charged moiety, that can interact with a nucleic acid, e.g., an iRNA agent, e.g., by ionic interactions. The condensing agent would preferably be a charged polymer, e.g., a polycationic chain. The condensing agent can be a polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, 5 peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quarternary salt of a polyamine, or an alpha helical peptide. A condensing agent can have the following characteristics: (a) at least 1Da in size; (b) has at least 2 charged groups, preferably between 2 and 100 charged groups; (c) is present in the complex at a ratio of at least 1:1 condensing agent to carrier agent; (d) is present in the complex 10 at a ratio of at least 1:1 condensing agent to fusogenic agent; (e) is present in the complex at a ratio of at least 1:1 condensing agent to targeting agent. Other suitable condensing agents can be tested and identified by a skilled artisan, e.g., by evaluating the ability of a test agent to interact with a nucleic acid, e.g., an iRNA agent. The ability of a test agent to interact with a nucleic acid, e.g., an iRNA agent, e.g., to condense or 15 protect the iRNA agent, can be evaluated by routine techniques. In one assay, a test agent is contacted with a nucleic acid, and the size and/or charge of the contacted nucleic acid is evaluated by a technique suitable to detect changes in molecular mass and/or charge. Such techniques include non-denaturing gel electrophoresis, immunological methods, e.g., immunoprecipitation, gel filtration, ionic interaction chromatography, and the like. A test agent 20 is identified as a condensing agent if it changes the mass and/or charge (preferably both) of the contacted nucleic acid, compared to a control. A two-step assay can also be performed, wherein a first assay evaluates the ability of a test compound alone to interact with, e.g., bind to, e.g., condense the charge and/or mass of, a nucleic cid; and a second assay evaluates the ability of a modular complex that includes the test compound to interact with, e.g., bind to, e.g., condense 25 the charge and/or mass of, a nucleic acid. Amphipathic Delivery Agents An RNA, e.g., an iRNA agent, described herein can be used with an amphipathic delivery conjugate or module, such as those described herein and those described in copending, co-owned United States Provisional Application Serial No. 60/455,050, filed on March 13, 2003, and 160 International Application Serial No. PCT/US04/07070, filed March 8, 2004, which is hereby incorporated by reference. In addition, described herein is an iRNA agent, e.g., a palindromic iRNA agent, an iRNA agent having a noncanonical pairing, an iRNA agent which targets a gene 5 described herein, e.g., a gene active in the liver, an iRNA agent having a chemical modification described herein, e.g., a modification which enhances resistance to degradation, an iRNA agent having an architecture or structure described herein, an iRNA agent administered as described herein,,or an iRNA agent formulated as described herein, combined with, associated with, and delivered by such an amphipathic delivery conjugate. 10 An amphipathic molecule is a molecule having a hydrophobic and a hydrophilic region. Such molecules can interact with (e.g., penetrate or disrupt) lipids, e.g., a lipid bylayer of a cell. As such, they can serve as delivery agent for an associated (e.g., bound) iRNA (e.g., an iRNA or sRNA described herein). A preferred amphipathic molecule to be used in the compositions described herein (e.g., the amphipathic iRNA constructs descriebd herein) is a polymer. The 15 polymer may have a secondary structure, e.g., a repeating secondary structure. One example of an amphipathic polymer is an amphipathic polypeptide, e.g., a polypeptide having a secondary structure such that the polypeptide has a hydrophilic and a hybrophobic face. The design of amphipathic peptide structures (e.g., alpha-helical polypeptides) is routine to one of skill in the art. For example, the following references provide guidance: 20 Grell et al. (2001) "Protein design and folding: template trapping of self-assembled helical bundles" J Pept Sci 7(3):146-51; Chen et al. (2002) "Determination of stereochemistry stability coefficients of amino acid side-chains in an amphipathic alpha-helix" J Pept Res 59(l):18-33; Iwata et al. (1994) "Design and synthesis of amphipathic 3(10)-helical peptides and their interactions with phospholipid bilayers and ion channel formation" J Biol Chem 269(7):4928-33; 25 Cornut et al. (1994) "The amphipathic alpha-helix concept. Application to the de novo design of ideally amphipathic Leu, Lys peptides with hemolytic activity higher than that of melittin" FEBS Lett 349(1):29-33; Negrete et al. (1998) "Deciphering the structural code for proteins: helical propensities in domain classes and statistical multiresidue information in alpha-helices," Protein Sci 7(6):1368-79. 161 Another example of an amphipathic polymer is a polymer made up of two or more amphipathic subunits, e.g., two or more subunits containing cyclic moieties (e.g., a cyclic moiety having one or more hydrophilic groups and one or more hydrophobic groups). For example, the subunit may contain a steroid, e.g., cholic acid; or a aromatic moiety. Such moieties preferably 5 can exhibit atropisomerism, such that they can form opposing hydrophobic and hydrophilic faces when in a polymer structure. The ability of a putative amphipathic molecule to interact with a lipid membrane, e.g., a cell membrane, can be tested by routine methods, e.g., in a cell free or cellular assay. For example, a test compound is combined or contacted with a synthetic lipid bilayer, a cellular 10 membrane fraction, or a cell, and the test compound is evaluated for its ability to interact with, penetrate or disrupt the lipid bilayer, cell membrane or cell. The test compound can labeled in order to detect the interaction with the lipid bilayer, cell membrane or cell. In another type of assay, the test compound is linked to a reporter molecule or an iRNA agent (e.g., an iRNA or sRNA described herein) and the ability of the reporter molecule or iRNA agent to penetrate the 15 lipid bilayer, cell membrane or cell is evaluated. A two-step assay can also be performed, wherein a first assay evaluates the ability of a test compound alone to interact with a lipid bilayer, cell membrane or cell; and a second assay evaluates the ability of a construct (e.g., a construct described herein) that includes the test compound and a reporter or iRNA agent to. interact with a lipid bilayer, cell membrane or cell. 20 An amphipathic polymer useful in the compositions described herein has at least 2, preferably at least 5, more preferably at least 10, 25, 50, 100, 200, 500, 1000, 2000, 50000 or more subunits (e.g., amino acids or cyclic subunits). A single amphipathic polymer can be linked to one or more, e.g., 2, 3, 5, 10 or more iRNA agents (e.g., iRNA or sRNA agents described herein). In some embodiments, an amphipathic polymer can contain both amino acid 25 and cyclic subunits, e.g., aromatic subunits. Described herein is a composition that includes an iRNA agent (e.g., an iRNA or sRNA described herein) in association with an amphipathic molecule. Such compositions may be referred to herein as "amphipathic iRNA constructs." Such compositions and constructs are useful in the delivery or targeting of iRNA agents, e.g., delivery or targeting of iRNA agents to a 162 cell. While not wanting to be bound by theory, such compositions and constructs can increase the porosity of, e.g., can penetrate or disrupt, a lipid (e.g., a lipid bilayer of a cell), e.g., to allow entry of the iRNA agent into a cell. Described herein is, a composition comprising an iRNA agent (e.g., an 5 iRNA or sRNA agent described herein) linked to an amphipathic molecule. The iRNA agent and the amphipathic molecule may be held in continuous contact with one another by either covalent or noncovalent linkages. The amphipathic molecule of the composition or construct is preferably other than a phospholipid, e.g., other than a micelle, membrane or membrane fragment. 10 The amphipathic molecule of the composition or construct is preferably a polymer. The polymer may include two or more amphipathic subunits. One or more hydrophilic groups and one or more hydrophobic groups may be present on the polymer. The polymer may have a repeating secondary structure as well as a first face and a second face. The distribution of the hydrophilic groups and the hydrophobic groups along the repeating secondary structure can be 15 such that one face of the polymer is a hydrophilic face and the other face of the polymer is a hydrophobic face. The amphipathic molecule can be a polypeptide, e.g., a polypeptide comprising an a-helical conformation as its secondary structure. In one embodiment, the amphipathic polymer includes one or more subunits containing 20 one or more cyclic moiety (e.g., a cyclic moiety having one or more hydrophilic groups and/or one or more hydrophobic groups). In one embodiment, the polymer is a polymer of cyclic moieties such that the moieties have alternating hydrophobic and hydrophilic groups. For example, the subunit may contain a steroid, e.g., cholic acid. In another example, the subunit may contain an aromatic moiety. The aromatic moiety may be one that can exhibit 25 atropisomerism, e.g., a 2,2'-bis(substituted)-1-1'-binaphthyl or a 2,2'-bis(substituted) biphenyl. A subunit may include an aromatic moiety of Formula (M): 163

R

3 R4 R2 R4 R1

R

3 (M) Described herein is a composition that includes an iRNA agent (e.g., an iRNA or sRNA described herein) in association with an amphipathic molecule. Such compositions may 5 be referred to herein as "amphipathic iRNA constructs." Such compositions and constructs are useful in the delivery or targeting of iRNA agents, e.g., delivery or targeting of iRNA agents to a cell. While not wanting to be bound by theory, such compositions and constructs can increase the porosity of, e.g., can penetrate or disrupt, a lipid (e.g., a lipid bilayer of a cell), e.g., to allow entry of the iRNA agent into a cell. 10 Described herein is a composition comprising an iRNA agent (e.g., an iRNA or sRNA agent described herein) linked to an amphipathic molecule. The iRNA agent and the amphipathic molecule may be held in continuous contact with one another by either covalent or noncovalent linkages. The amphipathic molecule of the composition or construct is preferably other than a 15 phospholipid, e.g., other than a micelle, membrane or membrane fragment. The amphipathic molecule of the composition or construct is preferably a polymer. The polymer may include two or more amphipathic subunits. One or more hydrophilic groups and 164 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 one or more hydrophobic groups may be present on the polymer. The polymer may have a repeating secondary structure as well as a first face and a second face. The distribution of the hydrophilic groups and the hydrophobic groups along the repeating secondary structure can be such that one face of the polymer is a hydrophilic face and the other face of the polymer is a 5 hydrophobic face. The amphipathic molecule can be a polypeptide, e.g., a polypeptide comprising an a-helical conformation as its secondary structure. In one embodiment, the amphipathic polymer includes one or more subunits containing one or more cyclic moiety (e.g., a cyclic moiety having one or more hydrophilic groups and/or 10 one or more hydrophobic groups). In one embodiment, the polymer is a polymer of cyclic moieties such that the moieties have alternating hydrophobic and hydrophilic groups. For example, the subunit may contain a steroid, e.g., cholic acid. In another example, the subunit may contain an aromatic moiety. The aromatic moiety may be one that can exhibit atropisomerism, e.g., a 2,2'-bis(substituted)--l-1'-binaphthyl or a 2,2'-bis(substituted) biphenyl. 15 A subunit may include an aromatic moiety of Formula (M): R3 R4 R2 R4 R 1 R3 (M) 165 Referring to Formula M, R 1 is C-Cioo alkyl optionally substituted with aryl, alkenyl, alkynyl, alkoxy or halo and/or optionally inserted with 0, S, alkenyl or alkynyl; C-C 1 OO perfluoroalkyl; or OR 5 . 5 R 2 is hydroxy; nitro; sulfate; phosphate; phosphate ester; sulfonic acid; OR 6 ; or C-Cioo alkyl optionally substituted with hydroxy, halo, nitro, aryl or alkyl sulfinyl, aryl or alkyl sulfonyl, sulfate, sulfonic acid, phosphate, phosphate ester, substituted or unsubstituted aryl, carboxyl, carboxylate, amino carbonyl, or alkoxycarbonyl, and/or optionally inserted with 0, NH, S, S(O),

SO

2 , alkenyl, or alkynyl. 10 R 3 is hydrogen, or when taken together with R 4 froms a fused phenyl ring.

R

4 is hydrogen, or when taken together with R 3 froms a fused phenyl ring.

R

5 is C-Cioo alkyl optionally substituted with aryl, alkenyl, alkynyl, alkoxy or halo and/or optionally inserted with 0, S, alkenyl or alkynyl; or C-CIOO perfluoroalkyl; and R 6 is C

C

1 00 alkyl optionally substituted with hydroxy, halo, nitro, aryl or alkyl sulfinyl, aryl or alkyl 15 sulfonyl, sulfate, sulfonic acid, phosphate, phosphate ester, substituted or unsubstituted aryl, carboxyl, carboxylate, amino carbonyl, or alkoxycarbonyl, and/or optionally inserted with 0, NH, S, S(0), SO 2 , alkenyl, or alkynyl. Increasing cellular uptake of dsRNAs A method described herein that can include the administration of an iRNA agent and a 20 drug that affects the uptake of the iRNA agent into the cell. The drug can be administered before, after, or at the same time that the iRNA agent is administered. The drug can be covalently linked to the iRNA agent. The drug can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF-KB. The drug can have a transient effect on the cell. 25 The drug can increase the uptake of the iRNA agent into the cell, for example, by disrupting the cell's cytoskeleton, e.g., by disrupting the cell's microtubules, microfilaments, and/or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, 166 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. The drug can also increase the uptake of the iRNA agent into the cell by activating an inflammatory response, for example. Exemplary drug's that would have such an effect include 5 tumor necrosis factor alpha (TNFalpha), interleukin-1 beta, or gamma interferon. iRNA conjugates An iRNA agent can be coupled, e.g., covalently coupled, to a second agent. For example, an iRNA agent used to treat a particular disorder can be coupled to a second therapeutic agent, e.g., an agent other than the iRNA agent. The second therapeutic agent can be one which is 10 directed to the treatment of the same disorder. For example, in the case of an iRNA used to treat a disorder characterized by unwanted cell proliferation, e.g., cancer, the iRNA agent can be coupled to a second agent which has an anti-cancer effect. For example, it can be coupled to an agent which stimulates the immune system, e.g., a CpG motif, or more generally an agent that activates a toll-like receptor and/or increases the production of gamma interferon. 15 iRNA Production An iRNA can be produced, e.g., in bulk, by a variety of methods. Exemplary methods include: organic synthesis and RNA cleavage, e.g., in vitro cleavage. Organic Synthesis An iRNA can be made by separately synthesizing each respective strand of a double 20 stranded RNA molecule. The component strands can then be annealed. A large bioreactor, e.g., the OligoPilot II from Pharmacia Biotec AB (Uppsala Sweden), can be used to produce a large amount of a particular RNA strand for a given iRNA. The OligoPilotII reactor can efficiently couple a nucleotide using only a 1.5 molar excess of a phosphoramidite nucleotide. To make an RNA strand, ribonucleotides amidites are used. 25 Standard cycles of monomer addition can be used to synthesize the 21 to 23 nucleotide strand for the iRNA. Typically, the two complementary strands are produced separately and then annealed, e.g., after release from the solid support and deprotection. 167 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Organic synthesis can be used to produce a discrete iRNA species. The complementary of the species to a particular target gene can be precisely specified. For example, the species may be complementary to a region that includes a polymorphism, e.g., a single nucleotide polymorphism. Further the location of the polymorphism can be precisely defined. In some 5 embodiments, the polymorphism is located in an internal region, e.g., at least 4, 5, 7, or 9 nucleotides from one or both of the termini. dsRNA Cleavage iRNAs can also be made by cleaving a larger ds iRNA. The cleavage can be mediated in vitro or in vivo. For example, to produce iRNAs by cleavage in vitro, the following method can 10 be used: In vitro transcription. dsRNA is produced by transcribing a nucleic acid (DNA) segment in both directions. For example, the HiScribeTM RNAi transcription kit (New England Biolabs) provides a vector and a method for producing a dsRNA for a nucleic acid segment that is cloned into the vector at a position flanked on either side by a T7 promoter. Separate templates are 15 generated for T7 transcription of the two complementary strands for the dsRNA. The templates are transcribed in vitro by addition of T7 RNA polymerase and dsRNA is produced. Similar methods using PCR and/or other RNA polymerases (e.g., T3 or SP6 polymerase) can also be used. In one embodiment, RNA generated by this method is carefully purified to remove endotoxins that may contaminate preparations of the recombinant enzymes. 20 In vitro cleavage. dsRNA is cleaved in vitro into iRNAs, for example, using a Dicer or comparable RNAse III-based activity. For example, the dsRNA can be incubated in an in vitro extract from Drosophila or using purified components, e.g. a purified RNAse or RISC complex (RNA-induced silencing complex ). See, e.g., Ketting et al. Genes Dev 2001 Oct 15;15(20):2654-9. and Hammond Science 2001 Aug 10;293(5532):1146-50. 25 dsRNA cleavage generally produces a plurality of iRNA species, each being a particular 21 to 23 nt fragment of a source dsRNA molecule. For example, iRNAs that include sequences complementary to overlapping regions and adjacent regions of a source dsRNA molecule may be present. 168 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Regardless of the method of synthesis, the iRNA preparation can be prepared in a solution (e.g., an aqueous and/or organic solution) that is appropriate for formulation. For example, the iRNA preparation can be precipitated and redissolved in pure double-distilled water, and lyophilized. The dried iRNA can then be resuspended in a solution appropriate for the 5 intended formulation process. Synthesis of modified and nucleotide surrogate iRNA agents is discussed below. FORMULATION The iRNA agents described herein can be formulated for administration to a subject For ease of exposition the formulations, compositions and methods in this section are 10 discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents, and such practice is within the invention. A formulated iRNA composition can assume a variety of states. In some examples, the composition is at least partially crystalline, uniformly crystalline, and/or anhydrous (e.g., less 15 than 80, 50, 30, 20, or 10% water). In another example, the iRNAis in an aqueous phase, e.g., in a solution that includes water. The aqueous phase or the crystalline compositions can, e.g., be incorporated into a delivery vehicle, e.g., a liposome (particularly for the aqueous phase) or a particle (e.g., a microparticle as can be appropriate for a crystalline composition). Generally, the iRNA 20 composition is formulated in a manner that is compatible with the intended method of administration (see, below). In particular embodiments, the composition is prepared by at least one of the following methods: spray drying, lyophilization, vacuum drying, evaporation, fluid bed drying, or a combination of these techniques; or sonication with a lipid, freeze-drying, condensation and 25 other self-assembly. A iRNA preparation can be formulated in combination with another agent, e.g., another therapeutic agent or an agent that stabilizes a iRNA, e.g., a protein that complexes with iRNA to 169 form an iRNP. Still other agents include chelators, e.g., EDTA (e.g., to remove divalent cations such as Mg), salts, RNAse inhibitors (eg., a broad specificity RNAse inhibitor such as RNAsin) and so forth. In one embodiment, the iRNA preparation includes another iRNA agent, e.g., a second 5 iRNA that can mediated RNAi with respect to a second gene, or with respect to the same gene. Still other preparation can include at least 3, 5, ten, twenty, fifty, or a hundred or more different iRNA species. Such iRNAs can mediated RNAi with respect to a similar number of different genes. In one embodiment, the iRNA preparation includes at least a second therapeutic agent 10 (e.g., an agent other than an RNA or a DNA). For example, a iRNA composition for the treatment of a viral disease, e.g. HIV, might include a known antiviral agent (e.g., a protease inhibitor or reverse transcriptase inhibitor). In another example, a iRNA composition for the treatment of a cancer might further comprise a chemotherapeutic agent. Exemplary formulations are discussed below: 15 Liposomes For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA s agents An iRNA agent, e.g., a 20 double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double stranded iRNA agent, or sRNA agent, or precursor thereof) preparation can be formulated for delivery in a membranous molecular assembly, e.g., a liposome or a micelle. As used herein, the term "liposome" refers to a vesicle composed of amphiphilic lipids arranged in at least one 25 bilayer, e.g., one bilayer or a plurality of bilayers. Liposomes include unilamellar and multilamellar vesicles that have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the iRNA composition. The lipophilic material isolates the aqueous interior from an aqueous exterior, which typically does not include the iRNA 170 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 composition, although in some examples, it may. Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomal bilayer fuses with bilayer of the cellular membranes. As the merging of the liposome 5 and cell progresses, the internal aqueous contents that include the iRNA are delivered into the cell where the iRNA can specifically bind to a target RNA and can mediate RNAi. In some cases the liposomes are also specifically targeted, e.g., to direct the iRNA to particular cell types, e.g., to cells of the liver, such as those described herein. A liposome containing a iRNA can be prepared by a variety of methods. 10 In one example, the lipid component of a liposome is dissolved in a detergent so that micelles are formed with the lipid component. For example, the lipid component can be an amphipathic cationic lipid or lipid conjugate. The detergent can have a high critical micelle concentration and may be nonionic. Exemplary detergents include cholate, CHAPS, octylglucoside, deoxycholate, and lauroyl sarcosine. The iRNA preparation is then added to the 15 micelles that include the lipid component. The cationic groups on the lipid interact with the iRNA and condense around the iRNA to form a liposome. After condensation, the detergent is removed, e.g., by dialysis, to yield a liposomal preparation of iRNA. If necessary a carrier compound that assists in condensation can be added during the condensation reaction, e.g., by controlled addition. For example, the carrier compound can be a 20 polymer other than a nucleic acid (e.g., spermine or spermidine). pH can also adjusted to favor condensation. Further description of methods for producing stable polynucleotide delivery vehicles, which incorporate a polynucleotide/cationic lipid complex as structural components of the delivery vehicle, are described in, e.g., WO 96/37194. Liposome formation can also include one 25 or more aspects of exemplary methods described in Felgner, P. L. et al., Proc. Natl. Acad. Sci., USA 8:7413-7417, 1987; U.S. Pat. No. 4,897,355; U.S. Pat. No. 5,171,678; Bangham, et al. M. Mol. Biol. 23:23 8, 1965; Olson, et al. Biochim. Biophys. Acta 557:9, 1979; Szoka, et al. Proc. Natl. Acad. Sci. 75: 4194, 1978; Mayhew, et al. Biochim. Biophys. Acta 775:169, 1984; Kim, et al. Biochin. Biophys. Acta 728:339, 1983; and Fukunaga, et al. Endocrinol. 115:757, 1984. 171 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Commonly used techniques for preparing lipid aggregates of appropriate size for use as delivery vehicles include sonication and freeze-thaw plus extrusion (see, e.g., Mayer, et al. Biochim. Biophys. Acta 858:161, 1986). Microfluidization can be used when consistently small (50 to 200 nm) and relatively uniform aggregates are desired (Mayhew, et al. Biochim. Biophys. Acta 5 775:169, 1984). These methods are readily adapted to packaging iRNA preparations into liposomes. Liposomes that are pH-sensitive or negatively-charged, entrap nucleic acid molecules rather than complex with them. Since both the nucleic acid molecules and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some nucleic acid 10 molecules are entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al., Journal of Controlled Release, 19, (1992) 269-274). One major type of liposomal composition includes phospholipids other than naturally 15 derived phosphatidyleholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such 20 as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol. Examples of other methods to introduce liposomes into cells in vitro and in vivo include U.S. Pat. No. 5,283,185; U.S. Pat. No. 5,171,678; WO 94/00569; WO 93/24640; WO 91/16024; Felgner, J. Biol. Chem. 269:2550, 1994; Nabel, Proc. Nati. Acad. Sci. 90:11307, 1993; Nabel, 25 Human Gene Ther. 3:649, 1992; Gershon, Biochem. 32:7143, 1993; and Strauss EMBO J. 11:417, 1992. In one embodiment, cationic liposomes are used. Cationic liposomes possess the advantage of being able to fuse to the cell membrane. Non-cationic liposomes, although not able 172 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 to fuse as efficiently with the plasma membrane, are taken up by macrophages in vivo and can be used to deliver iRNAs to macrophages. Further advantages of liposomes include: liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid 5 soluble drugs; liposomes can protect encapsulated iRNAs in their internal compartments from metabolism and degradation (Rosoff, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes. A positively charged synthetic cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N 10 trimethylammonium chloride (DOTMA) can be used to form small liposomes that interact spontaneously with nucleic acid to form lipid-nucleic acid complexes which are capable of fusing with the negatively charged lipids of the cell membranes of tissue culture cells, resulting in delivery of iRNA (see, e.g., Felgner, P. L. et al., Proc. Natl. Acad. Sci., USA 8:7413-7417, 1987 and U.S. Pat. No. 4,897,355 for a description of DOTMA and its use with DNA). 15 A DOTMA analogue, 1,2-bis(oleoyloxy)-3-(trimethylammonia)propane (DOTAP) can be used in combination with a phospholipid to form DNA-complexing vesicles. LipofectinTM Bethesda Research Laboratories, Gaithersburg, Md.) is an effective agent for the delivery of highly anionic nucleic acids into living tissue culture cells that comprise positively charged DOTMA liposomes which interact spontaneously with negatively charged polynucleotides to 20 form complexes. When enough positively charged liposomes are used, the net charge on the resulting complexes is also positive. Positively charged complexes prepared in this way spontaneously attach to negatively charged cell surfaces, fuse with the plasma membrane, and efficiently deliver functional nucleic acids into, for example, tissue culture cells. Another commercially available cationic lipid, 1,2-bis(oleoyloxy)-3,3-(trimethylammonia)propane 25 ("DOTAP") (Boehringer Mannheim, Indianapolis, Indiana) differs from DOTMA in that the oleoyl moieties are linked by ester, rather than ether linkages. Other reported cationic lipid compounds include those that have been conjugated to a variety of moieties including, for example, carboxyspermine which has been conjugated to one of two types of lipids and includes compounds such as 5-carboxyspermylglycine 173 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 dioctaoleoylamide ("DOGS") (TransfectamTM, Promega, Madison, Wisconsin) and dipalmitoylphosphatidylethanolamine 5-carboxyspermyl-amide ("DPPES") (see, e.g., U.S. Pat. No. 5,171,678). Another cationic lipid conjugate includes derivatization of the lipid with cholesterol 5 ("DC-Chol") which has been formulated into liposomes in combination with DOPE (See, Gao, X. and Huang, L., Biochim. Biophys. Res. Commun. 179:280, 1991). Lipopolylysine, made by conjugating polylysine to DOPE, has been reported to be effective for transfection in the presence of serum (Zhou, X. et al., Biochim. Biophys. Acta 1065:8, 1991). For certain cell lines, these liposomes containing conjugated cationic lipids, are said to exhibit lower toxicity and 10 provide more efficient transfection than the DOTMA-containing compositions. Other commercially available cationic lipid products include DMRIE and DMRIE-HP (Vical, La Jolla, California) and Lipofectamine (DOSPA) (Life Technology, Inc., Gaithersburg, Maryland). Other cationic lipids suitable for the delivery of oligonucleotides are described in WO 98/39359 and WO 96/37194. 15 Liposomal formulations are particularly suited for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer iRNA, into the skin. In some implementations, liposomes are used for delivering iRNA to epidermal cells and also to 20 enhance the penetration of iRNA into dermal tissues, e.g., into skin. For example, the liposomes can be applied topically. Topical delivery of drugs formulated as liposomes to the skin has been documented (see, e.g., Weiner et al., Journal ofDrug Targeting, 1992, vol. 2,405-410 and du Plessis et al., Antiviral Research, 18, 1992, 259-265; Mannino, R. J. and Fould-Fogerite, S., Biotechniques 6:682-690, 1988; Itani, T. et al. Gene 56:267-276. 1987; Nicolau, C. et al. Meth. 25 Enz. 149:157-176, 1987; Straubinger, R. M. and Papahadjopoulos, D. Meth. Enz. 101:512-527, 1983; Wang, C. Y. and Huang, L., Proc. Natl. Acad. Sci. USA 84:7851-7855, 1987). Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome I (glyceryl 174 dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome II (glyceryl distearate/ cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver a drug into the dermis of mouse skin. Such formulations with iRNA are useful for treating a dermatological disorder. Liposomes that include iRNA can be made highly deformable. Such deformability can 5 enable the liposomes to penetrate through pore that are smaller than the average radius of the liposome. For example, transfersomes are a type of deformable liposomes. Transferosomes can be made by adding surface edge activators, usually surfactants, to a standard liposomal composition. Transfersomes that include iRNA can be delivered, for example, subcutaneously by infection in order to deliver iRNA to keratinocytes in the skin. In order to cross intact 10 mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nn, under the influence of a suitable transdermal gradient. In addition, due to the lipid properties, these transferosomes can be self-optimizing (adaptive to the shape of pores, e.g., in the skin), self-repairing, and can frequently reach their targets without fragmenting, and often self-loading. The iRNA agents can include an RRMS tethered to a moiety which improves 15 association with a liposome. Surfactants For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. it should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, 20 e.g., modified iRNA agents. Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes (see above). iRNA (or a precursor, e.g., a larger dsRNA which can be processed into a iRNA, or a DNA which encodes a iRNA or precursor) compositions can include a surfactant. In one embodiment, the iRNA is formulated as an emulsion that includes a surfactant. The most 25 common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in "Pharmaceutical Dosage Forms," Marcel Dekker, Inc., New York, NY, 1988, p. 285). 175 WO 2004/091515 PCT/US2004/011255 Attomey's Docket No.: 14174-072W0 I If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, 5 propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class. 10 If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic 15 surfactant class are the alkyl sulfates and the soaps. If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class. 20 If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides. The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in "Pharmaceutical Dosage Forms," Marcel Dekker, Inc., New York, NY, 1988, p. 285). 25 Micelles and other Membranous Formulations For ease of exposition the micelles and other formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these micelles and other formulations, compositions and methods can 176 be practiced with other iRNA agents, e.g., modified iRNA agents. The iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor 5 thereof)) composition can be provided as a micellar formulation. "Micelles" are defined herein as a particular type of molecular assembly in which amphipathic molecules are arranged in a spherical structure such that all the hydrophobic portions of the molecules are directed inward, leaving the hydrophilic portions in contact with the surrounding aqueous phase. The converse arrangement exists if the environment is hydrophobic. 10 A mixed micellar formulation suitable for delivery through transdermal membranes may be prepared by mixing an aqueous solution of the iRNA composition, an alkali metal C 8 to C 22 alkyl sulphate, and a micelle forming compounds. Exemplary micelle forming compounds -include lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, 15 monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine and pharmaceutically acceptable salts thereof, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers and analogues thereof, polidocanol alkyl ethers and analogues thereof, chenodeoxycholate, deoxycholate, and mixtures thereof. The micelle forming compounds may be added at the same time or after addition of the alkali metal 20 alkyl sulphate. Mixed micelles will form with substantially any kind of mixing of the ingredients but vigorous mixing is preferred in order to provide smaller size micelles. In one method a first micellar composition is prepared which contains the iRNA composition and at least the alkali metal alkyl sulphate. The first micellar composition is then mixed with at least three micelle forming compounds to form a mixed micellar composition. In 25 another method, the micellar composition is prepared by mixing the iRNA composition, the alkali metal alkyl sulphate and at least one of the micelle forming compounds, followed by addition of the remaining micelle forming compounds, with vigorous mixing. Phenol and/or m-cresol may be added to the mixed micellar composition to stabilize the formulation and protect against bacterial growth. Alternatively, phenol and/or m-cresol may be 177 added with the micelle forming ingredients. An isotonic agent such as glycerin may also be added after formation of the mixed micellar composition. For delivery of the micellar formulation as a spray, the formulation can be put into an aerosol dispenser and the dispenser is charged with a propellant. The propellant, which is under 5 pressure, is in liquid form in the dispenser. The ratios of the ingredients are adjusted so that the aqueous and propellant phases become one, i.e. there is one phase. If there are two phases, it is necessary to shake the dispenser prior to dispensing a portion of the contents, e.g. through a metered valve. The dispensed dose of pharmaceutical agent is propelled from the metered valve in a fine spray. 10 The preferred propellants are hydrogen-containing chlorofluorocarbons, hydrogen containing fluorocarbons, dimethyl ether and diethyl ether. Even more preferred is HFA 134a (1,1,1,2 tetrafluoroethane). The specific concentrations of the essential ingredients can be determined by relatively straightforward experimentation. For absorption through the oral cavities, it is often desirable to 15 increase, e.g. at least double or triple, the dosage for through injection or administration through the gastrointestinal tract. The iRNA agents can include an RRMS tethered to a moiety which improves association with a micelle or other membranous formulation. Particles 20 For ease of exposition the particles, formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these particles, formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents, In another embodiment, an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., 25 a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) preparations may be incorporated into a particle, e.g., a microparticle. Microparticles can be produced by spray-drying, but may also be produced by other methods including 178 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 lyophilization, evaporation, fluid bed drying, vacuum drying, or a combination of these techniques. See below for further description. Sustained-Release Formulations. An iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA 5 agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) described herein can be formulated for controlled, e.g., slow release. Controlled release can be achieved by disposing the iRNA within a structure or substance which impedes its release. E.g., iRNA can be disposed within a porous matrix or in an erodable matrix, either of which allow release of the iRNA over a period of time. 10 Polymeric particles, e.g., polymeric in microparticles can be used as a sustained-release reservoir of iRNA that is taken up by cells only released from the microparticle through biodegradation. The polymeric particles in this embodiment should therefore be large enough to preclude phagocytosis (e.g., larger than 10 pm and preferably larger than 20 ptm). Such particles can be produced by the same methods to make smaller particles, but with less vigorous mixing of 15 the first and second emulsions. That is to say, a lower homogenization speed, vortex mixing speed, or sonication setting can be used to obtain particles having a diameter around 100 pm rather than 10 Am. The time of mixing also can be altered. Larger microparticles can be formulated as a suspension, a powder, or an implantable solid, to be delivered by intramuscular, subcutaneous, intradermal, intravenous, or intraperitoneal 20 injection; via inhalation (intranasal or intrapulmonary); orally; or by implantation. These particles are useful for delivery of any iRNA when slow release over a relatively long term is desired. The rate of degradation, and consequently of release, varies with the polymeric formulation. Microparticles preferably include pores, voids, hollows, defects or other interstitial 25 spaces that allow the fluid suspension medium to freely permeate or perfuse the particulate boundary. For example, the perforated microstructures can be used to form hollow, porous spray dried microspheres. 179 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Polymeric particles containing iRNA (e.g., a sRNA) can be made using a double emulsion technique, for instance. First, the polymer is dissolved in an organic solvent. A preferred polymer is polylactic-co-glycolic acid (PLGA), with a lactic/glycolic acid weight ratio of 65:35, 50:50, or 75:25. Next, a sample of nucleic acid suspended in aqueous solution is added 5 to the polymer solution and the two solutions are mixed to form a first emulsion. The solutions can be mixed by vortexing or shaking, and in a preferred method, the mixture can be sonicated. Most preferable is any method by which the nucleic acid receives the least amount of damage in the form of nicking, shearing, or degradation, while still allowing the formation of an appropriate emulsion. For example, acceptable results can be obtained with a Vibra-cell model VC-250 10 sonicator with a 1/8" microtip probe, at setting #3. Spray-Drying. An iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof)) can be prepared by spray drying. Spray dried iRNA can be administered to a subject or 15 be subjected to further formulation. A pharmaceutical composition of iRNA can be prepared by spray drying a homogeneous aqueous mixture that includes a iRNA under conditions sufficient to provide a dispersible powdered composition, e.g., a pharmaceutical composition. The material for spray drying can also include one or more of: a pharmaceutically acceptable excipient, or a dispersibility-enhancing amount of a physiologically acceptable, water-soluble protein. The 20 spray-dried product can be a dispersible powder that includes the iRNA. Spray drying is a process that converts a liquid or slurry material to a dried particulate form. Spray drying can be used to provide powdered material for various administrative routes including inhalation. See, for example, M. Sacchetti and M. M. Van Oort in: Inhalation Aerosols: Physical and Biological Basis for Therapy, A. J. Hickey, ed. Marcel Dekkar, New York, 1996. 25 Spray drying can include atomizing a solution, emulsion, or suspension to form a fine mist of droplets and drying the droplets. The mist can be projected into a drying chamber (e.g., a vessel, tank, tubing, or coil) where it contacts a drying gas. The mist can include solid or liquid pore forming agents. The solvent and pore forming agents evaporate from the droplets into the 180 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 drying gas to solidify the droplets, simultaneously forming pores throughout the solid. The solid (typically in a powder, particulate form) then is separated from the drying gas and collected. Spray drying includes bringing together a highly dispersed liquid, and a sufficient volume of air (e.g., hot air) to produce evaporation and drying of the liquid droplets. The preparation to 5 be spray dried can be any solution, course suspension, slurry, colloidal-dispersion, or paste that may be atomized using the selected spray drying apparatus. Typically, the feed is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector. The spent air is then exhausted with the solvent. Several different types of apparatus may be used to provide the desired product. For example, commercial spray dryers manufactured 10 by Buchi Ltd. or Niro Corp. can effectively produce particles of desired size. Spray-dried powdered particles can be approximately spherical in shape, nearly uniform in size and frequently hollow. There may be some degree of irregularity in shape depending upon the incorporated medicament and the spray drying conditions. In many instances the dispersion stability of spray-dried microspheres appears to be more effective if an inflating agent 15 (or blowing agent) is used in their production. Particularly preferred embodiments may comprise an emulsion with an inflating agent as the disperse or continuous phase (the other phase being aqueous in nature). An inflating agent is preferably dispersed with a surfactant solution, using, for instance, a commercially available microfluidizer at a pressure of about 5000 to 15,000 psi. This process forms an emulsion, preferably stabilized by an incorporated surfactant, typically 20 comprising submicron droplets of water immiscible blowing agent dispersed in an aqueous continuous phase. The formation of such dispersions using this and other techniques are common and well known to those in the art. The blowing agent is preferably a fluorinated compound (e.g. perfluorohexane, perfluorooctyl bromide, perfluorodecalin, perfluorobutyl ethane) which vaporizes during the spray-drying process, leaving behind generally hollow, porous 25 aerodynamically light microspheres. As will be discussed in more detail below, other suitable blowing agents include chloroform, freons, and hydrocarbons. Nitrogen gas and carbon dioxide are also contemplated as a suitable blowing agent. Although the perforated microstructures are preferably formed using a blowing agent as described above, it will be appreciated that, in some instances, no blowing agent is required and 181 an aqueous dispersion of the medicament and surfactant(s) are spray dried directly. In such cases, the formulation may be amenable to process conditions (e.g., elevated temperatures) that generally lead to the formation of hollow, relatively porous microparticles. Moreover, the medicament may possess special physicochemical properties (e.g., high crystallinity, elevated 5 melting temperature, surface activity, etc.) that make it particularly suitable for use in such techniques. The perforated microstructures may optionally be associated with, or comprise, one or more surfactants. Moreover, miscible surfactants may optionally be combined with the suspension medium liquid phase. It will be appreciated by those skilled in the art that the use of 10 surfactants may further increase dispersion stability, simplify formulation procedures or increase bioavailability upon administration. Of course combinations of surfactants, including the use of one or more in the liquid phase and one or more associated with the perforated microstructures are contemplated.- By "associated with or comprise" it is meant that the structural matrix or perforated microstructure may incorporate, adsorb, absorb, 15 be coated with or be formed by the surfactant. Surfactants suitable for use include any compound or composition that aids in the formation and maintenance of the stabilized respiratory dispersions by forming a layer at the interface between the structural matrix and the suspension medium. The surfactant may comprise a single compound or any combination of compounds, such as in the case of co-surfactants. 20 Particularly preferred surfactants are substantially insoluble in the propellant, nonfluorinated, and selected from.the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations of such agents. It should be emphasized that, in addition to the aforementioned surfactants, suitable (i.e. biocompatible) fluorinated surfactants are compatible with the teachings herein and may be used to provide the 25 desired stabilized preparations. Lipids, including phospholipids, from both natural and synthetic sources may be used in varying concentrations to form a structural matrix. Generally, compatible lipids comprise those that have a gel to liquid crystal phase transition greater than about 40 C. Preferably, the incorporated lipids are relatively long chain (i.e. C 6 -C2) saturated lipids and more preferably 182 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 comprise phospholipids. Exemplary phospholipids useful in the disclosed stabilized preparations comprise egg phosphatidylcholine, dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidyl-choline, disteroylphosphatidylcholine, short-chain phosphatidylcholines, phosphatidylethanolamine, dioleylphosphatidylethanolamine, 5 phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as, polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate. Due to their excellent 10 biocompatibility characteristics, phospholipids and combinations of phospholipids and poloxamers are particularly suitable for use in the stabilized dispersions disclosed herein. Compatible nonionic detergents comprise: sorbitan esters including sorbitan trioleate (SpansTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene 15 (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters. Other suitable nonionic detergents can be easily identified using McCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock, N.J.). Preferred block copolymers include diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic.RTM. F68), poloxamer 407 (Pluronic.RTM. F-127), and poloxamer 20 338. Ionic surfactants such as sodium sulfosuccinate, and fatty acid soaps may also be utilized. In preferred embodiments, the microstructures may comprise oleic acid or its alkali salt. In addition to the aforementioned surfactants, cationic surfactants or lipids are preferred especially in the case of delivery of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA 25 agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof). Examples of suitable cationic lipids include: DOTMA, N-[-(2,3 dioleyloxy)propyl]-N,N,N-trimethylammonium-chloride; DOTAP,1,2-dioleyloxy-3- . (trimethylammonio)propane; and DOTB, 1,2-dioleyl-3-(4'-trimethylammonio)butanoyl-sn glycerol. Polycationic amino acids such as polylysine, and polyarginine are also contemplated. 183 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 For the spraying process, such spraying methods as rotary atomization, pressure atomization and two-fluid atomization can be used. Examples of the devices used in these processes include "Parabisu [phonetic rendering] Mini-Spray GA-32" and "Parubisu Spray Drier DL-41", manufactured by Yamato Chemical Co., or "Spray Drier CL-8," "Spray Drier L-8," 5 "Spray Drier FL-12," "Spray Drier FL-16" or "Spray Drier FL-20," manufactured by Okawara Kakoki Co., can be used for the method of spraying using rotary-disk atomizer. While no particular restrictions are placed on the gas used to dry the sprayed material, it is recommended to use air, nitrogen gas or an inert gas. The temperature of the inlet of the gas used to dry the sprayed materials such that it does not cause heat deactivation of the sprayed 10 material. The range of temperatures may vary between about 50"C to about 200"C, preferably between about 50"C and 100'C. The temperature of the outlet gas used to dry the sprayed material, may vary between about 0"C and about 150"C, preferably between 0"C and 90"C, and even more preferably between 0"C and 60"C. The spray drying is done under conditions that result in substantially amorphous powder 15 of homogeneous constitution having a particle size that is respirable, a low moisture content and flow characteristics that allow for ready aerosolization. Preferably the particle size of the resulting powder is such that more than about 98% of the mass is in particles having a diameter of about 10 pm or less with about 90% of the mass being in particles having a diameter less than 5 Im. Alternatively, about 95% of the mass will have particles with a diameter of less than 10 20 pm with about 80% of the mass of the particles having a diameter of less than 5 ym. The dispersible pharmaceutical-based dry powders that include the iRNA preparation may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the iRNA concentration in the powder which is being delivered to a 25 patient, but may also serve to enhance the stability of the iRNA compositions and to improve the dispersibility of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the iRNA and to improve handling characteristics of the iRNA such as flowability and consistency to facilitate manufacturing and powder filling. 184 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Such carrier materials may be combined with the drug prior to spray drying, i.e., by adding the carrier material to the purified bulk solution. In that way, the carrier particles will be formed simultaneously with the drug particles to produce a homogeneous powder. Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder 5 drug by blending. The powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the drug powder, typically being in the range from 25 ptm to 100 tm. A preferred carrier material is crystalline lactose having a size in the above-stated range. 10 Powders prepared by any of the above methods will be collected from the spray dryer in a conventional manner for subsequent use. For use as pharmaceuticals and other purposes, it will frequently be desirable to disrupt any agglomerates which may have formed by screening or other conventional techniques. For pharmaceutical uses, the dry powder formulations will usually be measured into a single dose, and the single dose sealed into a package. Such packages 15 are particularly useful for dispersion in dry powder inhalers, as described in detail below. Alternatively, the powders may be packaged in multiple-dose containers. Methods for spray drying hydrophobic and other drugs and components are described in U.S. Pat. Nos. 5,000,888; 5,026,550; 4,670,419, 4,540,602; and 4,486,435. Bloch and Speison (1983) Pharm. Acta Helv 58:14-22 teaches spray drying of hydrochlorothiazide and 20 chlorthalidone (lipophilic drugs) and a hydrophilic adjuvant (pentaerythritol) in azeotropic solvents of dioxane-water and 2-ethoxyethanol-water. A number of Japanese Patent application Abstracts relate to spray drying of hydrophilic-hydrophobic product combinations, including JP 806766; JP 7242568; JP 7101884; JP 7101883; JP 71018982; JP 7101881; and JP 4036233. Other foreign patent publications relevant to spray drying hydrophilic-hydrophobic product 25 combinations include FR 2594693; DE 2209477; and WO 88/07870. LYOPHILIZATION. An iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) 185 preparation can be made by lyophilization. Lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen. The particular advantage associated with the lyophilization process is that biologicals and pharmaceuticals that are relatively unstable in an aqueous solution can be dried without elevated temperatures (thereby eliminating the 5 adverse thermal effects), and then stored in a dry state where there are few stability problems. With respect to the instant invention such techniques are particularly compatible with the incorporation of nucleic acids in perforated microstructures without compromising physiological activity. Methods for providing lyophilized particulates are known to those of skill in the art and it would clearly not require undue experimentation to provide dispersion compatible 10 microstructures in accordance with the teachings herein. Accordingly, to the extent that lyophilization processes may be used to provide microstructures having the desired porosity and size, they are conformance with the teachings herein and are expressly contemplated as being within the scope of the instant invention. Targeting 15 For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNAs. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents. In some embodiments, an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA 20 agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) is targeted to a particular cell. For example, a liposome or particle or other structure that includes a iRNA can also include a targeting moiety that recognizes a specific molecule on a target cell. The targeting moiety can be a molecule with a specific affinity for a 25 target cell. Targeting moieties can include antibodies directed against a protein found on the surface of a target cell, or the ligand or a receptor-binding portion of a ligand for a molecule found on the surface of a target cell. For example, the targeting moiety can recognize a cancer specific antigen of the liver or a viral antigen, thus delivering the iRNA to a cancer cell or a virus-infected cell. Exemplary targeting moieties include antibodies (such as IgM, IgG, IgA, 186 IgD, and the like, or a functional portions thereof), ligands for cell surface receptors (e.g., ectodomains thereof). An antigen, such as a-feto protein, can be used to target an iRNA to a liver cell. In one embodiment, the targeting moiety is attached to a liposome. For example, US 5 Patent 6,245,427 describes a method for targeting a liposome using a protein or peptide. In another example, a cationic lipid component of the liposome is derivatized with a targeting moiety. For example, WO 96/37194 describes converting N-glutaryldioleoylphosphatidyl ethanolamine to a N-hydroxysuccinimide activated ester. The product was then coupled to an RGD peptide. 10 GENES AND DISEASES Described herein is a method of treating a subject at risk for or afflicted with unwanted cell proliferation, e.g., malignant or nonmalignant cell proliferation. The method includes: providing an iRNA agent, e.g., an sRNA or iRNA agent described herein, e.g., an iRNA 15 having a structure described herein, where the iRNA is homologous to and can silence, e.g., by cleavage, a gene which promotes unwanted cell proliferation; administering an iRNA agent, e.g., an sRNA or iRNA agent described herein to a subject, preferably a human subject, thereby treating the subject. 20 In a preferred embodiment the gene is a growth factor or growth factor receptor gene, a kinase, e.g., a protein tyrosine, seine or threonine kinase gene, an adaptor protein gene, a gene encoding a G protein superfamily molecule, or a gene encoding a transcription factor. In a preferred embodiment the iRNA agent silences the PDGF beta gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted PDGF beta 25 expression, e.g., testicular and lung cancers. 187 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In another preferred embodiment the iRNA agent silences the Erb-B gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted Erb-B expression, e.g., breast cancer. In a preferred embodiment the iRNA agent silences the Src gene, and thus can be used to 5 treat a subject having or at risk for a disorder characterized by unwanted Src expression, e.g., colon cancers. In a preferred embodiment the iRNA agent silences the CRK gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted CRK expression, e.g., colon and lung cancers. 10 In a preferred embodiment the iRNA agent silences the GRB2 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted GRB2 expression, e.g., squamous cell carcinoma. In another preferred embodiment the iRNA agent silences the RAS gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted RAS 15 expression, e.g., pancreatic, colon and lung cancers, and chronic leukemia. In another preferred embodiment the iRNA agent silences the MEKK gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted MEKK expression, e.g., squamous cell carcinoma, melanoma or leukemia. In another preferred embodiment the iRNA agent silences the JNK gene, and thus can be 20 used to treat a subject having or at risk for a disorder characterized by unwanted JNK expression, e.g., pancreatic or breast cancers. In a preferred embodiment the iRNA agent silences the RAF gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted RAF expression, e.g., lung cancer or leukemia. 25 In a preferred embodiment the iRNA agent silences the Erkl/2 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted Erkl/2 expression, e.g., lung cancer. 188 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In another preferred embodiment the iRNA agent silences the PCNA(p21) gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted PCNA expression, e.g., lung cancer. In a preferred embodiment the iRNA agent silences the MYB gene, and thus can be used 5 to treat a subject having or at risk for a disorder characterized by unwanted MYB expression, e.g., colon cancer or chronic myelogenous leukemia. In a preferred embodiment the iRNA agent silences the c-MYC gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted c-MYC expression, e.g., Burkitt's lymphoma or neuroblastoma. 10 In another preferred embodiment the iRNA agent silences the JUN gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted JUN expression, e.g., ovarian, prostate or breast cancers. In another preferred embodiment the iRNA agent silences the FOS gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted FOS expression, 15 e.g., skin or prostate cancers. In a preferred embodiment the iRNA agent silences the BCL-2 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted BCL-2 expression, e.g., lung or prostate cancers or Non-Hodgkin lymphoma. In a preferred embodiment the iRNA agent silences the Cyclin D gene, and thus can be 20 used to treat a subject having or at risk for a disorder characterized by unwanted Cyclin D expression, e.g., esophageal and colon cancers. In a preferred embodiment the iRNA agent silences the VEGF gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted VEGF expression, e.g., esophageal and colon cancers. 25 In a preferred embodiment the iRNA agent silences the EGFR gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted EGFR expression, e.g., breast cancer. 189 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 In another preferred embodiment the iRNA agent silences the Cyclin A gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted Cyclin A expression, e.g., lung and cervical cancers. In another preferred embodiment the iRNA agent silences the Cyclin E gene, and thus 5 can be used to treat a subject having or at risk for a disorder characterized by unwanted Cyclin E expression, e.g., lung and breast cancers. In another preferred embodiment the iRNA agent silences the WNT-1 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted WINT-1 expression, e.g., basal cell carcinoma. 10 In another preferred embodiment the iRNA agent silences the beta-catenin gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted beta catenin expression, e.g., adenocarcinoma or hepatocellular carcinoma. In another preferred embodiment the iRNA agent silences the c-MET gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted c-MET 15 expression, e.g., hepatocellular carcinoma. In another preferred embodiment the iRNA agent silences the PKC gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted PKC expression, e.g., breast cancer. In a preferred embodiment the iRNA agent silences the NFKB gene, and thus can be used 20 to treat a subject having or at risk for a disorder characterized by unwanted NFKB expression, e.g., breast cancer. In a preferred embodiment the iRNA agent silences the STAT3 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted STAT3 expression, e.g., prostate cancer. 25 In another preferred embodiment the iRNA agent silences the survivin gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted survivin expression, e.g., cervical or pancreatic cancers. 190 In another preferred embodiment the iRNA agent silences the Her2/Neu gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted Her2/Neu expression, e.g., breast cancer. In another preferred embodiment the iRNA agent silences the topoisomerase I gene, and 5 thus can be used to treat a subject having or at risk for a disorder characterized by unwanted topoisomerase I expression, e.g., ovarian and colon cancers. In a preferred embodiment the iRNA agent silences the topoisomerase II alpha gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted topoisomerase II expression, e.g., breast and colon cancers. 10 In a preferred embodiment the iRNA agent silences mutations in the p73 gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted p73 expression, e.g., colorectal adenocarcinoma. In a preferred embodiment the iRNA agent silences mutations in the p21(WAF1/CIP1) gene, and thus can be used to treat a subject having or at risk for a disorder characterized by 15 unwanted p21(WAF1/CIP1) expression, e.g., liver cancer. In a preferred embodiment the iRNA agent silences mutations in the p27(KIP1) gene, and thus can be used to treat a subject having or at risk for a disorder characterized by unwanted*. p27(KIP1) expression, e.g., liver cancer. In preferred embodiments the iRNA agent silences mutations in tumor suppressor genes, 20 and thus can be used as a method to promote apoptotic activity in combination with chemotherapeutics. Described herein isa method of treating a subject, e.g., a human, at risk for or afflicted with a disease or disorder that may benefit by angiogenesis inhibition e.g., cancer. The method includes: 25 providing an iRNA agent, e.g., an iRNA agent having a structure described herein, which iRNA agent is homologous to and can silence, e.g., by cleavage, a gene which mediates angiogenesis; 191 administering the iRNA agent to a subject, thereby treating the subject. Described herein is a method of treating a subject infected with a virus or at risk for or afflicted with a disorder or disease associated with a viral infection. The 5 method includes: providing an iRNA agent, e.g., and iRNA agent having a structure described herein, which iRNA agent is homologous to and can silence, e.g., by cleavage, a viral gene of a cellular gene which mediates viral function, e.g., entry or growth; administering the iRNA agent to a subject, preferably a human subject, 10 thereby treating the subject. Described herein is a method of treating patients infected by the Human Papilloma Virus (HPV) or at risk for or afflicted with a disorder mediated by HPV, e.g, cervical cancer. HPV is linked to 95% of cervical carcinomas and thus an antiviral therapy is an attractive method to treat these cancers and other symptoms of viral infection. 15 In a preferred embodiment, the expression of a HPV gene is reduced. In another preferred embodiment, the HPV gene is one of the group of E2, E6, or E7. In a preferred embodiment the expression of a human gene that is required for HPV replication is reduced. Described herein is a method of treating patients infected by the Human 20 Immunodeficiency Virus (HIV) or at risk for or afflicted with a disorder mediated by HIV, e.g., Acquired Immune Deficiency Syndrome (AIDS). In a preferred embodiment, the expression of a HIV gene is reduced. In another preferred embodiment, the HIV gene is CCR5, Gag, or Rev. In a preferred embodiment the expression of a human gene that is required for HIV 25 replication is reduced. In another preferred embodiment, the gene is CD4 or Tsg101. 192 I)escrihed herein is ! a method for treating patients infected by the Hepatitis B Virus (HBV) or at risk for or afflicted with a disorder mediated by HBV, e.g., cirrhosis and heptocellular carcinoma. In a preferred embodiment, the expression of a HBV gene is reduced. In another 5 preferred embodiment, the targeted HBV gene encodes one of the group of the tail region of the HBV core protein, the pre-cregious (pre-c) region, or the cregious (c) region. In another preferred embodiment, a targeted HBV-RNA sequence is comprised of the poly(A) tail. In preferred embodiment the expression of a human gene that is required for HBV replication is reduced. 10 Described herein is , a method of treating patients infected by the Hepatitis A Virus (HAV), or at risk for or afflicted with a disorder mediated by HAV. In a preferred embodiment the expression of a human gene that is required for HAV replication is reduced. Described herein is a method of treating patients infected by the Hepatitis 15 C Virus (HCV), or at risk for or afflicted with a disorder mediated by HCV, e.g., cirrhosis In a preferred embodiment, the expression of a HCV gene is reduced. In another preferred embodiment the expression of a human gene that is required for HCV replication is reduced. Described herein is a method of treating patients infected by the any 20 of the group of Hepatitis Viral strains comprising hepatitis D, E, F, G, or H, or patients at risk for or afflicted with a disorder mediated by any of these strains of hepatitis. In a preferred embodiment, the expression of a Hepatitis, D, E, F, G, or H gene is reduced. In another preferred embodiment the expression of a human gene that is required for 25 hepatitis D, E, F, G or H replication is reduced. 193 Methods are described herein for treating patients infected by the Respiratory Syncytial Virus (RSV) or at risk for or afflicted with a disorder mediated by RSV, e.g, lower respiratory tract infection in infants and childhood asthma, pneumonia and other complications, e.g., in the elderly. 5 In a preferred embodiment, the expression of a RSV gene is reduced. In another preferred embodiment, the targeted HBV gene encodes one of the group of genes N, L, or P. In a preferred embodiment the expression of a human gene that is required for RSV replication is reduced. Methods are described herein for treating patients infected by the Herpes Simplex 10 Virus (HSV) or at risk for or afflicted with a disorder mediated by HSV, e.g, genital herpes and cold sores as well as life-threatening or sight-impairing disease mainly in immunocompromised patients. In a preferred embodiment, the expression of a HSV gene is reduced. In another preferred embodiment, the targeted HSV gene encodes DNA polymerase or the helicase 15 primase. In a preferred embodiment the expression of a human gene that is required for HSV replication is reduced. Described herein is -a method for treating patients infected by the herpes Cytomegalovirus (CMV) or at risk for or afflicted with a disorder mediated by CMV, e.g., 20 congenital virus infections and morbidity in immunocompromised patients. In a preferred embodiment, the expression of a CMV gene is reduced. In a preferred embodiment the expression of a human gene that is required for CMV replication is reduced. Methods are described herein for a method of treating patients infected by the 25 herpes Epstein Barr Virus (EBV) or at risk for or afflicted with a disorder mediated by EBV, e.g., NK/T-cell lymphoma, non-Hodgkin lymphoma, and Hodgkin disease. 194 In a preferred embodiment, the expression of a EBV gene is reduced. In a preferred embodiment the expression of a human gene that is required for EBV replication is reduced. Methods are described herein for treating patients infected by Kaposi's Sarcoma 5 associated Herpes Virus (KSHV), also called human herpesvirus 8, or patients at risk for or afflicted with a disorder mediated by KSHV, e.g., Kaposi's sarcoma, multicentric Castleman's disease and AIDS-associated primary effusion lymphoma. In a preferred embodiment, the expression of a KSHV gene is reduced. In a preferred embodiment the expression of a human gene that is required for KSHV 10 replication is reduced. Described herein is a method for treating patients infected by the JC Virus (JCV) or a disease or disorder associated with this virus, e.g., progressive multifocal leukoencephalopathy (PML). In a preferred embodiment, the expression of a JCV gene is reduced. 15 In preferred embodiment the expression of a human gene that is required for JCV replication is reduced. Methods are described herein for treating patients infected by the myxovirus or at risk for or afflicted with a disorder mediated by myxovirus, e.g., influenza. In a preferred embodiment, the expression of a myxovirus gene is reduced. 20 In a preferred embodiment the expression of a human gene that is required for myxovirus replication is reduced. Methods are described herein : for treating patients infected by the rhinovirus or at risk for of afflicted with a disorder mediated by rhinovirus, e.g., the common cold. In a preferred embodiment, the expression of a rhinovirus gene is reduced. 195 In preferred embodiment the expression of a human gene that is required for rhinovirus replication is reduced. Methods are described herein for treating patients infected by the coronavirus or at risk for of afflicted with a disorder mediated by coronavirus, e.g., the common cold. 5 In a preferred embodiment, the expression of a coronavirus gene is reduced. In preferred embodiment the expression of a human gene that is required for coronavirus replication is reduced. Methods are described herein for treating patients infected by the flavivirus West Nile or at risk for or afflicted with a disorder mediated by West Nile Virus. 10 In a preferred embodiment, the expression of a West Nile Virus gene is reduced. In another preferred embodiment, the West Nile Virus gene is one of the group comprising E, NS3, or NS5. In a preferred embodiment the expression of a human gene that is required for West Nile Virus replication is reduced. 15 Methods are described herein for treating patients infected by the St. Louis Encephalitis flavivirus, or at risk for or afflicted with a disease or disorder associated with this virus, e.g., viral haemorrhagic fever or neurological disease. In a preferred embodiment, the expression of a St. Louis Encephalitis gene is reduced. In a preferred embodiment the expression of a human gene that is required for St. Louis 20 Encephalitis virus replication is reduced. Methods are described herein for treating patients infected by the Tick-borne encephalitis flavivirus, or at risk for or afflicted with a disorder mediated by Tick-borne encephalitis virus, e.g., viral haemorrhagic fever and neurological disease. In a preferred embodiment, the expression of a Tick-borne encephalitis virus gene is 25 reduced. 196 In a preferred embodiment the expression of a human gene that is required for Tick borne encephalitis virus replication is reduced. Methods are described herein for treating patients infected by the Murray Valley encephalitis flavivirus, which commonly results in viral haemorrhagic fever and 5 neurological disease. In a preferred embodiment, the expression of a Murray Valley encephalitis virus gene is reduced. In a preferred embodiment the expression of a human gene that is required for Murray Valley encephalitis virus replication is reduced. 10 Described herein are methods for treating patients infected by the dengue flavivirus, or a disease or disorder associated with this virus, e.g., dengue haemorrhagic fever. In a preferred embodiment, the expression of a dengue virus gene is reduced. In a preferred embodiment the expression of a human gene that is required for dengue virus replication is reduced. 15 Methods are described herein for treating patients infected by the Simian Virus 40-(SV40) or at risk for or afflicted with a disorder mediated by SV40, e.g., tumorigenesis. In a preferred embodiment, the expression of a SV40 gene is reduced. In a preferred embodiment the expression of a human gene that is required for SV40 replication is reduced. 20 Described herein are methods for treating patients infected by the Human T Cell Lymphotropic Virus (HTLV), or a disease or disorder associated with this virus, e.g., leukemia and myelopathy. In a preferred embodiment, the expression of a HTLV gene is reduced. In another preferred embodiment the HTLV1 gene is the Tax transcriptional activator. 197 In a preferred embodiment the expression of a human gene that is required for HTLV replication is reduced. Methods are described herein for treating patients infected by the Moloney Murine Leukemia Virus (Mo-MuLV) or at risk for or afflicted with a disorder mediated by Mo 5 MuLV, e.g., T-cell leukemia. In a preferred embodiment, the expression of a Mo-MuLV gene is reduced. In a preferred embodiment the expression of a human gene that is required for Mo-MuLV replication is reduced. Methods are described herein , for treating patients infected by the 10 encephalomyocarditis virus (EMCV) or at risk for or afflicted with a disorder mediated by EMCV, e.g. myocarditis. EMCV leads to myocarditis in mice and pigs and is capable of infecting human myocardial cells. This virus is therefore a concern for patients undergoing xenotransplantation. In a preferred embodiment, the expression of a EMCV gene is reduced. 15 In a preferred embodiment the expression of a human gene that is required for EMCV replication is reduced. Described herein is a method for treating patients infected by the measles virus (MV) or at risk tor or attlicted witti a disorder mediated by MV, e.g. measles. In a preferred embodiment, the expression of a MV gene is reduced. 20 In a preferred embodiment the expression of a human gene that is required for MV replication is reduced. Described herein is a method for treating patients infected by the Vericella zoster virus (VZV) or at risk for or afflicted with a disorder mediated by VZV, e.g. chicken pox or shingles (also called zoster). 25 In a preferred embodiment, the expression of a VZV gene is reduced. 198 In a preferred embodiment the expression of a human gene that is required for VZV replication is reduced. Described herein is a method for treating patients infected by an adenovirus or at risk for or afflicted with a disorder mediated by an adenovirus, e.g. respiratory tract infection. 5 In a preferred embodiment, the expression of an adenovirus gene is reduced. In a preferred embodiment the expression of a human gene that is required for adenovirus replication is reduced. Described herein is a method for treating patients infected by a yellow fever virus (YFV) or at risk for or afflicted with a disorder mediated by a YFV, e.g. respiratory tract 10 infection. In a preferred embodiment, the expression of a YFV gene is reduced. In another preferred embodiment, the preferred gene is one of a group that includes the E, NS2A, or NS3 genes. In a preferred embodiment the expression of a human gene that is required for YFV 15 replication is reduced. Methods are described herein for treating patients infected by the poliovirus or at risk for or afflicted with a disorder mediated by poliovirus, e.g., polio. In a preferred embodiment, the expression of a poliovirus gene is reduced. In a preferred embodiment the expression of a human gene that is required for poliovirus 20 replication is reduced. Methods are described herein for treating patients infected by a poxvirus or at risk for or afflicted with a disorder mediated by a poxvirus, e.g., smallpox In a preferred embodiment, the expression of a poxvirus gene is reduced. 199 In a preferred embodiment the expression of a human gene that is required for poxvirus replication is reduced. Described herein are methods of treating a subject infected with a pathogen, e.g., a bacterial, amoebic, parasitic, or fungal pathogen. The method includes: 5 providing a iRNA agent, e.g., a siRNA having a structure described herein, where siRNA is homologous to and can silence, e.g., by cleavage of a pathogen gene; administering the iRNA agent to a subject, prefereably a human subject, thereby treating the subject. The target gene can be one involved in growth, cell wall synthesis, protein synthesis, 10 transcription, energy metabolism, e.g., the Krebs cycle, or toxin production. Described herein is a method of treating patients infected by a plasmodium that causes matana. In a preferred embodiment, the expression of a plasmodium gene is reduced. In another preferred embodiment, the gene is apical membrane antigen 1 (AMA1). 15 In a preferred embodiment the expression of a human gene that is required for plasmodium replication is reduced. Described herein are methods for treating patients infected by the Mycobacterium ulcerans, or a disease or disorder associated with this pathogen, e.g. Buruli ulcers. In a preferred embodiment, the expression of a Mycobacterium ulcerans gene is reduced. 20 In a preferred embodiment the expression of a human gene that is required for Mycobacterium ulcerans replication is reduced. Described herein are methods for treating patients infected by the Mycobacterium tuberculosis, or d uisease or aisoruer associated with this pathogen, e.g. tuberculosis. 200 In a preferred embodiment, the expression of a Mycobacterium tuberculosis gene is reduced. In a preferred embodiment the expression of a human gene that is required for Mycobacterium tuberculosis replication is reduced. 5 Described herein are methods for treating patients infected by the Mycobacterium leprae, or a disease or disorder associated with this pathogen, e.g. leprosy. In a preferred embodiment, the expression of a Mycobacterium leprae gene is reduced. In a preferred embodiment the expression of a human gene that is required for Mycobacterium leprae replication is reduced. 10 Described herein are methods for treating patients infected by the bacteria Staphylococcus aureus, or a disease or disorder associated with this pathogen, e.g. infections of the skin and muscous membranes. . In a preferred embodiment, the expression of a Staphylococcus aureus gene is reduced. In a preferred embodiment the expression of a human gene that is required for 15 Staphylococcus aureus replication is reduced. Described herein are methods for treating patients infected by the bacteria Streptococcus pneumoniae, or a disease or disorder associated with this pathogen, e.g. pneumonia or childhood lower respiratory tract infection. In a preferred embodiment, the expression of a Streptococcus pneumoniae gene is 20 reduced. In a preferred embodiment the expression of a human gene that is required for Streptococcus pneumoniae replication is reduced. Described herein are n ethods for treating patients infected by the bacteria Streptococcus pyogenes, or a disease or disorder associated with this pathogen, e.g. Strep throat 25 or Scarlet fever. 201 In a preferred embodiment, the expression of a Streptococcus pyogenes gene is reduced. In a preferred embodiment the expression of a human gene that is required for Streptococcus pyogenes replication is reduced. Described herein are methods for treating patients infected by the bacteria 5 Chlamydia pneumoniae, or a disease or disorder associated with this pathogen, e.g. pneumonia or childhood lower respiratory tract infection In a preferred embodiment, the expression of a Chlamydia pneumoniae gene is reduced. In a preferred embodiment the expression of a human gene that is required for Chlamydia pneumoniae replication is reduced. 10 Described herein are methods for treating patients infected by the bacteria Mycoplasma pneumoniae, or a disease or disorder associated with this pathogen, e.g. pneumonia or childhood lower respiratory tract infection In a preferred embodiment, the expression of a Mycoplasma pneumoniae gene is reduced. In a preferred embodiment the expression of a human gene that is required for 15 Mycoplasma pneumoniae replication is reduced. The loss of heterozygosity (LOH) can result in hemizygosity for sequence, e.g., genes, in the area of LOH. This can result in a significant genetic difference between normal and disease state cells, e.g., cancer cells, and provides a useful difference between normal and disease-state cells, e.g., cancer cells. This difference can arise because a gene or other sequence is 20 heterozygous in euploid cells but is hemizygous in cells having LOH. The regions of LOH will often include a gene, the loss of which promotes unwanted proliferation, e.g., a tumor suppressor gene, and other sequences including, e.g., other genes, in some cases a gene which is essential for normal function, e.g., growth. Methods described herein rely, in part, on the specific cleavage or silencing of one allele of an essential gene with an iRNA agent of the invention. The iRNA 25 agent is selected such that it targets the single allele of the essential gene found in the cells having LOH but does not silence the other allele, which is present in cells which do not show LOH. In essence, it discriminates between the two alleles, preferentially silencing the selected 202 allele. In essence polymorphisms, e.g., SNPs of essential genes that are affected by LOH, are used as a target for a disorder characterized by cells having LOH, e.g., cancer cells having LOH. E.g., one of ordinary skill in the art can identify essential genes which are in proximity to tumor suppressor genes, and which are within a LOH region which includes the tumor 5 suppressor gene. The gene encoding the large subunit of human RNA polymerase H, POLR2A, a gene located in close proximity to the tumor suppressor gene p53, is such a gene. It frequently occurs within a region of LOH in cancer cells. Other genes that occur within LOH regions and are lost in many cancer cell types include the group comprising replication protein A 70-kDa subunit, replication protein A 32-kD, ribonucleotide reductase, thymidilate synthase, TATA 1o associated factor 2H, ribosomal protein S 14, eukaryotic initiation factor 5A, alanyl tRNA synthetase, cysteinyl tRNA synthetase, NaK ATPase, alpha-1 subunit, and transferrin receptor. Accordingly, described herein is , a method of treating a disorder characterized by LOH, e.g., cancer. The method includes: optionally, determining the genotype of the allele of a gene in the region of LOH and 15 preferably determining the genotype of both alleles of the gene in a normal cell; providing an iRNA agent which preferentially cleaves or silences the allele found in the LOH cells; administerning the iRNA to the subject, thereby treating the disorder. 20 Also described herein is a iRNA agent disclosed herein, e.g, an iRNA agent which can preferentially silence, e.g., cleave, one allele of a polymorphic gene Also described herein is a method of cleaving or silencing more than one gene with an iRNA agent. In these embodiments the iRNA agent is selected so that it has sufficient homology to a sequence found in more than one gene. For example, the sequence 25 AAGC1GGCCCTGGACATGGAGAT (SEQ ID NO:6719) is conserved between mouse lamin B1, lamin B2, keratin complex 2-gene 1 and lamin A/C. Thus an iRNA agent targeted to this sequence would effectively silence the entire collection of genes. 203 Also described herein is an iRNA agent disclosed herein, which can silence more than one gene. ROUTE OF DELIVERY For ease of exposition the formulations, compositions and methods in this section are 5 discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents. A composition that includes a iRNA can be delivered to a subject by a variety of routes. Exemplary routes include: intravenous, topical, rectal, anal, vaginal, nasal, pulmonary, ocular. 10 The iRNA molecules described herein can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically include one or more species of iRNA and a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and 15 the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. The pharmaceutical compositions described herein may be administered in a 20 number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic, vaginal, rectal, intranasal, transdermal), oral or parenteral. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, or intrathecal or intraventricular administration. 25 The route and site of administration may be chosen to enhance targeting. For example, to target muscle cells, intramuscular injection into the muscles of interest would be a logical choice. Lung cells might be targeted by administering the iRNA in aerosol form. The vascular 204 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 endothelial cells could be targeted by coating a balloon catheter with the iRNA and mechanically introducing the DNA. Formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional 5 pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Compositions for oral administration include powders or granules, suspensions or solutions in water, syrups, elixirs or non-aqueous media, tablets, capsules, lozenges, or troches. In the case of tablets, carriers that can be used include lactose, sodium citrate and salts of 10 phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the nucleic acid compositions can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents 15 can be added. Compositions for intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Formulations for parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Intraventricular injection may be 20 facilitated by an intraventricular catheter, for example, attached to a reservoir. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl 25 methylcellulose or poly(vinyl alcohol), preservatives such as sorbic acid, EDTA or benzylchronium chloride, and the usual quantities of diluents and/or carriers. 205 Topical Delivery For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., 5 modified iRNA agents. /In a preferred embodiment, an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) is delivered to a subject via topical administration. "Topical administration" refers to the delivery to a subject by 10 contacting the formulation directly to a surface of the subject. The most common form of topical delivery is to the skin, but a composition disclosed herein can also be directly applied to other surfaces of the body, e.g., to the eye, a mucous membrane, to surfaces of a body cavity or to an internal surface. As mentioned above, the most common topical delivery is to the skin. The term encompasses several routes of administration including, but not limited to, topical and 15 transdermal. These modes of administration typically include penetration of the skin's permeability barrier and efficient delivery to the target tissue or stratum. Topical administration can be used as a means to penetrate the epidermis and dermis and ultimately achieve systemic delivery of the composition. Topical administration can also be used as a means to selectively deliver oligonucleotides to the epidermis or dermis of a subject, or to specific strata thereof, or to 20 an underlying tissue. The term "skin," as used herein, refers to the epidermis and/or dermis of an animal. Mammalian skin consists of two major, distinct layers. The outer layer of the skin is called the epidermis. The epidermis is comprised of the stratum comeum, the stratum granulosum, the stratum spinosum, and the stratum basale, with the stratum comeum being at the surface of the 25 skin and the stratum basale being the deepest portion of the epidermis. The epidermis is between 50 pm and 0.2 mm thick, depending on its location on the body. Beneath the epidermis is the dermis, which is significantly thicker than the epidermis. The dermis is primarily composed of collagen in the form of fibrous bundles. The collagenous 206 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 bundles provide support for, inter alia, blood vessels, lymph capillaries, glands, nerve endings and immunologically active cells. One of the major functions of the skin as an organ is to regulate the entry of substances into the body. The principal permeability barrier of the skin is provided by the stratum comeum, 5 which is formed from many layers of cells in various states of differentiation. The spaces between cells in the stratum corneum is filled with different lipids arranged in lattice-like formations that provide seals to further enhance the skins permeability barrier. The permeability barrier provided by the skin is such that it is largely impermeable to molecules having molecular weight greater than about 750 Da. For larger molecules to cross the 10 skin's permeability barrier, mechanisms other than normal osmosis must be used. Several factors determine the permeability of the skin to administered agents. These factors include the characteristics of the treated skin, the characteristics of the delivery agent, interactions between both the drug and delivery agent and the drug and skin, the dosage of the drug applied, the form of treatment, and the post treatment regimen. To selectively target the 15 epidermis and dermis, it is sometimes possible to formulate a composition that comprises one or more penetration enhancers that will enable penetration of the drug to a preselected stratum. Transdermal delivery is a valuable route for the administration of lipid soluble therapeutics. The dermis is more permeable than the epidermis and therefore absorption is much more rapid through abraded, burned or denuded skin. Inflammation and other physiologic 20 conditions that increase blood flow to the skin also enhance transdermal adsorption. Absorption via this route may be enhanced by the use of an oily vehicle (inunction) or through the use of one or more penetration enhancers. Other effective ways to deliver a composition disclosed herein via the transdermal route include hydration of the skin and the use of controlled release topical patches. The transdermal route provides a potentially effective means to deliver a composition 25 disclosed herein for systemic and/or local therapy. In addition, iontophoresis (transfer of ionic solutes through biological membranes under the influence of an electric field) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 163), phonophoresis or sonophoresis (use of ultrasound to enhance the 207 absorption of various therapeutic agents across biological membranes, notably the skin and the cornea) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 166), and optimization of vehicle characteristics relative to dose position and retention at the site of administration (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 168) 5 may be useful methods for enhancing the transport of topically applied compositions across skin and mucosal sites. The compositions and methods provided may also be used to examine the function of various proteins and genes in vitro in cultured or preserved dermal tissues and in animals. The methods described herein 10 can also be used therapeutically or prophylactically. For example, for the treatment of animals that are known or suspected to suffer from diseases such as psoriasis, lichen planus, toxic epidermal necrolysis, ertythema multiforme, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Paget's disease, Kaposi's sarcoma, pulmonary fibrosis, Lyme disease and viral, fungal and bacterial infections of the skin. 15 Pulmonary Delivery For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents, A composition that includes an 20 iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) can be administered to a subject by pulmonary delivery. Pulmonary delivery compositions can be delivered by inhalation by the patient of a dispersion so that the composition, preferably iRNA, 25 within the dispersion can reach the lung where it can be readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs. Pulmonary delivery can be achieved by different approaches, including the use of nebulized, aerosolized, micellular and dry powder-based formulations. Delivery can be achieved 208 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 with liquid nebulizers, aerosol-based inhalers, and dry powder dispersion devices. Metered-dose devices are preferred. One of the benefits of using an atomizer or inhaler is that the potential for contamination is minimized because the devices are self contained. Dry powder dispersion devices, for example, deliver drugs that may be readily formulated as dry powders. A iRNA 5 composition may be stably stored as lyophilized or spray-dried powders by itself or in combination with suitable powder carriers. The delivery of a composition for inhalation can be mediated by a dosing timing element which can include a timer, a dose counter, time measuring device, or a time indicator which when incorporated into the device enables dose tracking, compliance monitoring, and/or dose triggering to a patient during administration of the aerosol 10 medicament. The term "powder" means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli. Thus, the powder is said to be "respirable." Preferably the average particle size is 15 less than about 10 ym in diameter preferably with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 ym and most preferably less than about 5.0 tm. Usually the particle size distribution is between about 0.1 /m and about 5 tm in diameter, particularly about 0.3 Am to about 5 Am. The term "dry" means that the composition has a moisture content below about 10% by 20 weight (% w) water, usually below about 5% w and preferably less it than about 3% w. A dry composition can be such that the particles are readily dispersible in an inhalation device to form an aerosol. The term "therapeutically effective amount" is the amount present in the composition that is needed to provide the desired level of drug in the subject to be treated to give the anticipated 25 physiological response. The term "physiologically effective amount" is that amount delivered to a subject to give the desired palliative or curative effect. 209 The term "pharmaceutically acceptable carrier" means that the carrier can be taken into the lungs with no significant adverse toxicological effects on the lungs. The types of pharmaceutical excipients that are useful as carrier include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and 5 polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two. Bulking agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids or combinations thereof. Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as 10 lactose, trehalose, and the like; cyclodextrins, such as 2 -hydroxypropyl-.beta.-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like. A preferred group of carbohydrates includes lactose, threhalose, raffinose maltodextrins, and mannitol. Suitable polypeptides include aspartame. Amino acids include alanine and glycine, with glycine being preferred. 15 Additives, which are minor components of the composition described herein, may be included for conformational stability during spray drying and for improving dispersibility of the powder. These additives include hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine, and the like. Suitable pH adjusters or buffers include organic salts prepared from organic acids and 20 bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred. Pulmonary administration of a micellar iRNA formulation may be achieved through metered dose spray devices with propellants such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other non-CFC and CFC propellants. 25 Oral or Nasal Delivery For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, 210 that these formulations, compositions and methods can be practiced with other iRNA agents, e.g., modified iRNA agents, Both the oral and nasal membranes offer advantages over other routes of administration. For example, drugs administered through these membranes have a rapid onset of action, provide therapeutic plasma 5 levels, avoid first pass effect of hepatic metabolism, and avoid exposure of the drug to the hostile gastrointestinal (GI) environment. Additional advantages include easy access to the membrane sites so that the drug can be applied, localized and removed easily. In oral delivery, compositions can be targeted to a surface of the oral cavity, e.g., to sublingual mucosa which includes the membrane of ventral surface of the tongue and the floor of 10 the mouth or the buccal mucosa which constitutes the lining of the cheek. The sublingual mucosa is relatively permeable thus giving rapid absorption and acceptable bioavailability of many drugs. Further, the sublingual mucosa is convenient, acceptable and easily accessible. The ability of molecules to permeate through the oral mucosa appears to be related to molecular size, lipid solubility and peptide protein ionization. Small molecules, less than 1000 15 daltons appear to cross mucosa rapidly. As molecular size increases, the permeability decreases rapidly. Lipid soluble compounds are more permeable than non-lipid soluble molecules. Maximum absorption occurs when molecules are un-ionized or neutral in electrical charges. Therefore charged molecules present the biggest challenges to absorption through the oral mucosae. 20 A pharmaceutical composition of iRNA may also be administered to the buccal cavity of a human being by spraying into the cavity, without inhalation, from a metered dose spray dispenser, a mixed micellar pharmaceutical formulation as described above and a propellant. In one embodiment, the dispenser is first shaken prior to spraying the pharmaceutical formulation and propellant into the buccal cavity. 25 Devices For ease of exposition the devices, formulations, compositions and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, that these devices, formulations, compositions and methods can be practiced with other 211 iRNA agents, e.g., modified iRNA agents. An iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) can be disposed on or in a 5 device, e.g., a device which implanted or otherwise placed in a subject. Exemplary devices include devices which are introduced into the vasculature, e.g., devices inserted into the lumen of a vascular tissue, or which devices themselves form a part of the vasculature, including stents, catheters, heart valves, and other vascular devices. These devices, e.g., catheters or stents, can be placed in the vasculature of the lung, heart, or leg. 10 Other devices include non-vascular devices, e.g., devices implanted in the peritoneum, or in organ or glandular tissue, e.g., artificial organs. The device can release a therapeutic substance in addition to a iRNA, e.g., a device can release insulin. Other devices include artificial joints, e.g., hip joints, and other orthopedic implants. In one embodiment, unit doses or measured doses of a composition that includes iRNA 15 are dispensed by an implanted device. The device can include a sensor that monitors a parameter within a subject. For example, the device can include pump, e.g., and, optionally, associated electronics. Tissue, e.g., cells or organs, such as the liver, can be treated with an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which 20 can be processed into a sRNA agent, or a DNA which encodes an iRNA agent; e.g., a double stranded iRNA agent, or sRNA agent, or precursor thereof) ex vivo and then administered or implanted in a subject. The tissue can be autologous, allogeneic, or xenogeneic tissue. For example, tissue (e.g., liver) can be treated to reduce graft v. host disease. In other embodiments, the tissue is 25 allogeneic and the tissue is treated to treat a disorder characterized by unwanted gene expression in that tissue, such as in the liver. In another example, tissue containing hematopoietic cells, e.g., bone marrow hematopoietic cells, can be treated to inhibit unwanted cell proliferation. 212 Introduction of treated tissue, whether autologous or transplant, can be combined with other therapies. In some implementations, the iRNA treated cells are insulated from other cells, e.g., by a semi-permeable porous barrier that prevents the cells from leaving the implant, but enables 5 molecules from the body to reach the cells and molecules produced by the cells to enter the body. In one embodiment, the porous barrier is formed from alginate. In one embodiment, a contraceptive device is coated with or contains an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a 10 double-stranded iRNA agent, or sRNA agent, or precursor thereof). Exemplary devices include condoms, diaphragms, IUD (implantable uterine devices, sponges, vaginal sheaths, and birth control devices. In one embodiment, the iRNA is chosen to inactive sperm or egg. In another embodiment, the iRNA is chosen to be complementary to a viral or pathogen RNA, e.g., an RNA of an STD. In some instances, the iRNA composition can include a spermicide. 15 DOSAGE Described herein is -a method of administering an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, to a subject (e.g., a human subject). The method includes administering a unit dose of the iRNA agent, e.g., a sRNA agent, e.g., double stranded sRNA agent that (a) the double-stranded part is 19-25 nucleotides (nt) long, preferably 21-23 nt, 20 (b) is complementary to a target RNA (e.g., an endogenous or pathogen target RNA), and, optionally, (c) includes at least one 3' overhang 1-5 nucleotide long. In one embodiment, the unit dose is less than 1.4 mg per kg of bodyweight, or less than 10, 5, 2, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005 or 0.00001 mg per kg of bodyweight, and less than 200 mole of RNA agent (e.g. about 4.4 x 1016 copies) per kg of bodyweight, or less than 1500, 750, 300, 150, 25 75, 15, 7.5, 1.5, 0.75, 0.15, 0.075, 0.015, 0.0075, 0.0015, 0.00075, 0.00015 nmole of RNA agent per kg of bodyweight. The defined amount can be an amount effective to treat or prevent a disease or disorder, e.g., a disease or disorder associated with the target RNA, such as an RNA present in the liver. 213 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 The unit dose, for example, can be administered by injection (e.g., intravenous or intramuscular), an inhaled dose, or a topical application. Particularly preferred dosages are less than 2, 1, or 0.1 mg/kg of body weight. In a preferred embodiment, the unit dose is administered less frequently than once a day, 5 e.g., less than every 2, 4, 8 or 30 days. In another embodiment, the unit dose is not administered with a frequency (e.g., not a regular frequency). For example, the unit dose may be administered a single time. In one embodiment, the effective dose is administered with other traditional therapeutic modalities. In one embodiment, the subject has a viral infection and the modality is an antiviral 10 agent other than an iRNA agent, e.g., other than a double-stranded iRNA agent, or sRNA agent,. In another embodiment, the subject has atherosclerosis and the effective dose of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, is administered in combination with, e.g., after surgical intervention, e.g., angioplasty. In one embodiment, a subject is administered an initial dose and one or more 15 maintenance doses of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof). The maintenance dose or doses are generally lower than the initial dose, e.g., one-half less of the initial dose. A maintenance regimen can include treating the subject with a dose or 20 doses ranging from 0.01 pg to 1.4 mg/kg of body weight per day, e.g., 10, 1, 0.1, 0.01, 0.001, or 0.00001 mg per kg of bodyweight per day. The maintenance doses are preferably administered no more than once every 5, 10, or 30 days. Further, the treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease, its severity and the overall condition of the patient. In preferred embodiments the dosage may be delivered no more 25 than once per day, e.g., no more than once per 24, 36, 48, or more hours, e.g., no more than once for every 5 or 8 days. Following treatment, the patient can be monitored for changes in his condition and for alleviation of the symptoms of the disease state. The dosage of the compound may either be increased in the event the patient does not respond significantly to current dosage 214 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 .levels, or the dose may be decreased if an alleviation of the symptoms of the disease state is observed, if the disease state has been ablated, or if undesired side-effects are observed. The effective dose can be administered in a single dose or in two or more doses, as desired or considered appropriate under the specific circumstances. If desired to facilitate 5 repeated or frequent infusions, implantation of a delivery device, e.g., a pump, semi-permanent stent (e.g., intravenous, intraperitoneal, intracisternal or intracapsular), or reservoir may be advisable. In one embodiment, the iRNA agent pharmaceutical composition includes a plurality of iRNA agent species. In another embodiment, the iRNA agent species has sequences that are 10 non-overlapping and non-adjacent to another species with respect to a naturally occurring target sequence. In another embodiment, the plurality of iRNA agent species is specific for different naturally occurring target genes. In another embodiment, the iRNA agent is allele specific. In some cases, a patient is treated with a iRNA agent in conjunction with other therapeutic modalities. For example, a patient being treated for a liver disease can be 15 administered an iRNA agent specific for a target gene known to enhance the progression of the disease in conjunction with a drug known to inhibit activity of the target gene product. For example, a patient being treated for a cancer of the liver can be administered an iRNA agent specific for a target essential for tumor cell proliferation in conjunction with a chemotherapy. Following successful treatment, it may be desirable to have the patient undergo 20 maintenance therapy to prevent the recurrence of the disease state, wherein the compound of the invention is administered in maintenance doses, ranging from 0.01 pg to 100 g per kg of body weight (see US 6,107,094). The concentration of the iRNA agent composition is an amount sufficient to be effective in treating or preventing a disorder or to regulate a physiological condition in humans. The 25 concentration or amount of iRNA agent administered will depend on the parameters determined for the agent and the method of administration, e.g. nasal, buccal, pulmonary. For example, nasal formulations tend to require much lower concentrations of some ingredients in order to 215 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 avoid irritation or burning of the nasal passages. It is sometimes desirable to dilute an oral formulation up to 10-100 times in order to provide a suitable nasal formulation. Certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health 5 and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) can include a single treatment or, preferably, can include a series of 10 treatments. It will also be appreciated that the effective dosage of a iRNA agent such as a sRNA agent used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays as described herein. For example, the subject can be monitored after administering a iRNA agent composition. Based on information from the monitoring, an additional amount of the iRNA 15 agent composition can be administered. Dosing is dependent on severity and responsiveness of the disease condition to be treated,. with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can 20 easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual compounds, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In some embodiments, the animal models include transgenic animals that express a human gene, e.g. a gene that produces a target RNA. The transgenic animal can be deficient for the corresponding 25 endogenous RNA. In another embodiment, the composition for testing includes a iRNA agent that is complementary, at least in an internal region, to a sequence that is conserved between the target RNA in the animal model and the target RNA in a human. 216 The inventors have discovered that iRNA agents described herein can be administered to mammals, particularly large mammals such as nonhuman primates or humans in a number of 4 ways. In one embodiment, the administration of the iRNA agent, e.g., a double-stranded iRNA 5 agent, or sRNA agent, composition is parenteral, e.g. intravenous (e.g., as a bolus or as a diffusible infusion), intradermal, intraperitoneal, intramuscular, intrathecal, intraventricular, intracranial, subcutaneous, transmucosal, buccal, sublingual, endoscopic, rectal, oral, vaginal, topical, pulmonary, intranasal, urethral or ocular. Administration can be provided by the subject or by another person, e.g., a health care provider. The medication can be provided in 10 measured doses or in a dispenser which delivers a metered dose. Selected modes of delivery are discussed in more detail below. Described herein are methods, compositions, and kits, for rectal administration or delivery of iRNA agents described herein. Accordingly, an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., 15 a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes a an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) described herein, e.g., a therapeutically effective amount of a iRNA agent described herein, e.g., a iRNA agent having a double stranded region of less than 40, and preferably less than 30 nucleotides and having one or two 1-3 nucleotide single strand 3' 20 overhangs can be administered rectally, e.g., introduced through the rectum into the lower or upper colon. This approach is particularly useful in the treatment of, inflammatory disorders, disorders characterized by unwanted cell proliferation, e.g., polyps, or colon cancer. The medication can be delivered to a site in the colon by introducing a dispensing device, e.g., a flexible, camera-guided device similar to that used for inspection of the colon or removal 25 of polyps, which includes means for delivery of the medication. The rectal administration of the iRNA agent is by means of an enema. The iRNA agent of the enema can be dissolved in a saline or buffered solution. The rectal administration can also 217 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 by means of a suppository, which can include other ingredients, e.g., an excipient, e.g., cocoa butter or hydropropylmethylcellulose. Any of the iRNA agents described herein can be administered orally, e.g., in the form of tablets, capsules, gel capsules, lozenges, troches or liquid syrups. Further, the composition can 5 be applied topically to a surface of the oral cavity. Any of the iRNA agents described herein can be administered buccally. For example, the medication can be sprayed into the buccal cavity or applied directly, e.g., in a liquid, solid, or gel form to a surface in the buccal cavity. This administration is particularly desirable for the treatment of inflammations of the buccal cavity, e.g., the gums or tongue, e.g., in one 10 embodiment, the buccal administration is by spraying into the cavity, e.g., without inhalation, from a dispenser, e.g., a metered dose spray dispenser that dispenses the pharmaceutical composition and a propellant. Any of the iRNA agents described herein can be administered to ocular tissue. For example, the medications can be applied to the surface of the eye or nearby tissue, e.g., the inside 15 of the eyelid. They can be applied topically, e.g., by spraying, in drops, as an eyewash, or an ointment. Administration can be provided by the subject or by another person, e.g., a health care provider. The medication can be provided in measured doses or in a dispenser which delivers a metered dose. The medication can also be administered to the interior of the eye, and can be introduced by a needle or other delivery device which can introduce it to a selected area or 20 structure. Ocular treatment is particularly desirable for treating inflammation of the eye or nearby tissue. Any of the iRNA agents described herein can be administered directly to the skin. For example, the medication can be applied topically or delivered in a layer of the skin, e.g., by the use of a microneedle or a battery of microneedles which penetrate into the skin, but preferably 25 not into the underlying muscle tissue. Administration of the iRNA agent composition can be topical. Topical applications can, for example, deliver the composition to the dermis or epidermis of a subject. Topical administration can be in the form of transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids or powders. A composition for topical administration can be formulated as a liposome, micelle, emulsion, or other lipophilic 218 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 molecular assembly. The transdermal administration can be applied with at least one penetration enhancer, such as iontophoresis, phonophoresis, and sonophoresis. Any of the iRNA agents described herein can be administered to the pulmonary system. Pulmonary administration can be achieved by inhalation or by the introduction of a delivery 5 device into the puhnonary system, e.g., by introducing a delivery device which can dispense the medication. A preferred method of pulmonary delivery is by inhalation. The medication can be provided in a dispenser which delivers the medication, e.g., wet or dry, in a form sufficiently small such that it can be inhaled. The device can deliver a metered dose of medication. The subject, or another person, can administer the medication. 10 Pulmonary delivery is effective not only for disorders which directly affect pulmonary tissue, but also for disorders which affect other tissue. iRNA agents can be formulated as a liquid or nonliquid, e.g., a powder, crystal, or aerosol for pulmonary delivery. Any of the iRNA agents described herein can be administered nasally. Nasal 15 administration can be achieved by introduction of a delivery device into the nose, e.g., by introducing a delivery device which can dispense the medication. Methods of nasal delivery include spray, aerosol, liquid, e.g., by drops, or by topical administration to a surface of the nasal cavity. The medication can be provided in a dispenser with delivery of the medication, e.g., wet or dry, in a form sufficiently small such that it can be inhaled. The device can deliver a metered 20 dose of medication. The subject, or another person, can administer the medication. Nasal delivery is effective not only for disorders which directly affect nasal tissue, but also for disorders which affect other tissue iRNA agents can be formulated as a liquid or nonliquid, e.g., a powder, crystal, or for nasal delivery. 25 An iRNA agent can be packaged in a viral natural capsid or in a chemically or enzymatically produced artificial capsid or structure derived therefrom. 219 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 The dosage of a pharmaceutical composition including a iRNA agent can be administered in order to alleviate the symptoms of a disease state, e.g., cancer or a cardiovascular disease. A subject can be treated with the pharmaceutical composition by any of the methods mentioned above. 5 Gene expression in a subject can be modulated by administering a pharmaceutical composition including an iRNA agent. A subject can be treated by administering a defined amount of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent) composition that is in a powdered form, e.g., a collection of 10 microparticles, such as crystalline particles. The composition can include a plurality of iRNA agents, e.g., specific for one or more different endogenous target RNAs. The method can include other features described herein. A subject can be treated by administering a defined amount of an iRNA agent composition that is prepared by a method that includes spray-drying, i.e. atomizing a liquid 15 solution, emulsion, or suspension, immediately exposing the droplets to a drying gas, and collecting the resulting porous powder particles. The composition can include a plurality of iRNA agents, e.g., specific for one or more different endogenous target RNAs. The method can include other features described herein. The iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, 20 e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof), can be provided in a powdered, crystallized or other finely divided form, with or without a carrier, e.g., a micro- or nano-particle suitable for inhalation or other pulmonary delivery. This can include providing an aerosol preparation, e.g., an aerosolized spray-dried composition. The aerosol 25 composition can be provided in and/or dispensed by a metered dose delivery device. The subject can be treated for a condition treatable by inhalation, e.g., by aerosolizing a spray-dried iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes 220 an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) composition and inhaling the aerosolized composition. The iRNA agent can be an sRNA. The composition can include a plurality of iRNA agents, e.g., specific for one or more different endogenous target RNAs. The method can include other features described herein. 5 A subject can be treated by, for example, administering a composition including an effective/defined amount of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof), wherein the composition is prepared by a method that includes spray-drying, 10 lyophilization, vacuum drying, evaporation, fluid bed drying, or a combination of these techniques Described herein is a method that includes: evaluating a parameter related to the abundance of a transcript in a cell of a subject; comparing the evaluated parameter to a reference value; and if the evaluated parameter has a preselected relationship to the reference 15 value (e.g., it is greater), administering a iRNA agent (or a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes a iRNA agent or precursor thereof) to the subject. In one embodiment, the iRNA agent includes a sequence that is ' complementary to the evaluated transcript. For example, the parameter can be a direct measure of transcript levels, a measure of a protein level, a disease or disorder symptom or 20 characterization (e.g., rate of cell proliferation and/or tumor mass, viral load). Described herein is a method that includes: administering a first amount of a composition that comprises an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA 25 agent, or precursor thereof) to a subject, wherein the iRNA agent includes a strand substantially complementary to a target nucleic acid; evaluating an activity associated with a protein encoded by the target nucleic acid; wherein the evaluation is used to determine if a second amount should be administered. In a preferred embodiment the method includes administering a second amount 221 of the composition, wherein the timing of administration or dosage of the second amount is a function of the evaluating. The method can include other features described herein. Described herein is a method of administering a source of double stranded iRNA agent (ds iRNA agent) to a subject. The method includes administering or 5 implanting a source of a ds iRNA agent, e.g., a sRNA agent, that (a) includes a double-stranded region that is 19-25 nucleotides long, preferably 21-23 nucleotides, (b) is complementary to a target RNA (e.g., an endogenous RNA or a pathogen RNA), and, optionally, (c) includes at least one 3' overhang 1-5 nt long. In one embodiment, the source releases ds iRNA agent over time, e.g. the source is a controlled or a slow release source, e.g., a microparticle that gradually 10 releases the ds iRNA agent. In another embodiment, the source is a pump, e.g., a pump that includes a sensor or a pump that can release one or more unit doses. Described herein is a pharmaceutical compositions that includes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., 15 a double-stranded iRNA agent, or sRNA agent, or precursor thereof) including a nucleotide sequence complementary to a target RNA, e.g., substantially and/or exactly complementary. The target RNA can be a transcript of an endogenous human gene. In one embodiment, the iRNA agent (a) is 19-25 nucleotides long, preferably 21-23 nucleotides, (b) is complementary to an endogenous target RNA, and, optionally, (c) includes at least one 3' overhang 1-5 nt long. In one 20 embodiment, the pharmaceutical composition can be an emulsion, microemulsion, cream, jelly, or liposome. In one example the pharmaceutical composition includes an iRNA agent mixed with a topical delivery agent. The topical delivery agent can be a plurality of microscopic vesicles. The microscopic vesicles can be liposomes. In a preferred embodiment the liposomes are cationic 25 liposomes. In one embodiment, the pharmaceutical composition includes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double stranded iRNA agent, or sRNA agent, or precursor thereof) admixed with a topical penetration 222 enhancer. In one embodiment, the topical penetration enhancer is a fatty acid. The fatty acid can be arachidonic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monolein, dilaurin, glyceryl 1 monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1 .Io alkyl 5 ester, monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. In another embodiment, the topical penetration enhancer is a bile salt. The bile salt can be cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate, sodium glycodihydrofusidate, 10 polyoxyethylene-9-lauryl ether or a pharmaceutically acceptable salt thereof. In another embodiment, the penetration enhancer is a chelating agent. The chelating agent can be EDTA, citric acid, a salicyclate, a N-acyl derivative of collagen, laureth-9, an N amino acyl derivative of a beta-diketone or a mixture thereof. In another embodiment, the penetration enhancer is a surfactant, e.g., an ionic or nonionic 15 surfactant. The surfactant can be sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, a perfluorchemical emulsion or mixture thereof. In another embodiment, the penetration enhancer can be selected from a group consisting of unsaturated cyclic ureas, 1 -alkyl-alkones, 1-alkenylazacyclo-alakanones, steroidal anti inflammatory agents and mixtures thereof. In yet another embodiment the penetration enhancer 20 can be a glycol, a pyrrol, an azone, or a terpenes. Described herein is a pharmaceutical composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in a form suitable for oral 25 delivery. In one embodiment, oral delivery can be used to deliver an iRNA agent composition to a cell or a region of the gastro-intestinal tract, e.g., small intestine, colon (e.g., to treat a colon cancer), and so forth. The oral delivery form can be tablets, capsules or gel capsules. In one embodiment, the iRNA agent of the pharmaceutical composition modulates expression of a 223 cellular adhesion protein, modulates a rate of cellular proliferation, or has biological activity against eukaryotic pathogens or retroviruses. In another embodiment, the pharmaceutical composition includes an enteric material that substantially prevents dissolution of the tablets, capsules or gel capsules in a mammalian stomach. In a preferred embodiment the enteric 5 material is a coating. The coating can be acetate phthalate, propylene glycol, sorbitan monoleate, cellulose acetate trimellitate, hydroxy propyl methylcellulose phthalate or cellulose acetate phthalate. In another embodiment, the oral dosage form of the pharmaceutical composition includes a penetration enhancer. The penetration enhancer can be a bile salt or a fatty acid. The bile salt 10 can be ursodeoxycholic acid, chenodeoxycholic acid, and salts thereof. The fatty acid can be capric acid, lauric acid, and salts thereof. In another embodiment, the oral dosage form of the pharmaceutical composition includes an excipient. In one example the excipient is polyethyleneglycol. In another example the excipient is precirol. 15 In another embodiment, the oral dosage form of the pharmaceutical composition includes a plasticizer. The plasticizer can be diethyl phthalate, triacetin dibutyl sebacate, dibutyl phthalate or triethyl citrate. Described herein is a pharmaceutical composition including an iRNA agent and a delivery vehicle. In one embodiment, the iRNA agent is (a) is 19-25 nucleotides 20 long, preferably 21-23 nucleotides, (b) is complementary to an endogenous target RNA, and, optionally, (c) includes at least one 3' overhang 1-5 nucleotides long. In one embodiment, the delivery vehicle can deliver an iRNA agent, e.g., a double stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded 25 iRNA agent, or sRNA agent, or precursor thereof) to a cell by a topical route of administration. The delivery vehicle can be microscopic vesicles. In one example the microscopic vesicles are liposomes. In a preferred embodiment the liposomes are cationic liposomes. In another example the microscopic vesicles are micelles.In one aspect, the invention features a pharmaceutical 224 composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in an injectable dosage form. In one embodiment, the injectable dosage form of the 5 pharmaceutical composition includes sterile aqueous solutions or dispersions and sterile powders. In a preferred embodiment the sterile solution can include a diluent such as water; saline solution; fixed oils, polyethylene glycols, glycerin, or propylene glycol. Described herein is a pharmaceutical composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA 10 agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in oral dosage form. In one embodiment, the oral dosage form is selected from the group consisting of tablets, capsules and gel capsules. In another embodiment, the pharmaceutical composition includes an enteric material that substantially prevents dissolution of the tablets, capsules or gel capsules in a 15 mammalian stomach. In a preferred embodiment the enteric material is a coating. The coating can be acetate phthalate, propylene glycol, sorbitan monoleate, cellulose acetate trimellitate, hydroxy propyl methyl cellulose phthalate or cellulose acetate phthalate. In one embodiment, the oral dosage form of the pharmaceutical composition includes a penetration enhancer, e.g., a penetration enhancer. described herein. 20 Described herein is a pharmaceutical composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in a rectal dosage fonn. In one embodiment, the rectal dosage form is an enema. In another embodiment, the rectal dosage 25 form is a suppository. Described herein is a pharmaceutical composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in a vaginal dosage form. 225 In one embodiment, the vaginal dosage form is a suppository. In another embodiment, the vaginal dosage form is a foam, cream, or gel. Described herein is a pharmaceutical composition including an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA 5 agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) in a pulmonary or nasal dosage form. In one embodiment, the iRNA agent is incorporated into a particle, e.g., a macroparticle, e.g., a microsphere. The particle can be produced by spray drying, lyophilization, evaporation, fluid bed drying, vacuum drying, or a combination thereof. The microsphere can be 10 formulated as a suspension, a powder, or an implantable solid. Described herein is a spray-dried iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof) composition suitable for inhalation by a subject, 15 including: (a) a therapeutically effective amount of a iRNA agent suitable for treating a condition in the subject by inhalation; (b) a pharmaceutically acceptable excipient selected from the group consisting of carbohydrates and amino acids; and (c) optionally, a dispersibility-enhancing amount of a physiologically-acceptable, water-soluble polypeptide. In one embodiment, the excipient is a carbohydrate. The carbohydrate can be selected 20 from the group consisting of mono saccharides, disaccharides, trisaccharides, and polysaccharides. In a preferred embodiment the carbohydrate is a monosaccharide selected from the group consisting of dextrose, galactose, mannitol, D-mannose, sorbitol, and sorbose. In another preferred embodiment the carbohydrate is a disaccharide selected from the group consisting of lactose, maltose, sucrose, and trehalose. 25 In another embodiment, the excipient is an amino acid. In one embodiment, the amino acid is a hydrophobic amino acid. In a preferred embodiment the hydrophobic amino acid is selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. In yet another embodiment the amino acid is a polar amino acid. In a preferred embodiment the amino acid is selected from the group consisting of arginine, 226 histidine, lysine, cysteine, glycine, glutamine, serine, threonine, tyrosine, aspartic acid and glutamic acid. In one embodiment, the dispersibility-enhancing polypeptide is selected from the group consisting of human serum albumin, t-lactalbumin, trypsinogen, and polyalanine. 5 In one embodiment, the spray-dried iRNA agent composition includes particles having a mass median diameter (MM[D) of less than 10 microns. In another embodiment, the spray-dried iRNA agent composition includes particles having a mass median diameter of less than 5 microns. In yet another embodiment the spray-dried iRNA agent composition includes particles having a mass median aerodynamic diameter (MMAD) of less than 5 microns. 10 Described herein are kits that include a suitable container containing a pharmaceutical formulation of an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof). In certain embodiments the individual components of the 15 pharmaceutical formulation may be provided in one container. Alternatively, it may be desirable to provide the components of the pharmaceutical formulation separately in two or more containers, e.g., one container for an iRNA agent preparation, and at least another for a carrier compound. The kit may be packaged in a number of different configurations such as one or more containers in a single box. The different components can be combined, e.g., according to 20 instructions provided with the kit. The components can be combined according to a method described herein, e.g., to prepare and administer a pharmaceutical composition. The -kitcan also include a delivery device. Described herein is a device, e.g., an implantable device, wherein the device can dispense or administer a composition that includes an iRNA agent, e.g., a double 25 stranded iRNA agent, or sRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into a sRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or sRNA agent, or precursor thereof), e.g., a iRNA agent that silences an endogenous transcript. In one embodiment, the device is coated with the composition. In another embodiment the iRNA agent is disposed within the device. In another embodiment, the 227 device includes a mechanism to dispense a unit dose of the composition. In other embodiments the device releases the composition continuously, e.g., by diffusion. Exemplary devices include stents, catheters, pumps, artificial organs or organ components (e.g., artificial heart, a heart valve, etc.), and sutures. 5 As used herein, the term "crystalline" describes a solid'having the structure or characteristics of a crystal, i.e., particles of three-dimensional structure in which the plane faces intersect. at definite angles and in which there is a regular internal structure. The compositions described herein may have different crystalline forms. Crystalline forms can be prepared by a variety of methods, including, for example, spray drying. 10 The invention is further illustrated by the following examples, which should not be construed as further limiting. EXAMPLES Example 1: apoB protein as a therapeutic target for lipid-based diseases Apolipoprotein B (apoB) is a candidate target gene for the development of novel 15 therapies for lipid-based diseases. Methods described herein can be used to evaluate the efficacy of a particular siRNA as a therapeutic tool for treating lipid metabolism disorders resulting elevated apoB levels. Use of siRNA duplexes to selectively bind and inactivate the target apoB mRNA is an approach totreat these disorders. 20 Two approaches: i) Inhibition of apoB in ex-vivo models by transfecting siRNA duplexes homologous to human apoB mRNA in a human hepatoma cell line (Hep G2) and monitor the level of the protein and the RNA using the Western blotting and RT-PCR methods, respectively. siRNA molecules that efficiently inhibit apoB expression will be tested for similar effects in vivo. 25 ii) In vivo trials using an apoB transgenic mouse model (apoB 100 Transgenic Mice, C57BIJ6NTac-TgN (APOB100), Order Model #'s:1004-T (hemizygotes), B6 (control)). siRNA duplexes are designed to target apoB-100 or CETP/apoB double transgenic mice which express both cholesteryl ester transfer protein (CETP) and apoB. The effect of the siRNA on gene expression in vivo can be measured by monitoring the HDL/LDL cholesterol level in serum. The 228 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 results of these experiments would indicate the therapeutic potential of siRNAs to treat lipid based diseases, including hypercholesterolemia, HDL/LDL cholesterol imbalance, familial combined hyperlipidemia, and acquired hyperlipidemia. 5 Background Fats, in the form of triglycerides, are ideal for energy storage because they are highly reduced and anhydrous. An adipocyte (or fat cell) consists of a nucleus, a cell membrane, and triglycerides, and its function is to store triglycerides. The lipid portion of the human diet consists largely of triglycerides and cholesterol (and its esters). These must be emulsified and digested to be absorbed. Specifically, fats 10 (triacylglycerols) are ingested. Bile (bile acids, salts, and cholesterol), which is made in the liver, is secreted by the gall bladder. Pancreatic lipase digests the triglycerides to fatty acids, and also digests di-, and mono-acylglycerols, which are absorbed by intestinal epithelial cells and then are resynthesized into triacylglycerols once inside the cells. These triglycerides and some cholesterols are combined with apolipoproteins to produce chylomicrons. Chylomicrons consist 15 of approximately 95% triglycerides. The chylomicrons transport fatty acids to peripheral tissues. Any excess fat is stored in adipose tissue. Lipid transport and clearance from the blood into cells, and from the cells into the blood and the liver, is mediated by the lipoprotein transport proteins. This class of approximately 17 proteins can be divided into three groups: Apolipoproteins, lipoprotein processing proteins, and 20 lipoprotein receptors. Apolipoproteins coat lipoprotein particles, and include the A-I, A-II, A-IV, B, CI, CII, CIII, D, E, Apo(a) proteins. Lipoprotein processing proteins include lipoprotein lipase, hepatic lipase, lecithin cholesterol acyltransferase and cholesterol ester transfer protein. Lipoprotein receptors include the low density lipoprotein (LDL) receptor, chylomicron-remnant receptor (the 25 LDL receptor like protein or LDL receptor related protein - LRP) and the scavenger receptor. Lipoprotein Metabolism Since the triglycerides, cholesterol esters, and cholesterol absorbed into the small intestine are not soluble in aqueous medium, they must be combined with suitable proteins (apolipoproteins) in order to prevent them from fonning large oil droplets. The resulting 30 lipoproteins undergo a type of metabolism as they pass through the bloodstream and certain organs (notably the liver). 229 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Also synthesized in the liver is high density lipoprotein (HDL), which contains the apoproteins A-1, A-2, C-1, and D; HDL collects cholesterol from peripheral tissues and blood vessels and returns it to the liver. LDL is taken up by specific cell surface receptors into an endosome, which fuses with a lysosome where cholesterol ester is converted to free cholesterol. 5 The apoproteins (including apo B-100) are digested to amino acids. The receptor protein is recycled to the cell membrane. The free cholesterol formed by this process has two fates. First, it can move to the endoplasmic reticulum (ER), where it can inhibit HMG-CoA reductase, the synthesis of HMG CoA reductase, and the synthesis of cell surface receptors for LDL. Also in the ER, cholesterol 10 can speed up the degradation of HMG-CoA reductase. The free cholesterol can also be converted by acyl-CoA and acyl transferase (ACAT) to cholesterol esters, which form oil droplets. ApoB is the major apolipoprotein of chylomicrons of very low density lipoproteins (VLDL, which carry most of the plasma triglyceride) and low density lipoprotein (LDL, which 15 carry most of the plasma cholesterol). ApoB exists in human plasma in two isoforms, apoB-48 and apoB-100. ApoB-100 is the major physiological ligand for the LDL receptor. The ApoB precursor has 4563 amino acids, and the mature apoB-100 has 4536 amino acid residues. The LDL-binding domain of ApoB-100 is proposed to be located between residues 3129 and 3532. ApoB-100 is 20 synthesized in the liver and is required for the assembly of very low density lipoproteins VLDL and for the preparation of apoB-100 to transport triglycerides (TG) and cholesterol from the liver to other tissues. ApoB-100 does not interchange between lipoprotein particles, as do the other lipoproteins, and it is found in IDL and LDL particles. After the removal of apolipoproteins A, E and C, apoB is incorporation into VLDL by hepatocytes. ApoB-48 is present in chylomicrons 25 and plays an essential role in the intestinal absorption of dietary fats. ApoB-48 is synthesized in the small intestine. It comprises the N-terminal 48% of apoB-100 and is produced by a posttranscriptional apoB-100 mRNA editing event at codon 2153 (C to U). This editing event is a product of the apoBEC-1b enzyme, which is expressed in the intestine. This editing event creates a stop codon instead of a glutamine codon, and therefore apoB-48, instead of apoB- 100 is 30 expressed in the intestine (apoB-100 is expressed in the liver). 230 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 There is also strong evidence that plasma apoB levels may be a better index of the risk of coronary artery disease (CAD) than total or LDL cholesterol levels. Clinical studies have demonstrated the value of measuring apoB in hypertriglyceridemic, hypercholesterolemic and normalipidemic subjects. 5 231 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 Table 4. Reference Range Lipid level in the Blood Lipid Range (mmols/ L) Plasma Cholesterol 3.5-6.5 Low density lipoprotein 1.55-4.4 Very low density lipoprotein 0.128-0.645 High density lipoprotein/ triglycerides 0.5-2.1 Total lipid 4.0-10g / L Molecular genetics of lipid metabolism in both humans and induced mutant mouse models 5 Elevated plasma levels of LDL and apoB are associated with a higher risk for atherosclerosis and coronary heart disease, a leading cause of mortality. ApoB is the mandatory constituent of LDL particles. In addition to its role in lipoprotein metabolism, apoB has also been implicated as a factor in male infertility and fetal development. Furthermore, two quantitative trait loci regulating plasma apoB levels have been discovered, through the use of transgenic mouse 10 models. Future experiments will facilitate the identification of human orthologous genes encoding regulators of plasma apoB levels. These loci are candidate therapeutic targets for human disorders characterized by altered plasma apoB levels. Such disorders include non-apoB linked hypobetalipoproteinemia and familial combined hyperlipidemia. The identification of these genetic loci would also reveal possible new pathways involved in the regulation of apoB 15 secretion, potentially providing novel sites for pharmacological therapy. Diseases and Clinical Pharmacology Familial combined hyperlipemia (FCHL) affects an estimated one in 10 Americans. FCHL can cause premature heart disease. Familial Hypercholesterolemia (high level of apo B) A common genetic disorder of lipid 20 metabolism. Familial hypercholesterolemia is characterized by elevated serum TC in association with xanthelasma, tendon and tuberous xanthomas, accelerated atherosclerosis, and early death from myocardial infarction (MI). It is caused by absent or defective LDL cell receptors, resulting in delayed LDL clearance, an increase in plasma LDL levels, and an accumulation of LDL cholesterol in macrophages over joints and pressure points, and in blood vessels. 25 232 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Atherosclerosis (high level of apo B) Atherosclerosis develops as a deposition of cholesterol and fat in the arterial wall due to disturbances in lipid transport and clearance from the blood into cells and from the cells to blood and the liver. Clinical studies have demonstrated that elevation of total cholesterol (TC), low- density 5 lipoprotein cholesterol (LDL-C) and apoB-100 promote human atherosclerosis. Similarly, decreased levels of high - density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. ApoB may be a factor in the genetic cause of high cholesterol. The risk of coronary artery disease (CAD) (high level of apo B) Cardiovascular disease, 10 including coronary heart disease and stroke, is a leading cause of death and disability. The major risk factors include age, gender, elevated low-density lipoprotein cholesterol blood levels, decreased high-density lipoprotein cholesterol levels, cigarette smoking, hypertension, and diabetes. Emerging risk factors include elevated lipoprotein (a), remnant lipoproteins, and C reactive protein. Dietary intake, physical activity and genetics also impact cardiovascular risk. 15 Hypertension and age are the major risk factors for stroke. Abetalipoproteinemia, an inherited human disease characterized by a near-complete absence of apoB-containing lipoproteins in the plasma, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP). 20 Modelfor human atherosclerosis (Lipoprotein A transgenic mouse) Numerous studies have demonstrated that an elevated plasma level of lipoprotein(a) (Lp(a)) is a major independent risk factor for coronary heart disease (CHD). Current therapies, however, have little or no effect on apo(a) levels and the homology between apo(a) and plasminogen presents barriers to drug development. Lp(a) particles consist of apo(a) and apoB-100 proteins, and they are found only 25 in primates and the hedgehog. The development of LPA transgenic mouse requires the creation of animals that express both human apoB and apo(a) transgenes to achieve assembly of LP(a). An atherosclerosis mouse model would facilitate the study of the disease process and factors influencing it, and further would facilitate the development of therapeutic or preventive agents. There are several strategies for gene-oriented therapy. For example, the missing or non 30 functional gene can be replaced, or unwanted gene activity can be inhibited. 233 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO1 Modelfor lipid Metabolism and Atherosclerosis DNX Transgenic Sciences has demonstrated that both CETP/ApoB and ApoB transgenic mice develop atherosclerotic plaques. 5 Modelfor apoB-100 overexpression The apoB-100 transgenic mice express high levels of human apoB-100. They consequently demonstrate elevated serum levels of LDL cholesterol. After 6 months on a high-fat diet, the mice develop significant foam cell accumulation under the endothelium and within the media, as well as cholesterol crystals and fibrotic lesions. 10 Modelfor Cholesteryl ester transfer protein over expression The apoB-100 transgenic mice express the human enzyme, CETP, and consequently demonstrate a dramatically reduced level of serum HDL cholesterol. Modelfor apoB-100 and CETP overexpression The apoB-100 transgenic mice express both 15 CETP and apoB-100, resulting in mice with a human like serum HDL/LDL distribution. Following 6 months on a high-fat diet these mice develop significant foam cell accumulation underlying the endothelium and within the media, as well as cholesterol crystals and fibrotic lesions. 20 ApoB100 Transgenic Mice (Order Model #'s:1004-T (hemizygotes), B6 (control)) These mice express high levels of human apoB-100, resulting in mice with elevated serum levels of LDL cholesterol. These mice are useful in identifying and evaluating compounds to reduce elevated levels of LDL cholesterol and the risk of atherosclerosis. When fed a high fat cholesterol diet, these mice develop significant foam cell accumulation underly the endothelium 25 and within the media, and have significantly more complex atherosclerotic lesions than control animals. Double Transgenic Mice, CETP/ApoB100 (Order Model #: 1007-TT) These mice express both CETP and apoB-100, resulting in a human-like serum HDL/LDL distribution. These mice are 30 useful for evaluating compounds to treat hypercholesterolemia or HDL/LDL cholesterol imbalance to reduce the risk of developing atherosclerosis. When fed a high fat high cholesterol 234 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 diet, these mice develop significant foam cell accumulation underlying the endothelium and within the media, and have significantly more complex atherosclerotic lesions than control animals. 5 ApoE gene knockout mouse Homozygous apoE knockout mice exhibit strong hypercholesterolemia, primarily due to elevated levels of VLDL and IDL caused by a defect in lipoprotein clearance from plasma. These mice develop atherosclerotic lesions which progress with age and resemble human lesions (Zhang et al., Science 258:46-71, 1992; Plump et al., Cell 71:343-353, 1992; Nakashima et al., Arterioscler Thromp. 14:133-140, 1994; Reddick et al., 10 Arterioscler Tromb. 14:141-147, 1994). These mice are a promising model for studying the effect of diet and drugs on atherosclerosis. Low density lipoprotein receptor (LDLR) mediates lipoprotein clearance from plasma through the recognition of apoB and apoE on the surface of lipoprotein particles. Humans, who lack or have a decreased number of the LDL receptors, have familial hypercholesterolemia and 15 develop CHD at an early age. ApoE Knockout Mice (Order Model #: APOE-M) The apoE knockout mouse was created by gene targeting in embryonic stem cells to disrupt the apoE gene. ApoE, a glycoprotein, is a structural component of very low density lipoprotein (VLDL) synthesized by the liver and 20 intestinally synthesized chylomicrons. It is also a constituent of a subclass of high density lipoproteins (HDLs) involved in cholesterol transport activity among cells. One of the most important roles of apoE is to mediate high affinity binding of chylomicrons and VLDL particles that contain apoE to the low density lipoprotein (LDL) receptor. This allows for the specific uptake of these particles by the liver which is necessary for transport preventing the 25 accumulation in plasma of cholesterol-rich remnants. The homozygous inactivation of the apoE gene results in animals that are devoid of apoE in their sera. The mice appear to develop normally, but they exhibit five times the normal serum plasma cholesterol and spontaneous atherosclerotic lesions. This is similar to a disease in people who have a variant form of the apoE gene that is defective in binding to the LDL receptor and are at risk for early development 30 of atherosclerosis and increased plasma triglyceride and cholesterol levels. There are indications that apoE is also involved in immune system regulation, nerve regeneration and muscle 235 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 differentiation. The apoE knockout mice can be used to study the role of apoE in lipid metabolism, atherogenesis, and nerve injury, and to investigate intervention therapies that modify the atherogenic process. Apoe4 Targeted Replacement Mouse (Order Model #: 001549-M) ApoE is a plasma protein 5 involved in cholesterol transport, and the three human isoforms (E2, E3, and E4) have been associated with atherosclerosis and Alzheimer's disease. Gene targeting of 129 ES cells was used to replace the coding sequence of mouse apoE with human APOE4 without disturbing the murine regulatory sequences. The E4 isoform occurs in approximately 14% of the human population and is associated with increased plasma cholesterol and a greater risk of coronary 10 artery disease. The Taconic apoE4 Targeted Replacement model has normal plasma cholesterol and triglyceride levels, but altered quantities of different plasma lipoprotein particles. This model also has delayed plasma clearance of cholesterol-rich lipoprotein particles (VLDL), with only half the clearance rate seen in the apoE3 Targeted Replacement model. Like the apoE3 model, the apoE4 mice develop altered plasma lipoprotein values and atherosclerotic plaques on 15 an atherogenic diet. However, the atherosclerosis is more severe in the apoE4 model, with larger plaques and cholesterol apoE and apoB-48 levels twice that seen in the apoE3 model. The Taconic apoE4 Targeted Replacement model, along with the apoE2 and apoE3 Targeted Replacement Mice, provide an excellent tool for in vivo study of the human apoE isoforms. CETP Transgenic Mice (Order Model #: 1003-T) These animals express the human plasma 20 enzyme, CETP, resulting in mice with a dramatic reduction in serum HDL cholesterol. The mice can be useful in identifying and evaluating compounds that increase the levels of HDL cholesterol for reducing the risk of developing atherosclerosis Transgene/Promoter: human apolipoprotein A-I These mice produce mouse HDL cholesterol particles that contain human apolipoprotein A-I. Transgenic expression is life-long in both sexes 25 (Biochemical Genetics and Metabolism Laboratory, Rockefeller University, NY City). A Mouse Modelfor Abetalipoproteinemia Abetalipoproteinemia, an inherited human disease characterized by a near-complete absence of apoB-containing lipoproteins in the plasma, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP). Gene 236 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072WO I targeting was used to knock out the mouse MTP gene (Mttp). In heterozygous knockout mice (Mttp+"), the MTP mRNA, protein, and activity levels were reduced by 50% in both liver and intestine. Recent studies with heterozygous MTP knockout mice have suggested that half normal levels of MTP in the liver reduce apoB secretion. They hypothesized that reduced apoB 5 secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were true, half-normal levels of MTP might have little impact on lipoprotein secretion in the setting of half-normal levels of apoB synthesis (since the ratio of MTP to apoB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion 10 in the setting of apoB overexpression (since the ratio of MTP to apoB would be even lower). To test this hypothesis, they examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (heterozygous Apob deficiency), and increased levels of apoB synthesis (transgenic overexpression of human apoB). Contrary to their expectations, half-normal levels of MTP 15 reduced plasma apoB-100 levels to the same extent (~25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level of apoB synthesis. Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum, rather than the MTP:apoB ratio, is the critical determinant of lipoprotein secretion. Finally, heterozygosity for an apoB knockout mutation was found to lower 20 plasma apoB-100 levels more than heterozygosity for an MTP knockout allele. Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice. Cre/loxP tissue-specific recombination techniques were also used to generate liver-specific Mttp knockout mice. Inactivation of the Mttp gene in the liver caused a striking reduction in very low density lipoprotein (VLDL) triglycerides and 25 large reductions in both VLDL/low density lipoproteins (LDL) and high density lipoprotein cholesterol levels. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Currently being tested is the hypothesis that accumulation of triglycerides in the liver renders the liver more susceptible to injury by a second insult (e.g., lipopolysaccharide). Human apo B apolipoproteinn B) Transgene mice show apo B locus may have a causative role 30 male infertility The fertility of apoB (apolipoprotein B) (+/-) mice was recorded during the course of backcrossing (to C57BL/6J mice) and test mating. No apparent fertility problem was 237 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 observed in female apoB (+/-) and wild-type female mice, as was documented by the presence of vaginal plugs in female mice. Although apoB (+/-) mice mated normally, only 40% of the animals from the second backcross generation produced any offspring within the 4-month test period. Of the animals that produced progeny, litters resulted from < 50% of documented 5 matings. In contrast, all wild-type mice (6/6--i. e., 100%) tested were fertile. These data suggest genetic influence on the infertility phenotype, as a small number of male heterozygotes were not sterile. Fertilization in vivo was dramatically impaired in male apoB (+/-) mice. 74% of eggs examined were fertilized by the sperm from wild-type mice, whereas only 3% of eggs examined were fertilized by the sperm from apoB (+/-) mice. The sperm counts of apoB (+/-) mice were 10 mildly but significantly reduced compared with controls. However, the percentage of motile sperm was markedly reduced in the apoB (+/-) animals compared with that of the wild-type controls. Of the sperm from apoB (+/-) mice, 20% (i.e., 4.9% of the initial 20% motile sperm) remained motile after 6 hr of incubation, whereas 45% (i.e., 33.6% of the initial 69.5%) of the motile sperm retained motility in controls after this time. In vitro fertilization yielded no 15 fertilized eggs in three attempts with apo B (+/-) mice, while wild-type controls showed a fertilization rate of 53%. However, sperm from apoB (+/-) mice fertilized 84% of eggs once the zona pellucida had been removed. Numerous sperm from apoB (+/-) mice were seen binding to zona-intact eggs. However, these sperm lost their motility when observed 4-6 hours after binding, showing that sperm from apoB (+/-) mice were unable to penetrate the zona pellucida 20 but that the interaction between sperm and egg was probably not direct. Sperm binding to zona free oocytes was abnormal. In the apoB (+/-) mice, sperm binding did not attenuate, even after pronuclei had clearly formed, suggesting that apoB deficiency results in abnormal surface interaction between the sperm and egg. Knockout of the mouse apoB gene resulted in embryonic lethality in homozygotes, 25 protection against diet-induced hypercholesterolemia in heterozygotes, and developmental abnormalities in mice. Model of insulin resistance, dyslipidemia & overexpression of human apoB It was shown that the livers of apoB mice assemble and secrete increased numbers of VLDL particles. 238 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Example 2. Treatment of Diabetes Type-2 with iRNA Introduction The regulation of hepatic gluconeogenesis is an important process in the adjustment of the blood glucose level. Pathological changes in the glucose production of the liver are a central characteristic in type-2-diabetes. For example, the fasting hyperglycemia 5 observed in patients with type-2-diabetes reflects the lack of inhibition of hepatic gluconeogenesis and glycogenolysis due to the underlying insulin resistance in this disease. Extreme conditions of insulin resistance can be observed for example in mice with a liver specific insulin receptor knockout ('LIRKO'). These mice have an increased expression of the two rate-limiting gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and the 10 glucose-6-phosphatase catalytic subunit (G6Pase). Insulin is known to repress both PEPCK and G6Pase gene expression at the transcriptional level and the signal transduction involved in the regulation of G6Pase and PEPCK gene expression by insulin is only partly understood. While PEPCK is involved in a very early step of hepatic gluconeogenesis (synthesis of phosphoenolpyruvate from oxaloacetate), G6Pase catalyzes the terminal step of both, 15 gluconeogenesis and glycogenolysis, the cleavage of glucose-6-phosphate into phosphate and free glucose, which is then delivered into the blood stream. The pharmacological intervention in the regulation of expression of PEPCK and G6Pase can be used for the treatment of the metabolic aberrations associated with diabetes. Hepatic glucose production can be reduced by an iRNA-based reduction of PEPCK and G6Pase 20 enzymatic activity in subjects with type-2-diabetes. Targets for iRNA Glucose-6-phosphatase (G6Pase) G6Pase mRNA is expressed principally in liver and kidney, and in lower amounts in the 25 small intestine. Membrane-bound G6Pase is associated with the endoplasmic reticulum. Low activities have been detected in skeletal muscle and in astrocytes as well. G6Pase catalyzes the terminal step in gluconeogenesis and glycogenolysis. The activity of the enzyme is several fold higher in diabetic animals and probably in diabetic humans. Starvation and diabetes cause a 2-3-fold increase in G6Pase activity in the liver and a 2-4-fold 30 increase in G6Pase mRNA. 239 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Phosphoenolpyruvate carboxykinase (PEPCK) Overexpression of PEPCK in mice results in symptoms of type-2-diabetes mellitus. PEPCK overexpression results in a metabolic pattern that increases G6Pase mRNA and results in a selective decrease in insulin receptor substrate (IRS)-2 protein, decreased phosphatidylinositol 5 3-kinase activity, and reduced ability of insulin to suppress gluconeogenic gene expression. Table 5. Other targets to inhibit hepatic glucose production Target Comment FKHR good evidence for antidiabetic phenotype (Nakae et al., Nat Genetics 32:245(2002) Glucagon Glucagon receptor Glycogen phosphorylase regulates the cAMP response (and PGC-1 (PPAR-Gamma probably the PKB/FKHR-regulation) on Coactivator) PEPCK/G6Pase Fructose-1,6-bisphosphatase Glucose-6-phospate translocator Glucokinase inhibitory regulatory protein 10 Materials and Methods Animals: BKS.Cg-m +/+ Lepr db mice, which contain a point mutation in the leptin receptor gene are used to examine the efficacy of iRNA for the targets listed above. BKS.Cg-m +/+ Lepr db are available from the Jackson Laboratory (Stock Number 000642). These animals are obese at 3-4 weeks after birth, show elevation of plasma insulin at 15 10 to 14 days, elevation of blood sugar at 4 to 8 weeks, and uncontrolled rise in blood sugar. Exogenous insulin fails to control blood glucose levels and gluconeogenic activity increases. The following numbers of male animals (age>12 weeks) could be tested with the following iRNAs: PEPCK, 2 sequences, 5 animals per sequence 20 G6Pase, 2 sequences, 5 animals per sequence 1 nonspecific sequence, 5 animals 1 control group (only injected, no siRNA), 5 animals 1 control group (not injected, no siRNA), 5 animals 240 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 Reagents: Necessary reagents would ideally include a Glucometer Elite XL (Bayer, Pittsburgh, PA) for glucose quantification, and an Insulin Radioimmunoassay (RIA) kit (Amersham, Piscataway, NJ) for insulin quanitation. 5 Assays: G6P enzyme assays and PEPCK enzyme assays are used to measure the activity of the enzymes. Northern blotting is used to detect levels of G6Pase and PEPCK mRNA. Antibody-based techniques (e.g., immunoblotting, immunofluorescence) are used to detect levels of G6Pase and PEPCK protein. Glycogen staining is used to detect levels of glycogen in the liver. Histological 10 analysis is performed to analyze tissues. Gene information: G6Pase GenBank@ No.: NM_008061,Mus musculus glucose-6-phosphatase, catalytic (G6pc), mRNA 1..2259, ORF 83..1156; 15 GenBank@ No: U00445,Mus musculus glucose-6-phosphatase mRNA, complete cds L..2259, ORF 83..1156 GenBank@ No: BC013448 PEPCK GenBank@ No: NM_011044, Mus musculus phosphoenolpyruvate carboxykinase 1, cytosolic 20 (Pckl), mRNA.1..2618, ORF 141..2009 GenBank@ No: AF009605.1 Administration of iRNA: iRNA corresponding to the genes described above could be administered to mice with 25 hydrodynamic injection. One control group of animals would be treated with Metformin as a positive control for reduction in hepatic glucose levels. Experimental Protocol Mice could be housed in a facility in which there is light from 7:00 AM to 7:00 PM. 30 Mice would be fed ad libidum from 7:00 PM to 7:00 AM and fast from 7:00 AM to 7:00 PM. 241 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 Day 0: 7:00 PM: Approximately 100 dl blood would be drawn from the tail. Serum could be isolated to measure glucose, insulin, HbAlc (EDTA-blood), glucagon, FFAs, lactate, corticosterone, serum triglycerides. Day 1-7: Blood glucose could be measured daily at 8:00 AM and 6:00 PM (approx. 3-5 d; 5 measured with a Haemoglucometer) Day 8: Blood glucose could be measured daily at 8:00 AM and 6:00 PM. iRNA would be injected between 10:00 AM and 2:00 PM Day 9-20: Blood glucose could be measured daily at 8:00 AM and 6:00 PM. 10 Day 21: Mice could be sacrificed after 10 hours of fasting. Blood would be isolated. Glucose, insulin, HbAlc (EDTA-blood), glucagon, FFAs, lactate, corticosterone, serum triglycerides would be measured. Liver tissue would be isolated for histology, protein assays, RNA assays, glycogen quantitation, and enzyme assays. 15 Example 3: Inhibition of Glucose-6-Phosphatase iRNA in vivo iRNA targeted to the Glucose-6-Phosphatase (G6P) gene was used to examine the effects of inhibition of G6P expression on glucose metabolism in vivo. Female mice, 10 weeks of age, strain BKS.Cg-m +/+ Lepr db (The Jackson Laboratory) 20 were used for in vivo analysis of enzymes of the hepatic glucose production. Mice were housed under conditions where it was light from 6:30 am to 6:30 pm. Mice were fed (ad libidum) during the night period and fasted during the day period. On day 1, approximately 100pLl of blood was collected from test animals by puncturing the retroorbital plexus. On days 1-7, blood glucose was measured in blood obtained from tail 25 veins (approximately 3-5 ptl) using a Glucometer (Elite XL, Bayer). Blood glucose was sampled daily at 8 am and 6 pm. On day 7 at approximately 2pm, GL3 plasmid (10 pg) and siRNAs (100 pg G6Pase specific, Renilla nonspecific or no siRNA control) were delivered to animals using hydrodynamic coinjection. 242 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W01 On day 8, GL3 expression was analyzed by injection of luceferin (3 mg) after anaesthesia with avertin and imaging. This was done to control for successful hydrodynamic delivery. On days 8-10, blood glucose was measured in blood obtained from tail veins (approximately 3-5 ml) using a Glucometer (Elite XL, Bayer). 5 On day 10, mice were sacrificed after 10 hours of fasting. Blood and liver were isolated from sacrificed animals. Table 6 lists blood glucose levels (mg/dl) for mice injected with GL3 plasmid and G6Pase iRNA (G6P4), Renilla nonspecific iRNA (RL), or no iRNA (no). Days on which nucleic acids were injected are shaded. 10 Table 6. Blood glucose levels in mice plasmid GL3 GL3 GL3 GL3 GL3 GL3 GL3 GL3 siRNA G6P4 G6P4 G6P4 no G6P4 RL RL no mouse 03 mouse 04 mouse 05 mouse 07 mouse 09 mouse 14 mouse 15 mouse 17 day BG BG BG BG BG BG BG BG 1 512 250 537 241 196 275 538 437 2 555 437 339 556 408 315 524 386 3 483 446 356 567 283 491 600 459 4 579 543 552 423 404 457 548 375 5 600 501 600 277 198 441 533 430 6 464 600 408 454 461 412 490 301 7 214 201 245 3092 494 600 429 i jeion 8 600 566 246 521 277 600 576 404 9 35b 448 438 536 600 459 injecton 10 359 600 446 average day 1 to 6 532 463 465 420 325 399 539 398 15 Table 7 lists average blood glucose levels (mg/dl) on days 1-6 or day 7 for mice injected with GL3 plasmid and G6Pase iRNA (G6P4), Renilla nonspecific iRNA (RL), no iRNA (no), or for mice that were not injected, or for which injection failed. Table 7. Average blood glucose levels 20 G6P4 RL no RL and no (combined) mouse 03,04,05,09 mouse 14,15 mouse 07,17 mouse 14, 15, 07, 17 average (dl-6) 446 469 409 439 stddev (d1-6) 124 96 101 101 average (d7) 230 547 369 458 stddev (d7) 27 1 1 122 243 WO 2004/091515 PCT/US2004/011255 Attorney's Docket No.: 14174-072W0 1 FIGs. 6A, 6B, and 6C show graphs depicting blood glucose levels of animals injected with control or no siRNA, G6Pase RNA, or non-injected mice (respectively) at days 1-6 and day 7. FIG. 7 contains a graph of average blood glucose levels for mice injected with G6Pase RNA 5 (solid line) and mice injected with, Renilla nonspecific iRNA (RL) or no iRNA (no) (dashed line). Table 8 lists average blood glucose levels for mice injected with G6Pase iRNA or Renilla nonspecific iRNA (RL) and no iRNA. 10 Table 8. Average blood glucose levels iRNA G6P4 RL and no (combined) mouse 03,04,05,09 mouse 14, 15, 07,17 day amrage stddev arage stddev S374 176 373 139 2 435 90 445 114 3 392 90 529 65 4 520 79 451 73 5 475 190 420 106 6 483 82 414 82 7 230 27 458 122 8 422 187 525 87 91 412 54 532 71 101 472 1181_________ __ __ ___ Example 4: Selected Palindromic Sequences 15 Tables 9-14 below provide selected palindromic sequences from the following genes: human ApoB, human glucose-6-phosphatase, rat glucose-6-phosphatase, P-catenin, and hepatitis C virus (HCV). 244 WO 2004/091515 PCT/US2004/011255 Table 9. Selected palindromic sequences from human ApoB Source Start End Match Start End # B Index Index Index Index SEQ ID 1 ggccattccagaagggaag 509 528 SEQ ID 1004 cttccgttctgtaatggcc 5795 5814 1 9 NO: 'NO: SEQ ID 2 tgccatctcgagagttcca 4099 4118 SEQ ID 1005 tggaactctctccatggca 10876 10895 1 8 NO: NO: SEQ ID 3 catgtcaaacactttgtta 7056 7075 SEQ ID 1006 taacaaattccttgacatg 7358 7377 18 NO: NO: SEQ ID 4 tttgttataaatcttattg 7068 7087 SEQ ID 1007 caataagatcaatagcaaa 8990 9009 1 8 NO: IINO: SEQ ID 5 tctggaaaagggtcatgga 8880 8899. SEQ ID 1008 tccatgtcccatttacaga 11356 11375 1 8 NO: NO: SEQ ID 6 cagctcttgttcaggtcca 10900 10919 SEQ ID 1009 tggacctgcaccaaagctg 13952 13971 1 8 NO: NO: SEQ ID 7 ggaggttccccagctctgc 356 375 SEQ ID 1010 gcagccctgggaaaactcc 6447 6466 17 NO: NO: SEQ ID 8 ctgttttgaagactctcca 1081 1100 SEQ ID 1011 tggagggtagtcataacag 10327 10346 1 7 NO: NO: SEQ ID 9 agtggctgaaacgtgtgca 1297 1316 SEQ ID 1012 tgcagagctttctgccact 13508 13527 17 NO: NO: SEQ ID 10 ccaaaatagaagggaatct 2068 2087 SEQ ID 1013 agattcctttgccttttgg 4000 4019 1 7 NO: NO: SEQ ID 11 tgaagagaagattgaattt 3620 3639 SEQ ID 1014 aaattctcttttcttttca 9212 9231 1 7 NO: NO: SEQ ID 12 agtggtggcaacaccagca 4230 4249 SEQ ID 1015 tgctagtgaggccaacact 10649 10668 1 7 NO: , NO: SEQ ID 13 aaggctccacaagtcatca 5950 5969 SEQ ID 1016 tgatgatatctggaacctt 10724 10743 1 7 NO: NO: SEQ ID 14 gtcagccaggtttatagca 7725 7744 SEQ ID 1017 tgctaagaaccttactgac 7781' 7800 17 NO: NO: SEQ ID 15 tgatatctggaaccttgaa 10727 10746 SEQ ID 1018 ttcactgttcctgaaatca 7863 7882 17 NO: NO: SEQ ID 16 gtcaagttgagcaatttct 13423 13442 SEQ ID 1019 agaaaaggcacaccttgac 11072 11091 1 7 NO: I NO: SEQ ID 17 atccagatggaaaagggaa 13480 13499 SEQ ID 1020 ttccaatttccctgtggat 3680 3699 17 NO: NO: SEQ ID 18 atttgtttgtcaaagaagt 4543 4562 SEQ ID 1021 acttcagagaaatacaaat 11401 11420 46 NO: NO: SEQ ID 19 ctggaaaatgtcagcctgg 204 223 SEQ ID 1022 ccagacttccgtttaccag 8235 8254 26 NO: '_NO: SEQ ID 20 accaggaggttcttcttca 1729 1748 SEQ ID 1023 tgaagtgtagtctcctggt 5089 5108 26 NO: NO: SEQ ID 21 aaagaagttctgaaagaat 1956 1975 SEQ ID 1024 attccatcacaaatccttt 9661 9680 26 NO: NO: SEQ ID 22 gctacagcttatggctcca 3570 3589 SEQ ID 1025 tggatctaaatgcagtagc 11623 11642 2 6 NO: NO: SEQ ID 23 atcaatattgatcaatttg 6414 6433 SEQ ID 1026 caaagaagtcaagattgat 4553 4572 2 6 NO: I NO: SEQ ID 24 gaattatcttttaaaacat 7326 7345 SEQ ID 1027 atgtgttaacaaaatattc 11494 11513 26 N1O: NO: SEQ ID 25 cgaggcccgcgctgctggc 130 149 SEQ ID 1028 gccagaagtgagatcctcg 3507 3526 1 6 %JO: _NO: SEQ ID 26 acaactatgaggctgagag 271 290 SEQ ID 1029 ctctgagcaacaaatttgt 10309 10328 1 6 l\_O: iNO: 1 1 245 WO 2004/091515 PCT/US2004/011255 SEQ ID 2g 6ct'giagtccagtggag 282 301 SEQ ID 1030 ctccatggcaaatgtcagc 10885 10904 1 6 NO: NO: SEQ ID 28 tgaagaaaaccaagaactc 448 467 SEQ ID 1031 gagtcattgaggttcttca 4929 4948 1 6 NO: NO: SEQ ID 29 cctacttacatcctgaaca 558 577 SEQ ID 1032 tgttcataagggaggtagg 12766 12785 1 6 NO: I NO: SEQ ID 30 ctacttacatcctgaacat 559 578 SEQ ID 1033 atgttcataagggaggtag 12765 12784 1 6 NO: NO: SEQ ID 31 gagacagaagaagccaagc 615 634 SEQ ID 1034 gcttggttttgccagtctc 2459 2478 1 6 NO: NO: SEQ ID 32 cactcactttaccgtcaag 671 690 SEQ ID 1035 cttgaacacaaagtcagtg 6000 6019 1 6 NO: NO: I SEQ ID 33 ctgatcagcagcagccagt 822 841 SEQ ID 1036 actgggaagtgcttatcag 5237 5256 1 6 NO: NO: SEQ ID 34 actggacgctaagaggaag 854 873 SEQ ID 1037 cttccccaaagagaccagt 2890 2909 1 6 NO: _NO: 246 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 35 agaggaagcatgtggcaga 865 884 SEQ ID 1038 tctggcatttactttctct 5921 5940 1 6 NO: SEQ ID NO:36 tgaagactctccaggaact 1087 1106 SEQ ID 1039 agttgaaggagactattca 7216 7235 1 6 NO: SEQ ID NO:37 ctctgagcaaaatatccag 1121 1140 SEQ ID 1040 ctggttactgagctgagag 1161 1180 16 NO: SEQ ID NO: 38 atgaagcagtcacatctct 1189 1208 SEQ ID 1041 agagctgccagtccttcat 10016 10035 1 6 NO: SEQ ID NO:39 ttgccacagctgattgagg 1209 1228 SEQ ID 1042 cctcctacagtggtggcaa 4222 4241 1 6 NO: SEQ ID NO:40 agctgattgaggtgtccag 1216 1235 SEQ ID 1043 ctggattccacatgcagct 11847 11866 16 1___ NO: SEQ ID NO:41 tgctccactcacatcctcc 1278 1297 SEQ ID 1044 ggaggctttaagttcagca 7601 7620 1 6 NO: SEQ ID NO: 42 tgaaacgtgtgcatgccaa 1303 1322 SEQ ID 1045 ttgggagagacaagfttca 6500 6519 1 6 NO: SEQ ID NO: 43 gacattgctaattacctga 1503 1522 SEQ ID 1046 tcagaagctaagcaatgtc 7232 7251 1 6 NO: SEQ ID NO: 44 ttcttcttcagactttcct 1738 1757 SEQ ID 1047 aggagagtccaaattagaa 8498 8517 1 6 NO: SEQ ID NO:45 ccaatatcttgaactcaga 1903 1922 SEQ ID 1048 tctgaattcattcaattgg 6485 6504 1 6 NO: SEQ ID NO: 46 aaagttagtgaaagaagtt 1946 1965 SEQ ID 1049 aactaccctcactgccttt 2132 2151 1 6 NO: III SEQ ID NO:47 aagttagtgaaagaagttc 1947 1966 SEQ ID 1050 gaacctctggcatttactt 5916 5935 1 6 NO: SEQ ID NO: 48 aaagaagttctgaaagaat 1956 1975 SEQ ID 1051 attctctggtaactacttt 5482 5501 1 6 NO: SEQ ID NO: 49 tttggctataccaaagatg 2322 2341 SEQ ID 1052 catcttaggcactgacaaa 4997 5016 1 6 NO: SEQ ID NO: 50 tgttgagaagctgattaaa 2381 2400 SEQ ID 1053 tttagccatcggctcaaca 5700 5719 1 6 NO: SEQ ID NO: 51 caggaagggctcaaagaat 2561 2580 SEQ ID 1054 attcctttaacaattcctg 9492 9511 1 6 __ _ _NO: 3EQ ID NO: 52 aggaagggctcaaagaatg 2562 2581 SEQ ID 1055 cattcctttaacaattcct 9491 9510 1 6 NO: 3EQ ID NO: 53 gaagggctcaaagaatgac 2564 2583 SEQ ID 1056 gtcagtcttcaggctcttc 7914 7933 16 NO: EQ ID NO: 54 caaagaatgacttttttct 2572 2591 SEQ ID 1057 agaaggatggcattttttg 14000 14019 1 6 NO: 3EQ ID NO: 55 catggagaatgcctttgaa 2603 2622 SEQ ID 1058 ttcagagccaaagtccatg 7119 7138 1 6 _ _ 1 NO: II 3EQ ID NO: 56 ggagccaaggctggagtaa 2679 2698 SEQ ID 1059 ttactccaacgccagctcc 3050 3069 1 6 NO: 3EQ ID NO: 57 tcattccttccccaaagag 2884 2903 SEQ ID 1060 ctctctggggcatctatga 5139 5158 1 6 NO: 3EQ ID NO: 58 acctatgagctccagagag 3165 3184 SEQ ID 1061 ctctcaagaccacagaggt 12976 12995 16 NO: 3EQ ID NO: 59 gggcaaaacgtettacaga 3365 3384 SEQ ID 1062 tctgaaagacaacgtgccc 12317 12336 1 6 NO: 3EQ ID NO: 60 accctggacattcagaaca 3387 3406 SEQ ID 1063 tgttgctaaggttcagggt 5675 5694 1 6 NO: 3EQ ID NO: 61 atgggcgacctaagttgtg 3429 3448 SEQ ID 1064 cacaaattagtttcaccat 8941 8960 1 6 NO: 'EQ ID NO: 62 gatgaagagaagattgaat 3618 3637 SEQ ID 1065 attccagcttccccacatc 8330 8349 1 6 247 WO 2004/091515. PCT/US2004/011255 NO: SEQ ID NO: 63 caatgtagataccaaaaaa 3656 3675 SEQ ID 1066 ttttttggaaatgccattg 8643 8662 1 6 1_ NO: SEQ ID NO: 64 gtagataccaaaaaaatga 3660 3679 SEQ ID 1067 tcatgtgatgggtctctac 4371 4390 1 6 NO: SEQ ID NO: 65 gcttcagttcatttggact 4509 4528 SEQ ID 1068 agtcaagaaggacttaagc 5304 5323 16 ___ NO: SEQ ID NO: 66 tttgtttgtcaaagaagtc 4544 4563 SEQ ID 1069 gacttcagagaaatacaaa 11400 11419 6 _____ ___ NO: SEQ ID NO: 67 ttgtttgtcaaagaagtca 4545 4564 SEQ ID 1070 tgacttcagagaaatacaa 113991141816 _____ ___ NO: SEQ ID NO: 68 tggcaatgggaaactcgct 5846 5865 SEQ ID 1071 agcgagaatcaccctgcca 8219 8238 1 _____ ___ NO: SEQ ID NO: 69 aacctctggcatttacttt 5917 5936 SEQ ID 1072 aaaggagatgtcaagggtt 10599 10618 16 1 1 NO:I SEQ ID NO: 70 catttactttctctcatga 5926 5945 SEQ ID 1073 tcatttgaaagaataaatg 7026 7045 16 ______NO: SEQ ID NO:71 aaagtcagtgccctgctta 6009 6028 SEQ ID 1074 taagaaccttactgacttt 7784 7803 16 ______ NO: ___ SEQ ID NO:72 tcccattttttgagacctt 6322 6341 SEQ ID 1075 aaggacttcaggaatggga 12004 12023 1 6 NO: SEQ ID NO:73 catcaatattgatcaattt 6413 6432 SEQ ID 1076 aaattaaaaagtcttgatg 6732 6751 1 6 NO: SEQ ID NO:74 taaagatagttatgattta 6665 6684 SEQ ID 1077 taaaccaaaacttggttta 9019 9038 1 6 NO: SEQ ID NO: 75 tattgatgaaatcattgaa 6713 6732 SEQ ID 1078 ttcaaagacttaaaaaata 8007 8026 16 NO: SEQ ID NO:76 atgatctacatttgtttat 6790 6809 SEQ ID 1079 ataaagaaattaaagtcat 7380 7399 1 6 NO: SEQ ID NO:77 agagacacatacagaatat 6919 6938 SEQ ID 1080 atatattgtcagtgcctct 13382 13401.1 6 _____ ____ __ __ ___NO: _ _ _ _ _ _ _ _ SEQ ID NO: 78 gacacatacagaatataga 6922 6941 SEQ ID 1081 tctaaattcagttcttgtc 11327 11346 1 6 NO: SEQ ID NO: 79 agcatgtcaaacactttgt 7054 7073 SEQ ID 1082 acaaagtcagtgccctgct 6007 6026 1 6 1_ NO: SEQ ID NO: 80 tttttagaggaaaccaagg 7515 7534 SEQ ID 1083 cctttgtgtacaccaaaaa 11230 11249 16 NO: I SEQ ID NO: 81 ttttagaggaaaccaaggc 7516 7535 SEQ ID 1084 gcctttgtgtacaccaaaa 11229 112481 6 _____________NO:_ _ _ SEQ ID NO:82 ggaagatagacttcctgaa 9307 9326 SEQ ID 1085 ttcagaaatactgttttcc 12824 12843 16 NO: SEQ ID NO: 83 cactgtttctgagtcccag 9334 9353 SEQ ID 1086 ctgggacctaccaagagtg 12523 12542 16 NO: SEQ ID NO: 84 cacaaatcctttggctgtg 9668 9687 SEQ ID 1087 cacatttcaaggaattgtg 10063 10082 1 6 NO: SEQ ID NO:85 ttcctggatacactgttcc 9853 9872 SEQ ID 1088 ggaactgttgactcaggaa 12569 12588 16 NO: SEQ ID NO: 86 gaaatctcaagctttctct 1004210061 SEQ ID 1089 agagccaggtcgagctttc 11044 11063 16 NO: SEQ ID NO: 87 tttcttcatcttcatctgt 1021010229 SEQ ID 1090 acagctgaaagagatgaaa 13055 130741 6 ______NO: SEQ ID NO: 88 tctaccgctaaaggagcag 1052110540SEQ ID 1091 ctgcacgctttgaggtaga 1176111780 16 ______ NO: SEQ ID NO: 89 ctaccgctaaaggagcagt 1052210541 SEQ ID 1092 actgcacgctttgaggtag 11760 11779 1 6 NO: SEQ ID NO: 90 agggcctctttttcaccaa 1083110850 SEQ ID 1093 ttggccaggaagtggccct 1095710976 1 6 248 WO 2004/091515. . _ _ PCT/US2004/011255 NO: SEQ ID NO: 91 ttctccatccctgtaaaag 1126511284 SEQ ID 1094 ctttttcaccaacggagaa 10838 10857 1 6 NO: SEQ ID NO:92 gaaaaacaaagcagattat 1181611835SEQ ID 1095 ataaactgcaagatttttc 13600 13619 16 NO: SEQ ID NO:93 actcactcattgattttct 1268212701 SEQ ID 1096 agaaaatcaggatctgagt 14027 140461 6 NO: SEQ ID NO: 94 taaactaatagatgtaatc 1289012909 SEQ ID 1097 gattaccaccagcagttta 13578 13597 16 NO: SEQ ID NO:95 caaaacgagcttcaggaag 1320013219 SEQ ID 1098 cttcgtgaagaatattttg 13260 132791 6 NO: SEQ ID NO: 96 tggaataatgctcagtgtt 2366 2385 SEQ ID 1099 aacacttacttgaattcca 10662 10681 35 NO: SEQ ID NO: 97 gatttgaaatccaaagaag 2400 2419 SEQ ID 1100 cttcagagaaatacaaatc 11402 114213 5 NO: SEQ ID NO:98 atttgaaatccaaagaagt 2401 2420 SEQ ID 1101 acttcagagaaatacaaat 11401 11420 3 5 NO: SEQ ID NO: 99 atcaacagccgcttctttg 990 1009 SEQ ID 1102 caaayaagtcaagattgat 4553 4572 25 NO: 3EQ ID NO: 100 tgttttgaagactctccag 1082 1101 SEQ ID 1103 ctggaaagttaaaacaaca 6955 6974 2 5 NO: SEQ ID NO: 101 cccttctgatagatgtggt 1324 1343 SEQ ID 1104 accaaagctggcaccaggg 13961 139802 5 NO: SEQ ID NO: 102 tgagcaagtgaagaacttt 1868 1887 SEQ ID 1105 aaagccattcagtctctca 12963 12982 2 5 NO: SEQ ID NO: 103 atttgaaatccaaagaagt 2401 420 SEQ ID 1106 acttttctaaacttgaaat 9055 9074 25 NO: SEQ ID NO: 104 atccaaagaagtcccggaa 2408 2427 SEQ ID 1107 ttccggggaaacctgggat 12721 12740 2 5 NO: SEQ ID NO: 105 agagcctacctccgcatct 2430 2449 SEQ ID 1108 agatggtacgttagcctct 11921 11940 2 5 NO: SEQ ID NO: 106 aatgcctttgaactcccca 2610 2629 SEQ ID 1109 tgggaactacaatttcatt 7012 7031 2 5 NO: SEQ ID NO: 107 gaagtccaaattccggatt 3297 3316 SEQ ID 1110 aatcttcaatttattcttc 13815 13834 2 5 I I NO: SEQ ID NO: 108 tgcaagcagaagccagaag 3496 3515- SEQ ID 1111 cttcaggttccatcgtgca 11376 113952 5 NO: SEQ ID NO: 109 gaagagaagattgaatttg 3621 3640 SEQ ID 1112 caaaacctactgtctcttc 10459 10478 2 5 NO: SEQ ID NO: 110 atgctaaaggcacatatgg 4597 4616 SEQ ID 1113 ccatatgaaagtcaagcat 12656 12675 2 5 NO: SEQ ID NO: 111 tccctcacctccacctctg 4737 4756 SEQ ID 1114 cagattctcagatgaggga 8912 8931 25 NO: SEQ ID NO: 112 atttacagctctgacaagt 5427 5446 SEQ ID 1115 acttttctaaacttgaaat 9055 9074 25 NO: SEQ ID NO: 113 aggagcctaccaaaataat 5594 5613 SEQ ID 1116 attatgttgaaacagtcct 11830 11849 2 5 NO: )EQ ID NO: 114 aaagctgaagcacatcaat 6401 6420 SEQ ID 1117 attgttgctcatctccttt 10194 10213 2 5 NO: 3EQ ID NO: 115 ctgctggaaacaacgagaa 9418 9437 SEQ ID 1118 ttctgattaccaccagcag 13574 13593 2 5 NO: SEQ ID NO: 116 ttgaaggaattcttgaaaa 9582 9601 SEQ ID 1119 ttttaaaagaaatcttcaa 1380513822 5 NO: 3EQ ID NO:117 gaagtaaaagaaaattttg 1074310762 SEQ ID 1120 caaaacctactgtctcttc 10459 1047825 SEQ ID NO: 118 tgaagaagatggcaaattt 1198412003 SEQ ID 1121 aaatgtcagctcttgttca 10894 1091325 249 ~O 2004091515,. ,','.PCT/US2004/011255 NO: SEQ ID NO: 119 aggatctgagttattttgc 1403514054 SEQ ID 1122 gcaagtcagcccagttcct 10920 10939 2 5 NO: SEQ ID NO: 120 gtgcccttctcggttgctg 18 37 SEQ ID 1123 cagccattgacatgagcac 5740 5759 1 5 NO: SEQ ID NO: 121 ggcgctgcctgcgctgctg 146 165 SEQ ID 1124 cagctccacagactccgcc 3062 3081 1 5 NO: SEQ ID NO: 122 ctgcgctgctgctgctgct 154 173 SEQ ID 1125 agcagaaggtgcgaagcag 3224 3243 1 5 __ _NO: SEQ ID NO: 123 gctgctggcgggcgccagg 170 189 SEQ ID 1126 cctggattccacatgcagc 11846 118651 5 NO: SEQ ID NO: 124 aagaggaaatgctggaaaa 193 212 SEQ ID 1127 tttttcttcactacatctt 2584 2603 1 5 1 __ INO: SEQ ID NO: 125 ctggaaaatgtcagcctgg 204 223 SEQ ID 1128 ccagacttccacatcccag 3915 3934 1 5 NO: SEQ ID NO: 126 tggagtccctgggactgct 296 315 SEQ ID 1129 agcatgcctagtttctcca 9945 9964 1 5 NO: SEQ ID NO: 127 ggagtccctgggactgctg 297 316 SEQ ID 1130 cagcatgcctagtttctcc 9944 9963 1 5 NO: SEQ ID NO: 128 tgggactgctgattcaaga 305 324 SEQ ID 1131 tcttccatcacttgaccca 2042 2061 1 5 NO: SEQ ID NO: 129 ctgctgattcaagaagtgc 310 329 SEQ ID 1132 gcacaccttgacattgcag 11079 11098 1 5 1_ _ INO: SEQ ID NO: 130 tgccaccaggatcaactgc 326 345 SEQ ID 1133 gcaggctgaactggtggca 2717 2736 1 5 NO: SEQ ID NO: 131 gccaccaggatcaactgca 327 346 SEQ ID 1134 tgcaggctgaactggtggc 2716 2735 1 5 NO: SEQ ID NO: 132 tgcaaggttgagctggagg 342 361 SEQ ID 1135 cctccacctctgatctgca 4744 4763, 1 5 NO: SEQ ID NO: 133 caaggttgagctggaggtt 344 363 SEQ ID 1136 aacccctacatgaagcttg 13755 13774 1 5 NO: SEQ ID NO: 134 ctctgcagcttcatcctga 369 388 SEQ ID 1137 tcaggaagcttctcaagag 1321113230 1 5 NO: SEQ ID NO: 135 cagcttcatcctgaagacc 374 393 SEQ ID 1138 ggtcttgagttaaatgctg 4977 4996 1 5 NO: SEQ ID NO: 136 gcttcatcctgaagaccag 376 395 SEQ ID 1139 ctggacgctaagaggaagc 855 874 1 5 NO: SEQ ID NO: 137 tcatcctgaagaccagcca 379 398 SEQ ID 1140 tggcatggcattatgatga 3604 3623 1 5 NO: SEQ ID NO: 138 gaaaaccaagaactctgag 452 471 SEQ ID 1141 ctcaaccttaatgattttc 8286 8305 1 5 NO: SEQ ID NO: 139 agaactctgaggagtttgc 460 479 SEQ ID 1142 gcaagctatacagtattct 8377 8396 1 5 NO: SEQ ID NO: 140 tctgaggagtttgctgcag 465 484 SEQ ID 1143 ctgcaggggatcccccaga 2526 2545 1 5 1_ _NO: SEQ ID NO: 141 tttgctgcagccatgtcca 474 493 SEQ ID 1144 tggaagtgtcagtggcaaa 10372 10391 1 5 NO: SEQ ID NO: 142 caagaggggcatcatttct 578 597 SEQ ID 1145 agaataaatgacgttcttg 7035 7054 1 5 NO: SEQ ID NO: 143 tcactttaccgtcaagacg 674 693 SEQ ID 1146 cgtctacactatcatgtga 4360 4379 1 5 NO: SEQ ID NO: 144 tttaccgtcaagacgagga 678 697 SEQ ID 1147 tccttgacatgttgataaa 7366 7385 1 5 NO: SEQ ID NO: 145 cactggacgctaagaggaa 853 872 SEQ ID 1148 ttccagaaagcagccagtg 12498 12517 1 5 NO: SEQ ID NO: 146 aggaagcatgtggcagaag 867 886 SEQ ID 1149 cttcatacacattaatcct 9988 10007 1 5 250 WO2004/091515 _ _ 1.. PCT/US2004/011255 NO: SEQ ID NO: 147 caaggagcaacacctcttc 893 912 SEQ ID 1150 gaagtagtactgcatcttg 6835 6854 1 5 NO: SEQ ID NO: 148 acagactttgaaacttgaa 959 978 SEQ ID 1151 ttcaattcttcaatgctgt 10500 10519 1 5 NO: SEQ ID NO: 149 tgatgaagcagtcacatct 1187 1206 SEQ ID 1152 agatttgaggattccatca 7976 7995 1 5 NO: SEQ ID NO: 150 agcagtcacatctctcttg 1193 1212 SEQ ID 1153 caaggagaaactgactgct 6524 6543 15 SEQ ID NO: 151 ccagccccatcactttaca 1231 1250 SEQ ID 1154 tgtagtctcctggtgctgg 5094 5113 15 NO: SEQ ID NO: 152 ctccactcacatcctccag 1280 1299 SEQ ID 1155 ctggagcttagtaatggag 8709 8728 1 5 NO: SEQ ID NO: 153 catgccaacccccttctga 1314 1333 SEQ ID 1156 tcagatgagggaacacatg 8919 8938 1 5 _NO: SEQ ID NO: 154 gagagatcttcaacatggc 1390 1409 SEQ ID 1157 gccaccctggaactctctc 10869 108881 5 NO: SEQ ID NO: 155 tcaacatggcgagggatca 1399 1418 SEQ ID 1158 tgatcccacctctcattga 2965 2984 1 5 NO: SEQ ID NO: 156 ccaccttgtatgcgctgag 1429 1448 SEQ ID 1159 ctcagggatctgaaggtgg 8187 8206 1 5 NO: SEQ ID NO: 157 gtcaacaactatcataaga 1455 1474 SEQ ID 1160 tcttgagttaaatgctgac 4979 4998 1 5 NO: SEQ ID NO:158 tggacattgctaattacct 1501 1520 SEQ ID 1161 aggtatattcgaaagtcca 12799 12818 1 5 NO: SEQ ID NO: 159 ggacattgctaattacctg 1502 1521 SEQ ID 1162 caggtatattcgaaagtcc 12798 128171 5 NO: SEQ ID NO: 160 ttctgcgggtcattggaaa 1573 1592 SEQ ID 1163 tttcacatgccaaggagaa 6514 65331 1 5 NO: SEQ ID NO: 161 ccagaactcaagtcttcaa 1620 1639 SEQ ID 1164 ttgaagtgtagtctcctgg 5088 5107 1 5 NO: SEQ ID NO: 162 agtcttcaatcctgaaatg 1630 1649 SEQ ID 1165 catttctgattggtggact 7757 7776: 1 5 NO: SEQ ID NO: 163 tgagcaagtgaagaacttt 1868 1887 SEQ ID 1166 aaagtgccacttttactca 6183 6202 1 5 NO: SEQ ID NO: 164 agcaagtgaagaactttgt 1870 1889 SEQ ID 1167 acaaagtcagtgccctgct 6007 6026 1 5 NO: SEQ ID NO: 165 tctgaaagaatctcaactt 1964 1983 SEQ ID 1168 aagtccataatggttcaga 12811 12830 1 5 NO: SEQ ID NO: 166 actgtcatggacttcagaa 1986 2005 SEQ ID 1169 ttctgaatatattgtcagt 13376 13395 1 5 NO: SEQ ID NO: 167 acttgacccagcctcagcc 2051 2070 SEQ ID 1170 ggctcaccctgagagaagt 12391 12410 1 5 NO: SEQ ID NO: 168 tccaaataactaccttcct 2096 2115 SEQ ID 1171 aggaagatatgaagatgga 4712 4731 1 5 NO: SEQ ID NO: 169 actaccctcactgcctttg 2133 2152 SEQ ID 1172 caaatttgtggagggtagt 10319 10338 1 5 NO: SEQ ID NO: 170 ttggatttgcttcagctga 2149 2168 SEQ ID 1173 tcagtataagtacaaccaa 9392 9411 1 5 NO: SEQ ID NO: 171 ttggaagctctttttggga 2211 2230 SEQ ID 1174 tcccgattcacgcttccaa 11577 11596 15 NO: SEQ ID NO: 172 ggaagctctttttgggaag 2213 2232 SEQ ID 1175 cttcagaaagctaccttcc 7929 7948 1 5 NO: SEQ ID NO: 173 tttttcccagacagtgtca 2238 2257 SEQ ID 1176 tgaccttctctaagcaaaa 4876 4895 1 5 1_ _ 1_ NO: 1 11 SEQ ID NO: 174 agacagtgtcaacaaagct 246 2265 SEQ ID 1177 agcttggttttgccagtct 2458 2477 1 5 251 __.__ WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 175 ctttggctataccaaagat 2321 2340 SEQ ID 1178 atctcgtgtctaggaaaag 5968 5987 1 5 NO: SEQ ID NO: 176 caaagatgataaacatgag 2333 2352 SEQ ID 1179 ctcaaggataacgtgtttg 12609 126281 5 NO: SEQ ID NO: 177 gatatggtaaatggaataa 2355 2374 SEQ ID 1180 ttatcttattaattatatc 13079 13098 1 5 NO: SEQ ID NO: 178 ggaataatgctcagtgttg 2367 2386 SEQ ID 1181 caacacttacttgaattcc 10661 106801 5 _ _NO: SEQ ID NO: 179 tttgaaatccaaagaagtc 2402 2421 SEQ ID 1182 gacttcagagaaatacaaa 11400 114191 5 NO: SEQ ID NO: 180 gatcccccagatgattgga 2534 2553 SEQ ID 1183 tccaatttccctgtggatc 3681 3700 1 5 NO: SEQ ID NO: 181 cagatgattggagaggtca 2541 2560 SEQ ID 1184 tgaccacacaaacagtctg 5363 5382 15 NO: SEQ ID NO: 182 agaatgacttttttcttca 2575 2594 SEQ ID 1185 tgaagtccggattcattet 11015 11034 1 5 NO: SEQ ID NO: 183 gaactccccactggagctg 2619 2638 SEQ ID 1186 cagctcaaccgtacagttc 1186111880 1 5 ______NO: SEQ ID NO: 184 atatcttcatctggagtca 2652 2671 SEQ ID 1187 tgacttcagtgcagaatat 11966 11985 1 5 NO: SEQ ID NO: 185 gtcattgctcccggagcca 2667 2686 SEQ ID 1188 tggccccgtttaccatgac 5809 5828 1 5 NO: SEQ ID NO: 186 gctgaagtttatcattcct 2873 2892 SEQ ID 1189 aggaggctttaagttcagc 7600 7619 1 5 NO: SEQ ID NO: 187 attccttccccaaagagac 2886 905 SEQ ID 1190 gtctcttcctccatggaat 10470 10489 1 5 _ _NO: SEQ ID NO: 188 ctcattgagaacaggcagt 2976 2995 SEQ ID 1191 actgactgcacgctttgag 11756 11775 1 5 NO: SEQ ID NO:189 ttgagcagtattctgtcag 3142 3161 SEQ ID 1192 ctgagagaagtgtcttcaa 12399 1241815 NO: SEQ ID NO: 190 accttgtccagtgaagtcc 3285 3304 SEQ ID 1193 ggacggtactgtcccaggt 12784 12803 1 5 NO: SEQ ID NO: 191 ccagtgaagtccaaattcc 3292 3311 SEQ ID 1194 ggaaggcagagtttactgg 9148 9167 1 5 NO: SEQ ID NO: 192 acattcagaacaagaaaat 3394 3413 SEQ ID 1195 atttcctaaagctggatgt 11167 11186 1 5 NO: SEQ ID NO: 193 gaaaaatcaagggtgttat 3463 3482 SEQ ID 1196 ataaactgcaagatttttc 13600 13619 1 5 NO: SEQ ID NO: 194 aaatcaagggtgttatttc 3466 3485 SEQ ID 1197 gaaacaatgcattagattt 9745 9764 1 5 NO: SEQ ID NO: 195 tggcattatgatgaagaga 3609 3628 SEQ ID 1198 tctcccgtgtataatgcca 1178111800 1 5 NO: SEQ ID NO: 196 aagagaagattgaatttga 3622 3641 SEQ ID 1199 tcaaaacctactgtctctt 10458 10477 1 5 NO: SEQ ID NO: 197 aaatgacttccaatttccc 3673 3692 SEQ ID 1200 gggaactacaatttcattt 7013 7032 1 5 NO: SEQ ID NO: 198 atgacttccaatttccctg 3675 3694 SEQ ID 1201 caggctgattacgagtcat 4917 4936 1 5 NO: SEQ ID NO: 199 acttccaatttccctgtgg 3678 3697 SEQ ID 1202 ccacgaaaaatatggaagt 10360 10379 1 5 NO: SEQ ID NO: 200 agttgcaatgagctcatgg 3803 3822 SEQ ID 1203 ccatcagttcagataaact 7989 8008 1 5 NO: SEQ ID NO:201 tttgcaagaccacctcaat 3860 3879 SEQ ID 1204 attgacctgtccattcaaa 13671 13690 1 5 _ __NO: SEQ ID NO: 202 gaaggagttcaacctccag 3884 3903 SEQ ID 1205 ctggaattgtcattccttc 11728 11747 1 5 252 WO 2004/091515, PCT/US2004/011255 NO: SEQ ID NO:203 acttccacatcccagaaaa 3919 3938 SEQ ID - 1206 ttttaacaaaagtggaagt 6821 6840 1 5 NO: SEQ ID NO: 204 ctcttcttaaaaagcgatg 3939 3958 SEQ ID 1207 catcactgccaaaggagag 8486 8505 15 NO: SEQ ID NO:205 aaaagcgatggccgggtca 3948 3967 SEQ ID 1208 tgactcactcattgatttt 12680 12699 1 5 NO: SEQ ID NO:206 ttcctttgccttttggtgg 4003 4022 SEQ ID 1209 ccacaaacaatgaagggaa 9256 9275 15 NO: SEQ ID NO:207 caagtctgtgggattccat 4079 4098 SEQ ID 1210 atgggaaaaaacaggcttg 9566 9585 1 5 NO: SEQ ID NO:208 aagtccctacttttaccat 4117 4136 SEQ ID 1211 atgggaagtataagaactt 4834 4853 15 NO: SEQ ID NO: 209 tgcctctcctgggtgttct 4159 4178 SEQ ID 1212 agaaaaacaaacacaggca 9643 9662 1 5 NO: SEQ ID NO:210 accagcacagaccatttca 4242 4261 SEQ ID 1213 tgaagtgtagtctcctggt 5089 5108 1 5 ____ __ _ _ ____ ___ ___ ___ NO: SEQ ID NO: 211 ccagcacagaccatttcag 4243 4262 SEQ ID 1214 ctgaaatacaatgctctgg 5511 5530 15 ___ NO: SEQ ID NO:212 actatcatgtgatgggtct 4367 4386 SEQ ID 1215 agacacctgattttatagt 7948 7967 15 NO: SEQ ID NO: 213 accacagatgtctgcttca 4496 4515 SEQ ID 1216 tgaaggctgactctgtggt 4282 4301 1 5 ___ ___NO: SEQ ID NO:214 ccacagatgtctgcttcag 4497 4516 SEQ ID 1217 ctgagcaacaaatttgtgg 10311 10330 15 1__ NO: SEQ ID NO:215 tttggactccaaaaagaaa 4520 4539 SEQ ID 1218 tttctctcatgattacaaa 5933 5952 15 NO: SEQ ID NO:216 tcaaagaagtcaagattga 4552 4571 SEQ ID 1219 tcaaggataacgtgtttga 12610 126291 5 NO: SEQ ID NO: 217 atgagaactacgagctgac 4798 4817 SEQ ID 1220 gtcagatattgttgctcat 10187 10206 15 NO: SEQ ID NO:218 ttaaaatctgacaccaatg 4818 4837 SEQ ID 1221 cattcattgaagatgttaa 7342 7361 1 5 NO: SEQ ID NO: 219 gaagtataagaactttgcc 4838 4857 SEQ ID 1222 ggcaaatttgaaggacttc 11994 12013 1 5 NO: SEQ ID NO:220 aagtataagaactttgcca 4839 4858 SEQ ID 1223 tggcaaatttgaaggactt 11993 12012 15 1 1 NO: SEQ ID NO: 221 ttcttcagcctgctttctg 4941 4960 SEQ ID 1224 cagaatccagatacaagaa 6884 6903 15 NO: SEQ ID NO: 222 ctggatcactaaattccca 4957 4976 SEQ ID 1225 tgggtctttccagagccag 11033 11052 1 5 NO: 3EQ.ID NO:223 aaattaatagtggtgctca 5014 5033 SEQ ID 1226 tgagaagccccaagaattt 6248 6267 15 NO: 3EQ ID NO: 224 agtgcaacgaccaacttga 5073 5092 SEQ ID 1227 tcaaattcctggatacact 9848 9867 1 5 __ _ _NO:II 3EQ ID NO: 225 ctgggaagtgcttatcagg 5238 5257 SEQ ID 1228 cctgaccttcacataccag 8310 8329 1 I__INO: 3EQ ID NO: 226 gcaaaaacattttcaactt 5278 5297 SEQ ID 1229 aagtaaaagaaaattttgc 10744 107631 5 _____NO:I 3EQ ID NO: 227 aaaaacattttcaacttca 5280 5299 SEQ ID 1230 tgaagtaaaagaaaatttt 10742 107611 5 NO: 'EQ ID NO: 228 tcagtcaagaaggacttaa 5302 5321 SEQ ID 1231 ttaaggacttccattctga 13363 13382 1 5 NO: 3EQ ID NO: 229 tcaaatgacatgatgggct 5325 5344 SEQ ID 1232 agcccatcaatatcattga 6205 6224 15 ____ ________ ____NO: 5]_ _________ 'EQ ID NO: 230 cacacaaacagtctgaaca 5367 5386 SEQ ID 1233 tgtttcaactgcctttgtg 11219112381 5 253 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO:231 tcttcaaaacttgacaaca 5409 5428 SEQ ID 1234 tgttttcctatttccaaga 12835 12854 1 5 NO: SEQ ID NO:232 caagttttataagcaaact 5441 5460 SEQ ID 1235 agttattttgctaaacttg 14043 14062 1 5 _______NO: SEQ ID NO:233 tggtaactactttaaacag 5488 5507 SEQ ID 1236 ctgtttttagaggaaacca 7512 7531 15 NO: SEQ ID NO:234 aacagtgacctgaaataca 5502 5521 SEQ ID 1237 tgtatagcaaattcctgtt 5890 5909 15 NO: SEQ ID NO:235 gggaaactacggctagaac 5544 5563 SEQ ID 1238 gttccttccatgatttccc 10933 10952 15 NO: SEQ ID NO: 236 aacacatctatgccatctc 5620 5639 SEQ ID 1239 gagacagcatcttcgtgtt 11204 11223 1 5 NO: SEQ ID NO:237 tcagcaagctataaagcag 5652 5671 SEQ ID 1240 ctgctaagaaccttactga 7780 7799 15 NO: SEQ ID NO: 238 gcagacactgttgctaagg 5667 5686 SEQ ID 1241 cctttcaagcactgactgo 11746 11765 1 5 NO: SEQ ID NO: 239 tctggggagaacatactgg 5866 5885 SEQ ID 1242 ccaggttttccacaccaga 8038 8057 15 NO: SEQ ID NO: 240 ttctctcatgattacaaag 5934 5953 SEQ ID 1243 ctttttcaccaacggagaa 10838 10857 1 5 NO: SEQ ID NO:241 ctgagcagacaggcacctg 6034 6053 SEQ ID 1244 caggaggctttaagttcag 7599 7618 1 5 NO: I SEQ ID NO: 242 caatttaacaacaatgaat 6066 6085 SEQ ID 1245 attccttcctttacaattg 8082 8101 1 5 NO: SEQ ID NO: 243 tggacgaactctggctgac 6140 6159 SEQ ID 1246 gtcagcccagttccttcca 10924 10943 1 5 NO: SEQ ID NO: 244 cttttactcagtgagccca 6192 6211 SEQ ID 1247 tgggctaaacgtatgaaag 7827 7846' 1 5 NO: SEQ ID NO: 245 tcattgatgctttagagat 6217 6236 SEQ ID 1248 atcttcataagttcaatga 13174 13193 1 5 1 NO: 1 SEQ ID NO:246 aaaaccaagatgttcactc 6295 6314 SEQ ID 1249 gagtgaaatgctgtttttt 8630 8649, 1 5 NO: 3EQ ID NO:247 aggaatcgacaaaccatta 6357 6376 SEQ ID 1250 taatgattttcaagttcct 8294 8313 1 5 NO: 3EQ ID NO: 248 tagttgtactggaaaacgt 6376 6395 SEQ ID 1251 acgttagcctctaagacta 11928 11947 1 5 NO: 3EQ ID NO:249 ggaaaacgtacagagaaag 6386 6405 SEQ ID 1252 cttttacaattcattttcc 13014 13033 15 NO: )EQ ID NO: 250 gaaaacgtacagagaaagc 6387 6406 SEQ ID 1253 gctttctcttccacatttc 10052 10071 15 NO: 3EQ ID NO: 251 aaagctgaagcacatcaat 6401 6420 SEQ ID 1254 attgatgttagagtgcttt 6984 7003 1 5 NO: 3EQ ID NO: 252 aagctgaagcacatcaata 6402 6421 SEQ ID 1255 tattgatgttagagtgctt 6983 7002 1 5 ______________ NO: _ _ _ _ _ _ _ _ _ 3EQ ID NO: 253 tgaagcacatcaatattga 6406 6425 SEQ ID 1256 tcaaccttaatgattttca 8287 8306 1 5 NO: 3EQ ID NO: 254 atcaatattgatcaatttg 6414 6433 SEQ ID 1257 caaagccatcactgatgat 1660 1679 15 NO: EQ ID NO: 255 taatgattatctgaattca 6476 6495 SEQ ID 1258 tgaaatcattgaaaaatta 6719 6738 1 5 NO: )EQ ID NO: 256 gattatctgaattcattca 6480 6499 SEQ ID 1259 tgaagtagctgagaaatc 7094 7113 1 5 NO: _ _ _ _ _ _ _ _ _ 'EQ ID NO: 257 aattgggagagacaagttt 6498 6517 SEQ ID 1260 aaacattcctttaacaatt 9488 9507 1 5 ~E DNO 5 aatgcatctaa 6693 6712 ISEQ ID 1261 tattgaaaatattgatttt 6806 6825 1 5 254 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 259 aaaattaaaaagtcttgat 6731 6750 SEQ ID 1262 atcatatccgtgtaatttt 6757 6776 1 5 NO: SEQ ID NO: 260 ttgaaaatattgattttaa 6808 6827 SEQ ID 1263 ttaatcttcataagttcaa 13171 131901 5 NO: SEQ ID NO: 261 agacatccagcacctagct 6938 6957 SEQ ID 1264 agcttggttttgccagtct 2458 2477 15 NO: SEQ ID NO:262 caatttcatttgaaagaat 7021 7040 SEQ ID 1265 attccttcctttacaattg 8082 8101 15 NO: SEQ ID NO: 263 aggttttaatggataaatt 7174 7193 SEQ ID 1266 aattgttgaaagaaaacct 13147 131661 5 NO: SEQ ID NO: 264 cagaagctaagcaatgtcc 7233 7252 SEQ ID 1267 ggacaaggcccagaatctg 12545 12564 1 5 NO: SEQ ID NO: 265 taagataaaagattacttt 7262 7281 SEQ ID 1268 aaagaaaacctatgcctta 13155 131741 5 NO: SEQ ID NO:266 aaagattactttgagaaat 7269 7288 SEQ ID 1269 atttcttaaacattccttt 9481 9500 1 5 _______NO: SEQ ID NO:267 gagaaattagttggattta 7281 7300 SEQ ID 1270 taaagccattcagtctctc 12962 12981 15 NO: SEQ ID NO:268 atttattgatgatgctgtc 7295 7314 SEQ ID 1271 gacatgttgataaagaaat 7371 7390 1 5 _______NO: SEQ ID NO:269 gaattatcttttaaaacat 7326 7345 SEQ ID 1272 atgtatcaaatggacattc 7677 7696 15 NO: SEQ ID NO:270 ttaccaccagtttgtagat 7403 7422 SEQ ID 1273 atctggaaccttgaagtaa 10731 1075015 NO: SEQ ID NO:271 ttgcagtgtatctggaaag 7540 7559 SEQ ID 1274 cttttcacattagatgcaa 8412 8431 1 5 _____ NO: SEQ ID NO:272 cattcagcaggaacttcaa 7691 7710 SEQ ID 1275 ttgaaggacttcaggaatg 12001 1202015 NO: SEQ ID NO: 273 acacctgattttatagtcc 7950 7969 SEQ ID 1276 ggactcaaggataacgtgt 12606 12625 1 5 NO: SEQ ID NO:274 ggattccatcagttcagat 7984 8003 SEQ ID 1277 atcttcaatgattatatcc 13116S1313515 NO: SEQ ID NO: 275 ttgtagaaatgaaagtaaa 8104 8123 SEQ ID 1278 tttatgattatgtcaacaa 12352 12371 1 5 NO: SEQ ID NO:276 ctgaacagtgagctgcagt 8148 8167 SEQ ID 1279 actggacttctctagtcag 8801 8820 1 5 NO: SEQ ID NO: 277 aatccaatctcctcttttc 8399 8418 SEQ ID 1280 gaaaaatgaagtccggatt 11009 11028 1 5 _______NO: SEQ ID NO:278 attttgattttcaagcaaa 8524 8543 SEQ ID 1281 tttgcaagttaaagaaaat 14015 14034 15 NO: SEQ ID NO:279 ttttgattttcaagcaaat 8525 8544 SEQ ID 1282 atttgatttaagtgtaaaa 9614 9633 15 NO: SEQ ID NO: 280 tgattttcaagcaaatgca 8528 8547 SEQ ID 1283 tgcaagttaaagaaaatca 14017 14036 1 5 ___ NO: SEQ ID NO:281 atgctgttttttggaaatg 8637 8656 SEQ ID 1284 cattggtaggagacagcat 111951121415 NO: SEQID NO:282 tgctgttttttggaaatgc 8638 8657 SEQID 1285 gcattggtaggagacagca 111941121315 ____ __ ___ ____ ___ ___NO: SEQ ID NO:283 aaaaaaatacactggagct 8698 8717 SEQ ID 1286 agctagagggcctcttttt 108251084415 NO: 3EQ ID NO: 284 tctggaggtagtaatgga 8708 8727 SEQ ID 1287 tccactcacatcctccagt 1281 1300 1 5 NO: 3EQ ID NO: 285 fttCtggaaaagggtcatg 8878 8897 SEQ ID 1288 catgaacccctacatgaag 13751 13770 1 5 3 EQ ID NO:286 ggaaaagggtcatggaaat 8883 8902 SEQ ID 1289 atttgaaagttcgttttcc 9274 9293 15 255 WO 2004/091515 PCT/US2004/011255 NO: SEQIDNO:287 gggcctgccccagattctc 8902 8921 SEQ ID 1290 gagaacattatggaggccc 9432 9451 15 NO: SEQ ID NO: 288 ttctcagatgagggaacac 8916 8935 SEQ ID 1291 gtgtcttcaaagctgagaa 12408 124271 5 NO: SEQ ID NO:289 gatgagggaacacatgaat 8922 8941 SEQ ID 1292 attccagcttccccacatc 8330 8349 1 5 NO: SEQ ID NO: 290 ctttggactgtccaataag 8978 8997 SEQ ID 1293 cttatgggatttcctaaag 11159 11178 1 5 NO: SEQ ID NO: 291 gcatccacaaacaatgaag 9252 9271 SEQ ID 1294 cttcatctgtcattgatgc 10219 10238 1 5 NO: SEQ ID NO: 292 cacaaacaatgaagggaat 9257 9276 SEQ ID 1295 attccctgaagttgatgtg 11480 11499 1 5 NO: SEQ ID NO: 293 ccaaaatttctctgctgga 9407 9426 SEQ ID 1296 tccatcacaaatcctttgg 9663 9682 15 NO: 3EQ ID NO:294 caaaatttctctgctggaa 9408 9427 SEQ ID 1297 ttccatcacaaatcctttg 9662 9681 1 5 NO: III 3EQ ID NO: 295 tctgctggaaacaacgaga 9417 9436 SEQ ID 1298 tctcaagagttacagcaga 13221 132401 5 NO: 3EQ ID NO: 296 ctgctggaaacaacgagaa 9418 9437 SEQ ID 1299 ttctcaagagttacagcag 13220 13239 1 5 ______NO: 3EQ ID NO: 297 agaacattatggaggccca 9433 9452 SEQ ID 1300 tgggcctgccccagattct 8901 8920 15 NO: 3EQ ID NO: 298 agaagcaaatctggatttc 9467 9486 SEQ ID 1301 gaaatcttcaatttattct 13813 13832 1 5 NO: 3EQ ID NO: 299 tttctctctatgggaaaaa 9557 9576 SEQ ID 1302 tttttgcaagttaaagaaa 14013 140321 5 NO: )EQ ID NO: 300 tcagagcatcaaatccttt 9704 9723 SEQ ID 1303 aaagaaaatcaggatctga 14025 14044 1 5 1 _ _ _ NO: II 3EQ ID NO: 301 cagaaacaatgcattagat 9743 9762 SEQ ID 1304 atctatgccatctcttctg 5625 5644 15 NO: 3EQ ID NO: 302 tacacattaatcctgccat 9993 10012 SEQ ID 1305 atggagtctttattgtgta 14081 141001 5 NO: 3EQ ID NO: 303 agtcagatattgttgctca 1018610205 SEQ ID 1306 tgagaactacgagctgact 4799 4818 1 5 NO: 3EQ ID NO: 304 ggagggtagtcataacagt 1032810347 SEQ ID 1307 actggtggcaaaaccctcc 2726 2745 1 5 NO: EQ ID NO: 305 caaaagccgaaattccaat 1039610415 SEQ ID 1308 attgaagtacctacttttg 8358 8377 1 5 NO: 3EQ ID NO: 306 aaaagccgaaattccaatt 1039710416 SEQ ID 1309 aattgaagtacctactttt 8357 8376 1 5 NO: 3EQ ID NO: 307 ttcaagcaagaacttaatg 1042810447 SEQ ID 1310 cattatggcccttcgtgaa 13250 13269 1 5 NO: 3EQ ID NO: 308 cctcttacttttccattga 1057010589 SEQ ID 1311 tcaaaagaagcccaagagg 12939 12958 1 5 NO: EQ ID NO: 309 tgaggccaacacttacttg 1065510674 SEQ ID 1312 caagcatctgattgactca 12668 126871 5 NO: 1 EQ ID NO: 310 cacttacttgaattccaag 1066410683 SEQ ID 1313 cttgaacacaaagtcagtg 6000 6019 1 5 NO: EQ ID NO: 311 gaagtaaaagaaaattttg 1074310762SEQ ID 1314 caaaaacattttcaacttc 5279 5298 1 5 _ INO: EQ ID NO: 312 cctggaactctctccatgg 1087410893 SEQ ID 1315 ccatttacagatcttcagg 11364 113831 5 _ _ NO: EQ ID NO: 313 agctggatgtaaccaccag 1117611195 SEQ ID 1316 ctggattccacatgcagct 11847 11866 15 NO: EQ ID NO: 314 aaaattccctgaagttgat 1147711496 SEQ ID 1317 atcatatccgtgtaatttt 6757 6776 1 5 256 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 315 cagatggcattgctgcttt 1160511624SEQ ID 1318 aaagctgagaagaaatctg 12416 124351 5 _ NO: SEQ ID NO:'316 agatggcattgctgctttg 1160611625SEQ ID 1319 caaagctgagaagaaatct 1241512434 15 NO: SEQ ID NO: 317 tgttgaaacagtcctggat 1183411853 SEQ ID 1320 atccaagatgagatcaaca 13095-131141 5 NO: SEQ ID NO: 318 catattcaaaactgagttg 1222112240 SEQ ID 1321 caactctctgattactatg 13623 13642 1 5 NO: SEQ ID NO: 319 aaagatttatcaaaagaag 1293012949 SEQ ID 1322 cttcaatttattcttcttt 13818 138371 5 _______ ~~NO:____ _____ SEQ ID NO: 320 attttccaactaatagaag 1302613045 SEQ ID 1323 cttcaaagacttaaaaaat 8006 8025 1 5 NO: SEQ ID NO: 321 aattatatccaagatgaga 1308913108SEQ ID 1324 tctcttcctccatggaatt 10471 10490 1 5 NO: SEQ ID NO: 322 ttcaggaagcttctcaaga 1321013229 SEQ ID 1325 tcttcataagttcaatgaa 1317513194 1 5 NO: SEQ ID NO: 323 ttgagcaatttctgcacag 13429134481SEQ ID 1326 ctgttgaaagatttatcaa 12924 12943 1 5 NO: SEQ ID NO:324 ctgatatacatcacggagt 1370413723SEQ ID 1327 actcaatggtgaaattcag 7457 7476 15 1 _____ __ _ NO: SEQ ID NO: 325 acatcacggagttactgaa 1371113730 SEQ ID 1328 ttcagaagctaagcaatgt 7231 7250 15 |NO: SEQ ID NO: 326 actgcctatattgataaaa 1387413893 SEQ ID 1329 ttttggcaagctatacagt 8372 8391 1 5 ______ ~~~NO:_____ ____ SEQ ID NO: 327 aggatggcattttttgcaa 1400314022SEQ ID 1330 ttgcaagcaagtctttcct 3005 3024 1 5 NO: SEQ ID NO: 328 ttttttgcaagttaaagaa 1401214031 SEQ ID 1331 ttctctctatgggaaaaaa 9558 9577 1 5 NO: SEQ ID NO:329 tccagaactcaagtcttca 1619 1638 SEQ ID 1332 tgaaatgctgttttttgga 8633 8652 34 NO: SEQ ID NO: 330 agttagtgaaagaagttct 1948 1967 SEQ ID 1333 agaatctgtaccaggaact 12556 12575 3 4 NO: SEQ ID NO: 331 atttacagctctgacaagt 5427 5446 SEQ ID 1334 acttcagagaaatacaaat 11401 11420 3 4 NO: SEQ ID NO: 332 gattatctgaattcattca 6480 6499 SEQ ID 1335 tgaaaccaatgacaaaatc 7421 7440 3 4 NO: SEQ ID NO: 333 gtgcccttctcggttgctg 18 37 SEQ ID 1336 cagctgagcagacaggcac 6031 6050 24 NO: SEQ ID NO: 334 attcaagcacctccggaag 245 264 SEQ ID 1337 cttcataagttcaatgaat 13176 13195 2 4 NO: 3EQ ID NO: 335 gactgctgattcaagaagt 308 327 SEQ ID 1338 acttcccaactctcaagtc 13407 13426 2 4 NO: 3EQ ID NO: 336 ttgctgcagccatgtccag 475 494 SEQ ID 1339 ctgggcagctgtatagcaa 5881 5900 24 NO: 3EQ ID NO: 337 agaaagatgaacctactta 547 566 SEQ ID 1340 taagtatgatttcaattct 10490 10509 2 4 NO: 3EQ ID NO: 338 tgaagactctccaggaact 1087 1106 SEQ ID 1341 agttcaatgaatttattca 13183 13202 2 4 1___1_ NO: 3EQ ID NO:339 atctctcttgccacagctg 1202 1221 SEQ ID 1342 cagcccagccatttgagat 9229 9248 24 NO: 3EQ ID NO: 340 tctctcttgccacagctga 1203 1222 SEQ ID 1343 tcagcccagccatttgaga 9228 9247 24 NO: 3EQ ID NO: 341 tgaggtgtccagccccatc 1223 1242 SEQ ID 1344 gatgggaaagccgccctca 5208 5227 24 NO: 3EQ ID NO: 342 ccagaactcaagtcttcaa 1620 1639 SEQ ID 1345 ttgaaagcagaacctctgg 5907 5926 24 257 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 343 ctgaaaaagttagtgaaag 1941 1960 SEQ ID 1346 ctttctcgggaatattcag 10623 1064224 NO: _ _ _ _ _ _ _ _ _ _ _ _ SEQ ID NO: 344 tttttcccagacagtgtca 2238 2257 SEQ ID 1347 tgacaggcattttgaaaaa 9722 9741 24 __ NO: I SEQ ID NO: 345 ttttcccagacagtgtcaa 2239 2258 SEQ ID 1348 ttgacaggcattttgaaaa 9721 9740 24 1_ NO: SEQ ID NO:346 cattcagaacaagaaaatt 3395 3414 SEQ ID 1349 aattccaattttgagaatg 104061 042524 _____ _ _______NO: SEQ ID NO:347 tgaagagaagattgaattt 3620 3639 SEQ ID 1350 aaatgtcagctcttgttca 10894 10913 2 4 NO: SEQ ID NO: 348 tttgaatggaacacaggca 3636 3655 SEQ ID 1351 tgccagtttgaaaaacaaa 118071182624 _______NO: SEQ ID NO: 349 ttctagattcgaatatcaa 4399 4418 SEQ ID 1352 ttgacatgttgataaagaa 7369 7388 2 4 _______NO: SEQ ID NO:350 gattcgaatatcaaattca 4404 4423 SEQ ID 1353 tgaagtagaccaacaaatc 7154 7173 24 1_ INO: SEQ ID NO: 351 tgcaacgaccaacttgaag 5075 5094 SEQ ID 1354 cttcaggttccatcgtgca 11376 11395 2 4 _______NO: SEQ ID NO: 352 ttaagctctcaaatgacat 5317 5336 SEQ ID 1355 atgttgataaagaaattaa 7374 7393 24 NO: SEQ ID NO: 353 caatttaacaacaatgaat 6066 6085 SEQ ID 1356 attcaaactgcctatattg 13868 13887 2 4 NO: SEQ ID NO: 354 tgaatacagccaggacttg 6080 6099 SEQ ID 1357 caagagcacacggtcttca 10679 1069824 NO: SEQ ID NO:355 catcaatattgatcaattt 6413 6432 SEQ ID 1358 aaattccctgaagttgatg 11478 11497 24 NO: SEQ ID NO: 356 ttgagcatgtcaaacactt 7051 7070 SEQ ID 1359 aagtaagtgctaggttcaa 9373 9392 24 NO: SEQ ID NO:357 tgaaggagactattcagaa 7219 7238 SEQ ID 1360 ttctgcacagaaatattca 13438 13457 2 4 NO: SEQ ID NO: 358 ttcaggctcttcagaaagc 7921 7940 SEQ ID 1361 gcttgctaacctctctgaa 12304 12323 2 4 NO: SEQ ID NO: 359 tccacaaattgaacatccc 8779 8798 SEQ ID 1362 gggacctaccaagagtgga 12525 12544 24 NO: SEQ ID NO: 360 tgaataccaatgctgaact 1015910178SEQ ID 1363 agttcaatgaatttattca 13183 13202 2 4 NO: SEQ ID NO: 361 taaactaatagatgtaatc 1289012909 SEQ ID 1364 gattactatgaaaaattta 13632 13651 2 4 NO: SEQ ID NO: 362 ttgacctgtccattcaaaa 1367213691 SEQ ID 1365 ttttaaaagaaatcttcaa 13805 138242 4 NO: SEQ ID NO: 363 gggctgagtgcccttctcg 11 30 SEQ ID 1366 cgaggccaggccgcagccc 76 95 14 NO: SEQ ID NO:364 ggctgagtgcccttctcgg 12 31 SEQ ID 1367 ccgaggccaggccgcagcc 75 94 1 4 NO: SEQ ID NO: 365 ctgagtgcccttctcggtt 14 33 SEQ ID 1368 aaccgtgcctgaatctcag 11549 11568 1 4 __ _ __ _ __ _ __ _ _NO:II I SEQ ID NO: 366 tctcggttgctgccgctga 25 44 SEQ ID 1369 tcagctgacctcatcgaga 2160 2179 14 ____ ____ ___NO: SEQ ID NO:367 caggccgcagcccaggagc 82 101 SEQ ID 1370 gctctgcagcttcatcctg 368 387 1 4 NO: SEQ ID NO:368 gctggcgctgcctgcgctg 143 162 SEQ ID 1371 cagcacagaccatttcagc 4244 4263 14 NO: SEQ ID NO:369 tgctgctggcgggcgccag 169 188 SEQ ID 1372 ctggatgtaaccaccagca 11178 1119714 NO: SEQ ID NO:370 ctggtctgtccaaaagatg 219 238 SEQ ID 1373 catcctgaagaccagccag 380 399 1 4 258 WO 2004/091515 _ . _ PCT/US2004/011255 NO: SEQ ID NO:371 ctgagagttccagtggagt 283 302 SEQ ID 1374 actcaccctggacattcag 3383 3402 14 NO: SEQ ID NO:372 tccagtggagtccctggga 291 310 SEQ ID 1375 tcccggagccaaggctgga 2675 2694 1 4 NO: SEQ ID NO: 373 aggttgagctggaggttcc 346 365 SEQ ID 1376 ggaaccctctccctcacct 4728 4747 1 4 NO: SEQ ID NO:374 tgagctggaggttccccag 350 369 SEQ ID 1377 ctgggaggcatgatgctca 9163 9182 1 4 NO: SEQ ID NO: 375 tctgcagcttcatcctgaa 370 389 SEQ ID 1378 ttcaaatataatcggcaga 3261 3280 1 4 NO: SEQ ID NO: 376 gccagtgcaccctgaaaga 394 413 SEQ ID 1379 tcttccgttctgtaatggc 5794 5813 1 4 NO: SEQ ID NO: 377 ctctgaggagtttgctgca 464 483 SEQ ID 1380 tgcaagaatattttgagag 6340 6359 1 4 1_____ NO: SEQ ID NO:378 aggtatgagctcaagctgg 492 511 SEQ ID 1381 ccagtttccggggaaacct 12716 12735 14 __ NO:I SEQ ID NO: 379 tcctttacccggagaaaga 535 554 SEQ ID 1382 tctttttgggaagcaagga 2219 2238 1 4 NO: SEQ ID NO: 380 catcaagaggggcatcatt 575 594 SEQ ID 1383 aatggtcaagttcctgatg 2277 2296 1 4 NO: SEQ ID NO: 381 tcctggttcccccagagac 601 620 SEQ ID 1384 gtctctgaactcagaagga 13988 14007 1 4 NO: SEQ ID NO: 382 aagaagccaagcaagtgtt 622 641 SEQ ID 1385 aacaaataaatggagtctt 14072 14091 1 4 NO: SEQ ID NO: 383 aagcaagtgttgtttctgg 630 649 SEQ ID 1386 ccagagccaggtcgagctt 11042 11061 1 4 NO: SEQ ID NO: 384 tctggataccgtgtatgga 644 663 SEQ ID 1387 tccatgtcccatttacaga 11356 113751 4 NO: SEQ ID NO: 385 ccactcactttaccgtcaa 670 689 SEQ ID 1388 ttgattttaacaaaagtgg 6817 6836 1 4 NO: II SEQ ID NO:386 aggaagggcaatgtggcaa 693 712 SEQ ID 1389 ttgcaagcaagtctttcct 3005 3024 14 NO: SEQ ID NO:387 gcaatgtggcaacagaaat 700 719 SEQ ID 1390 atttccataccccgtttgc 3480 3499 1 4 NO: SEQ ID NO: 388 caatgtggcaacagaaata 701 720 SEQ ID 1391 tattcttcttttccaattg 13826 13845 1 4 NO: 3EQ ID NO: 389 tggcaacagaaatatccac 706 725 SEQ ID 1392 gtggcttcccatattgcca 1887 1906 1 4 NO: SEQ ID NO: 390 agagacctgggccagtgtg 729 748 SEQ ID 1393 cacattacatttggtctct 2930 2949 1 4 NO: 3EQ ID NO:391 tgtgatcgcttcaagccca 744 763 SEQ ID 1394 tgggaaagccgccctcaca 5210 5229 1 4 NO: 3EQ ID NO: 392 gtgatcgcttcaagcccat 745 764 SEQ ID 1395 atgggaaagccgccctcac 5209 5228 1 4 NO: 3EQ ID NO: 393 cagcccacttgctctcatc 776 795 SEQ ID 1396 gatgctgaacagtgagctg 8144 8163 14 NO: 3EQ ID NO: 394 gctctcatcaaaggcatga 786 805 SEQ ID 1397 tcataacagtactgtgagc 10337 10356 1 4 NO: 3EQ ID NO: 395 ccttgtcaactctgatcag 811 830 SEQ ID 1398 ctgagtgggtttatcaagg 12445124641 4 ____1_ NO: I II 3EQ ID NO: 396 cttgtcaactctgatcagc 812 831 SEQ ID 1399 gctgagtgggtttatcaag 12444 12463 1 4 NO: 3EQ ID NO: 397 agccatctgcaaggagcaa 884 903 SEQ ID 1400 ttgcaatgagctcatggct 3805 3824 1 4 NO: 3EQ ID NO: 398 gccatctgcaaggagcaac 885 904 SEQ ID 1401 gttgcaatgagctcatggc 3804 3823 1 4 259 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 399 cttcctgcctttctcctac 908 927 SEQ ID 1402 gtaggaataaatggagaag 9453 9472 1 4 NO: SEQ ID NO: 400 ctttctcctacaagaataa 916 935 SEQ ID 1403 ttattgctgaatccaaaag 13648 136671 4 NO: SEQ ID NO: 401 gatcaacagccgcttcttt 989 1008 SEQ ID 1404 aaagccatcactgatgatc 1661 1680 1 4 NO: SEQ ID NO: 402 atcaacagccgcttctttg 990 1009 SEQ ID 1405 caaagccatcactgatgat 1660 1679 1 4 NO: SEQ ID NO: 403 acagccgcttctttggtga 994 1013 SEQ ID 1406 tcacaaatcctttggctgt 9667 9686 1 4 NO: SEQ ID NO:404 aagatgggcctcgcatttg 1023 1042 SEQ ID 1407 caaaatagaagggaatctt 2069 2088 14 NO: SEQ ID NO: 405 tgttttgaagactctccag 1082 1101 SEQ ID 1408 ctggtaactactttaaaca 5487 5506 14 NO: SEQ ID NO: 406 ttgaagactctccaggaac 1086 1105 SEQ ID 1409 gttcaatgaatttattcaa 13184 13203 1 4 NO: SEQ ID NO:407 aactgaaaaaactaaccat 1102 1121 SEQ ID 1410 atggcattttttgcaagtt 140061402514 NO: SEQ ID NO: 408 ctgaaaaaactaaccatct 1104 1123 SEQ ID 1411 agattgatgggcagttcag 4564 4583 1 4 NO: SEQ ID NO: 409 aaaactaaccatctctgag 1109 1128 SEQ ID 1412 ctcaaagaatgactttttt 2570 2589 14 NO: SEQ ID NO: 410 tgagcaaaatatccagaga 1124 1143 SEQ ID 1413 tctccagataaaaaactca 12201 1222014 NO: SEQ ID NO: 411 caataagctggttactgag 1154 1173 SEQ ID 1414 ctcagatcaaagttaattg 12265 12284 1 4 NO: SEQ ID NO: 412 tactgagctgagaggcctc 1166 1185 SEQ ID 1415 gagggtagtcataacagta 10329 10348 1 4 ____ ____ ___NO: SEQ ID NO: 413 gcctcagtgatgaagcagt 1180 1199 SEQ ID 1416 actgttgactcaggaaggc 12572 12591 1 4 1___1_ NO: SEQ ID NO:414 agtcacatctctcttgcca 1196 1215 SEQ ID 1417 tggccacatagcatggact 8858 8877 14 NO: 3EQ ID NO:415 atctctcttgccacagctg 1202 1221 SEQ ID 1418 cagctgacctcatcgagat 2161 2180 14 NO: 3EQ ID NO:416 tcttcttgccacagctga 1203 1222 SEQ ID 1419 tcagctgacctcatcgaga 2160 2179 14 NO: 3EQ ID NO: 417 tgccacagctgattgaggt 1210 1229 SEQ ID 1420 acctgcaccaaagctggca 13955 139741 4 NO: 3EQ ID NO: 418 gccacagctgattgaggtg 1211 1230 SEQ ID 1421 caccaaaaaccccaatggc 112401125914 1 1 NO:I I I 3EQ ID NO:419 tcactttacaagccttggt 1240 1259 SEQ ID 1422 accagatgctgaacagtga 8140 8159 114 NO: SEQ ID NO: 420 cccttctgatagatgtggt 1324 1343 SEQ ID 1423 accacttacagctagaggg 10816 108351 4 NO: 3EQ ID NO:421 gtcacctacctggtggccc 1341 1360 SEQ ID 1424 gggcgacctaagttgtgac 3431 3450 14 NO: 3EQ ID NO: 422 ccttgtatgcgctgagcca 1432 1451 SEQ ID 1425 tggctggtaacctaaaagg 5578 5597 1 4 NO: 3EQ ID NO: 423 gacaaaccctacagggacc 1472 1491 SEQ ID 1426 ggtcctttatgattatgtc 12347 12366114 NO: 3EQ ID NO:424 tgctaattacctgatggaa 1508 1527 SEQ ID 1427 ttcccaaaagcagtcagca 9930 9949 14 NO: 3EQ ID NO: 425 tgactgcactggggatgaa 1538 1557 SEQ ID 1428 ttcaggtccatgcaagtca 10909 109281 4 NO: 3EQ ID NO:1426 actgcactggggatgaaga 1540 1559 SEQ ID 1429 tcttgaacacaaagtcagt 5999 6018 1 4 260 .. ,WO 2004/091515 -..- .- PCT/US2004/011255 NO: SEQ ID NO:427 atgaagattacacctattt 1552 1571 SEQ ID 1430 aaatgaaagtaaagatcat 8110 8129 1 4 SEQ ID NO:428 accatggagcagttaactc 1602 1621 SEQ ID 1431 gagtaaaccaaaacttggt 9016 9035 14 NO: SEQ ID NO: 429 gcagttaactccagaactc 1610 1629 SEQ ID 1432 gagttactgaaaaagctgc 13719 13738 1 4 NO: SEQ ID NO: 430 cagaactcaagtcttcaat 1621 1640 SEQ ID 1433 attggatatccaagatctg 1925 1944 1 4 NO: SEQ ID NO: 431 caggctctgcggaaaatgg 1695 1714 SEQ ID 1434 coatgacctccagctcctg 2477 2496 1 4 I I NO: SEQ ID NO:432 ccaggaggttcttcttcag 1730 1749 SEQ ID 1435 ctgaaatacaatgctctgg 5511 5530 1 4 NO: SEQ ID NO:433 ggttcttcttcagactttc 1736 1755 SEQ ID 1436 gaaaaacttggaaacaacc 4431 4450 14 NO: SEQ ID NO:434 tttccttgatgatgcttct 1751 1770 SEQ ID 1437 agaatccagatacaagaaa 6885 6904 14 __ NO: SEQ ID NO:435 ggagataagcgactggctg 1773 1792 SEQ ID 1438 cagcatgcctagtttctcc 9944 9963 14 NO: SEQ ID NO:436 gctgcctatcttatgttga 1788 1807 SEQ ID 1439 tcaatatcaaaagcccagc 12037 12056 14 ______ NO:___ SEQ ID NO:437 actttgtggcttcccatat 1882 1901 SEQ ID 1440 atatctggaaccttgaagt 10729 10748 14 NO: SEQ ID NO: 438 gccaatatcttgaactcag 1902 1921 SEQ ID 1441 ctgaactcagaaggatggc 13992 140111 4 ______NO: SEQ ID NO:439 aatatcttgaactcagaag 1905 1924 SEQ ID 1442 cttccattctgaatatatt 13370 13389 14 NO: SEQ ID NO:440 ctcagaagaattggatatc 1916 1935 SEQ ID 1443 gataaaagattactttgag 7265 7284 14 NO: SEQ ID NO:441 aagaattggatatccaaga 1921 1940 SEQ ID 1444 tcttcaatttattcttctt 138175138361 4 NO: SEQ ID NO:442 agaattggatatccaagat 1922 1941 SEQ ID 1445 atcttcaatttatcttct 13816 13835 14 NO: SEQ ID NO:443 tggatatccaagatctgaa 1927 1946 SEQ ID 1446 ttcacataccagaattcca 8317 8336 1 4 NO: SEQ ID NO:444 atatccaagatctgaaaaa 1930 1949 SEQ ID 1447 tttttaaccagtcagatat 10177 101961 4 1 1 NO: SEQ ID NO: 445 tatccaagatctgaaaaag 1931 1950 SEQ ID 1448 cttttaaccagtgagata 10176 1019514 NO: SEQ ID NO:446 caagatctgaaaaagttag 1935 1954 SEQ ID 1449 ctaaattccatggtcttg 4965 4984 1 4 NO: SEQ ID NO: 447 aagatctgaaaaagttagt 1936 1955 SEQ ID 1450 actaaattcccatggtctt 4964 4983 1 4 NO: I__ _ _ __ _ _ _ SEQ ID NO:448 tgaaaaagttagtgaaaga 1942 1961 SEQ ID 1451 tctttctcgggaatattca 10622 1041 14 NO: SEQ ID NO:449 tccaactgtcatggacttc 1982 2001 SEQ ID 1452 gaagcacatatgaactgga 13937 13956 14 NO: SEQ ID NO:450 tcagaaaattctctcggaa 1999 2018 SEQ ID 1453 ttcctttaacaattcctga 9493 9512 1 4 _____ __ _ ____ _____ ___ NO:_ _ _ SEQ ID NO:451 ttccatcacttgacccagc 2044 2063 SEQ ID 1454 gctgacatagggaatggaa 8433 8452 1 4 NO: SEQ ID NO:452 cccagcctcagccaaaata 2057 2076 SEQ ID 1455 tattctatccaagattggg 7812 7831 14 NO: SEQ ID NO:453 agcctcagccaaaatagaa 2060 2079 SEQ ID 1456 ttctatccaagattgggct 7814 7833 1 4 ,NO: I II SEQ ID NO: 454 atcttatatttgatccaaa 2083 2102 SEQ ID 1457 tttgaaaaacaaagcagat 11813 11832 14 261 __.__ , WO 2004/091515, -- , PCT/US2004/011255 NO: SEQ ID NO: 455 tcttatatttgatccaaat 2084 2103 SEQ ID 1458 attttttgcaagttaaaga 14011 14030 1 4 NO: SEQ ID NO:456 cttcctaaagaaagcatgc 2109 2128 SEQ ID 1459 gcatggcattatgatgaag 3606 3625 14 _____ _ ___ NO: SEQ ID NO:457 ctaaagaaagcatgctgaa 2113 2132 SEQ ID 1460 ttcagggtgtggagtttag 5686 5705 14 ___ NO: SEQ ID NO:458 taaagaaagcatgctgaaa 2114 2133 SEQ ID 1461 tttcttaaacattccttta 9482 9501 14 ___ ___NO: SEQ ID NO:459 gagattggcttggaaggaa 2175 2194 SEQ ID 1462 ttccctccattaagttctc 11701 1172014 NO: SEQ ID NO:460 ctttgagccaacattggaa 2198 2217 SEQ ID 1463 ttccaatgaccaagaaaag 11060 11079 14 _____ _ ___ NO: SEQ ID NO:461 cagacagtgtcaacaaagc 2245 2264 SEQ ID 1464 gcttactggacgaactctg 6134 6153 14 NO: SEQ ID NO:462 cagtgtcaacaaagctttg 2249 2268 SEQ ID 1465 caaattcctggatacactg 9849 9868 14 NO: SEQ ID NO:463 agtgtcaacaaagctttgt 2250 2269 SEQ ID 1466 acaagaatacgtctacact 4351 4370 14 NO: SEQ ID NO:464 ctgatggtgtctctaaggt 2290 2309 SEQ ID 1467 acctcggaacaatcctcag 3325 3344 14 NO: SEQ ID NO:465 tgatggtgtctctaaggtc 2291 2310 SEQ ID 1468 gacctgcgcaacgagatca 8823 8842 1,4 NO: SEQ ID NO:466 aaacatgagcaggatatgg 2343 2362 SEQ ID 1469 ccatgatctacatttgttt 6788 6807 14 _ 1 NO: SEQ ID NO:467 gaagctgattaaagatttg 2387 2406 SEQ ID 1470 caaaaacattttcaacttc 5279 5298 T4 NO: SEQ ID NO: 468 aaagatttgaaatccaaag 2397 2416 SEQ ID 1471 ctttaagttcagcatcttt 7606 7625. 1 4 NO: SEQ ID NO:469 gatgggtgcccgcactctg 2510 2529 SEQ ID 1472 cagatttgaggattccatc 7975 7994 14 NO: SEQ ID NO:470 gggatcccccagatgattg 2532 2551 SEQ ID 1473 caatcacaagtcgattccc 9075 9094 1 4 NO: SEQ ID NO:471 ttttcttcactacatcttc 2585 2604 SEQ ID 1474 gaagtgtcagtggcaaaaa 10374 10393 14 NO: SEQ ID NO:472 tcttcactacatcttcatg 2588 2607 SEQ ID 1475 catggcattatgatgaaga 3607 3626 14 1___ NO: SEQ ID NO:473 tacatcttcatggagaatg 2595 2614 SEQ ID 1476 cattatggaggcccatgta 9437 9456 1 4 NO: SEQ ID NO:474 ttcatggagaatgcctttg 2601 2620 SEQ ID 1477 caaaatcaactttaatgaa 6599 6618 1 4 1 _ NO: SEQ ID NO:475 tcatggagaatgcctttga 2602 2621 SEQ ID 1478 tcaacacaatcttcaatga 131081312714 NO: SEQ ID NO:476 tttgaactccccactggag 2616 2635 SEQ ID 1479 ctccccaggacctttcaaa 9834 9853 1 4 NO: SEQ ID NO:477 ttgaactccccactggagc 617 2636 SEQ ID 1480 gctccccaggacctttcaa 9833 9852 14 NO: SEQ ID NO:478 tgaactccccactggagct 2618 2637 SEQ ID 1481 agctccccaggacctttca 9832 9851 14 NO: SEQ ID NO:479 cactggagctggattacag 2627 2646 SEQ ID 1482 ctgtttctgagtcccagtg 9336 9355 1 4 NO: SEQ ID NO:480 actggagctggattacagt 2628 647 SEQ ID 1483 actgtttctgagtcccagt 9335 9354 14 NO: SEQ ID NO:481 agttgcaaatatcttcatc 2644 2663 SEQ ID 1484 gatgatgccaaaatcaact 6591 6610 1 NO: SEQ ID NO:1482 gttgcaaatatcttcatct 2645 2664 SEQ ID 1485 agatgatgccaaaatcaac 6590 6609 1 4 262 WO 2004/091515. ........... ... - PCT/US2004/011255 NO: SEQ ID NO:483 aaatatcttcatctggagt 2650 2669 SEQ ID 1486 actcagaaggatggcattt 13996 140151 4 ____ __ ____ ___ ____ ___ ___ NO: SEQ ID NO:484 taaaactggaagtagccaa 2695 2714 SEQ ID 1487 ttggttacaggaggcttta 7592 7611 14 NO: SEQ ID NO:485 ggctgaactggtggcaaaa 2720 2739 SEQ ID 1488 ttttcttttcagcccagcc 9220 9239 1 4 _____ _ ___ NO: SEQ ID NO:486 tgtggagtttgtgacaaat 2750 2769 SEQ ID 1489 attttcaagcaaatgcaca 8530 8549 14 _____ _ __ ___NO: SEQ ID NO:487 ttgtgacaaatatgggcat 2758 2777 SEQ ID 1490 atgcgtctaccttacacaa 9513 9532 14 NO: SEQ ID NO:488 atgaacaccaacttcttcc 2811 2830 SEQ ID 1491 ggaagctgaagtttatcat 2869 2888 14 NO: SEQ ID NO:489 cttccacgagtcgggtctg 2825 2844 SEQ ID 1492 cagagctatcactgggaag 5227 5246 1 4 NO: SEQ ID NO:490 gagtcgggtctggaggctc 2832 2851 SEQ ID 1493 gagcttactggacgaactc 6132 6151 14 NO: SEQ ID NO: 491 cctaaaagctgggaagctg 2858 2877 SEQ ID 1494 cagcctccccagccgtagg 12112 12131 1 4 ___ NO: SEQ ID NO:492 agctgggaagctgaagttt 2864 2883 SEQ ID 1495 aaactgttaatttacagct 5455 5474 1 4 NO: SEQ ID NO: 493 ccagattagagctggaact 3106 3125 SEQ ID 1496 agtttccggggaaacctgg 12718 12737 1 4 NO: SEQ ID NO: 494 ggataccctgaagtttgta 3200 3219 SEQ ID 1497 tacagtattctgaaaatcc 8385 8404 1 4 NO: SEQ ID NO:495 ctgaggctaccatgacatt 3244 3263 SEQ ID 1498 aatgagctcatggcttcag 3809 3828 1 4 NO: SEQ ID NO: 496 tgtccagtgaagtccaaat 3289 3308 SEQ ID 1499 attttgagaggaatcgaca 6349 6368; 1 4 NO: SEQ ID NO:497 aattccggattttgatgtt 3305 3324 SEQID 1500 aacacatgaatcacaaatt 8930 8949 14 NO: SEQ ID NO: 498 ttccggattttgatgttga 3307 3326 SEQ ID 1501 tcaaaacgagcttcaggaa 13199 13218 14 NO: SEQ ID NO:499 cggaacaatcctcagagtt 3329 3348 SEQ ID 1502 aacttgtacaactggtccg 4203 4222 14 NO: SEQ ID NO: 500 tcctcagagttaatgatga 3337 3356 SEQ ID 1503 tcatcaattggttacagga 7585 7604 1 4 NO: SEQ ID NO: 501 ctcaccctggacattcaga 3384 3403 SEQ ID 1504 tctgcagaacaatgctgag 12431 12450 14 NO: SEQ ID NO: 502 cattcagaacaagaaaatt 3395 3414 SEQID 1505 aattgactttgtagaaatg 8096 8115 14 NO: SEQ ID NO:503 actgaggtcgccctcatgg 3414 3433 SEQ ID 1506 ccatgcaagtcagcccagt 10916 1093514 NO: SEQ ID NO: 504 ttatttccataccccgttt 3478 3497 SEQ ID 1507 aaactgcctatattgataa 13872 13891 1 4 NO: SEQ ID NO: 505 gtttgcaagcagaagccag 3493 3512 SEQ ID 1508 ctggacttctcttcaaaac 5400 5419 14 NO: SEQ ID NO: 506 tttgcaagcagaagccaga 3494 3513 SEQ ID 1509 tctgggtgtcgacagcaaa 5264 5283 14 NO: SEQ ID NO: 507 ttgcaagcagaagccagaa 3495 3514 SEQ ID 1510 ttctgggtgtcgacagcaa 5263 5282 14 NO: SEQ ID NO: 508 ctgcttctccaaatggact 3546 3565 SEQ ID 1511 agtcaagattgatgggcag 4559 4578 1 4 NO: SEQ ID NO: 509 tgctacagcttatggctcc 3569 3588 SEQ ID 1512 ggaggctttaagttcagca 7601 7620 1 4 NO: SEQ ID NO: 510 acagcttatggctccacag 3573 3592 SEQ ID 1513 ctgtatagcaaattcctgt 5889 5908 1 4 263 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 511 tttccaagagggtggcatg 3592 3611 SEQ ID 1514 catggacttcttctggaaa 8869 8888 14 NO: SEQ ID NO: 512 ccaagagggtggcatggca 3595 3614 SEQ ID 1515 tgcccagcaagcaagttgg 9353 9372 14 NO: SEQ ID NO: 513 gtggcatggcattatgatg 3603 3622 SEQ ID 1516 catccttaacaccttccac 8063 8082 14 NO: SEQ ID NO: 514 tgatgaagagaagattgaa 3617 3636 SEQ ID 1517 ttcactgttcctgaaatca 7863 7882 14 NO: SEQ ID NO: 515 gaagagaagattgaatttg 3621 3640 SEQ ID 1518 caaaaacattttcaacttc 5279 5298 14 NO: SEQ ID NO: 516 gagaagattgaatttgaat 3624 3643 SEQ ID 1519 attcataatcccaactctc 8270 8289 1 4 NO: __ _ SEQ ID NO: 517 tttgaatggaacacaggca 3636 3655 SEQ ID 1520 tgcctttgtgtacaccaaa 11228 11247 14 NO: SEQ ID NO: 518 aggcaccaatgtagatacc 3650 3669 SEQ ID 1521 ggtaacctaaaaggagcct 5583 5602 1 4 NO: SEQ ID NO: 519 caaaaaaatgacttccaat 3668 3687 SEQ ID 1522 attgaagtacctacttttg 8358 8377 1 4 NO: SEQ ID NO: 520 aaaaaaatgacttccaatt 3669 3688 SEQ ID 1523 aattgaagtacctactttt 8357 8376 1 4 NO: SEQ ID NO: 521 aaaaaatgacttccaattt 3670 3689 SEQ ID 1524 aaatccaatctcctctttt 8398 8417 1 4 NO: SEQ ID NO: 522 cagagtccctcaaacagac 3752 3771 SEQ ID 1525 gtctgtgggattccatctg 4082 4101 14 NO: SEQ ID NO: 523 aaattaatagttgcaatga 3795 3814 SEQ ID 1526 tcataagttcaatgaattt 13178 131971 4 NO: SEQ ID NO: 524 ttcaacctccagaacatgg 3891 3910 SEQ ID 1527 ccattgaccagatgctgaa 8134 8153 1 4 NO: SEQ ID NO: 525 tgggattgccagacttcca 3907 3926 SEQ ID 1528 tggaaatgggcctgcccca 8895 8914 1 4 NO: SEQ ID NO: 526 cagtttgaaaattgagatt 3986 4005 SEQ ID 1529 aatcacaactcctccactg 9533 9552 14 NO: SEQ ID NO: 527 gaaaattgagattcctttg 3992 4011 SEQ ID 1530 caaaactaccacacatttc 13686 137051 4 NO: SEQ ID NO: 528 tttgccttttggtggcaaa 4007 4026 SEQ ID 1531 tttgagaggaatcgacaaa 6351 6370 14 NO: SEQ ID NO: 529 ctccagagatctaaagatg 4028 4047 SEQ ID 1532 catcaattggttacaggag 7586 7605 1 4 NO: SEQ ID NO: 530 tctaaagatgttagagact 4037 4056 SEQ'ID 1533 agtccttcatgtccctaga 10025 10044 14 NO: SEQ ID NO:531 ctgtgggattccatctgcc 4084 4103 SEQ ID 1534 ggcattttgaaaaaaacag 9727 9746 1 4 NO: SEQ ID NO: 532 atctgccatctcgagagtt 4096 4115 SEQ ID 1535 aactctcaaaccctaagat 8548 8567 14 NO: SEQ ID NO: 533 tctcgagagttccaagtcc 4104 4123 SEQ ID 1536 ggacattcctctagcgaga 8207 8226 14 NO: SEQ ID NO:534 agtccctacttttaccatt 4118 137 SEQ ID 1537 aatgaatacagccaggact 6078 6097 14 NO: SEQ ID NO: 535 acttttaccattcccaagt 4125 144 SEQ ID 1538 actttgtagaaatgaaagt 8101 8120 14 ___ NO: SEQ ID NO: 536 cattcccaagttgtatcaa 4133 152 SEQ ID 1539 ttgaaggacttcaggaatg 12001 12020 14 NO: SEQ ID NO: 537 accacatgaaggctgactc 4276 295 SEQ ID 1540 gagtaaaccaaaacttggt 9016 9035 1 4 NO: SEQ ID NO: 538 tttcctacaatgtgcaagg 4309 328 SEQ ID 1541 cctttaacaattcctgaaa 9495 9514 14 264 WO 2004/091515- .... .... PCT/US2004/011255 NO: SEQ ID NO: 539 ctggagaaacaacatatga 4330 4349 SEQ ID 1542 tcattctgggtctttccag 11027 11046 14 NO: SEQ ID NO: 540 atcatgtgatgggtctcta 4370 4389 SEQ ID 1543 tagaattacagaaaatgat 6557 6576 1 4 NO: SEQ ID NO:541 catgtgatgggtctctacg 4372 4391 SEQ ID 1544 cgtaggcaccgtgggcatg 12125 121441 4 NO: SEQ ID NO: 542 ttctagattcgaatatcaa 4399 4418 SEQ ID 1545 ttgatgatgctgtcaagaa 7300 7319 14 NO: SEQ ID NO: 543 tggggaccacagatgtctg 4491 510 SEQ ID 1546 cagaattccagcttcccca 8326 8345 1 4 1_ _ _NO: I SEQ ID NO: 544 ctaacactggccggctcaa 4636 4655 SEQ ID 1547 ttgaggctattgatgttag 6976 6995 1 4 NO: SEQ ID NO: 545 taacactggccggctcaat 4637 4656 SEQ ID 1548 attgaggctattgatgtta 6975 6994 1 4 NO: SEQ ID NO: 546 aacactggccggctcaatg 4638 4657 SEQ ID 1549 cattgaggctattgatgtt 6974 6993 1 4 ______NO: SEQ ID NO: 547 ctggccggctcaatggaga 4642 4661 SEQ ID 1550 tctccatctgcgctaccag 12065 12084 14 1__ NO: SEQ ID NO: 548 agataacaggaagatatga 4705 4724 SEQ ID 1551 tcatctcctttcttcatct 10202 10221 1 4 NO: SEQ ID NO: 549 tccctcacctccacctctg 4737 4756 SEQ ID 1552 cagatatatatctcaggga 8176 8195 1 4 NO: SEQ ID NO: 550 agctgactttaaaatctga 4810 4829 SEQ ID 1553 tcaggctcttcagaaagct 7922 7941 1 4 NO: SEQ ID NO: 551 ctgactttaaaatctgaca 4812 4831 SEQ ID 1554 tgtcaagataaacaatcag 8732 8751 1 4 NO: SEQ ID NO: 552 caagatggatatgaccttc 4865 4884 SEQ ID 1555 gaagtagtactgcatcttg 6835 6854, 1 4 NO: SEQ ID NO: 553 gctgcgttctgaatatcag 4901 4920 SEQ ID 1556 ctgagtcccagtgcccagc 9342 9361 1 4 NO: SEQ ID NO:554 cgttctgaatatcaggctg 4905 4924 SEQ ID 1557 cagcaagtacctgagaacg 8603 8622 1 4 NO: 3EQ ID NO: 555 aattcccatggtcttgagt 4968 4987 SEQ ID 1558 actcagatcaaagttaatt 12264 12283 1 4 NO: 3EQ ID NO: 556 tggtcttgagttaaatgct 4976 995 SEQ ID 1559 agcacagtacgaaaaacca 10801 10820 1 4 r NO: )EQ ID NO: 557 cttgagttaaatgctgaca 4980 4999 SEQ ID 1560 tgtccctagaaatctcaag 10034 10053 1 4 ____ __ NO: EQ ID NO: 558 ttgagttaaatgctgacat 4981 5000 SEQ ID 1561 atgtccctagaaatctcaa 10033 10052 14 _ NO: )EQ ID NO: 559 tgagttaaatgctgacatc 4982 5001 SEQ ID 1562 gatggaaccctctccctca 4725 4744 1 4 NO: EQ ID NO: 560 acttgaagtgtagtctcct 5086 5105 SEQ ID 1563 aggaaactcagatcaaagt 12259 122781 4 NO: )EQ ID NO: 561 agtgtagtctcctggtgct 5092 5111 SEQ ID 1564 agcagccagtggcaccact 12506 12525 1 4 NO: 3EQ ID NO: 562 gtgctggagaatgagctga 5106 5125 SEQ ID 1565 tcagccaggtttatagcac 7726 7745 1 4 NO: 3EQ ID NO: 563 ctggggcatctatgaaatt 5143 5162 SEQ ID 1566 aatttctgattaccaccag 13571 13590 1 4 NO: EQ ID NO: 564 atggccgcttcagggaaca 5170 5189 SEQ ID 1567 tgttttttggaaatgccat 8641 8660 1 4 1 _ _ _ NO: 3EQ ID NO:565 ttcagtctggatgggaaag 5199 5218 SEQ ID 1568 ctttgacaggcattttgaa 9719 9738 14 NO: 3EQ ID NO: 566 ccatgattctgggtgtcga 5257 5276 SEQ ID 1569 tcgatgcacatacaaatgg 5830 5849 1 4 265 WO 2004/091515.. PCT/US2004/01 1255 NO: SEQ ID NO: 567 aaaacattttcaacttcaa 5281 5300 SEQ ID 1570 ttgatgttagagtgctttt 6985 7004 14 NO: SEQ ID NO:568 cttaagctctcaaatgaca 5316 5335 SEQ ID 1571 tgtcctacaacaagttaag 7247 7266 14 NO: SEQ ID NO:569 ttaagctctcaaatgacat 5317 5336 SEQ ID 1572 atgtcctacaacaagttaa 7246 7265 14 NO: SEQ ID NO:570 catgatgggctcatatgct 5333 5352 SEQ ID 1573 agcatctttggctcacatg 7616 7635 14 NO: 3EQ ID NO: 571 tgggctcatatgctgaaat 5338 5357 SEQ ID 1574 atttatcaaaagaagccca 12934 12953 14 NO: SEQ ID NO: 572 actggacttctcttcaaaa 5399 5418 SEQ ID 1575 ttttggcaagctatacagt 8372 8391 14 NO: 3EQ ID NO:573 acttctcttcaaaacttga 5404 5423 SEQ ID 1576 tcaattgggagagacaagt 6496 6515 1 4 NO: 3EQ ID NO:574 ctgacaagttttataagca 5437 5456 SEQ ID 1577 tgctttgtgagtttatcag 9685 9704 1 4 NO: 3EQ ID NO: 575 aagttttataagcaaactg 5442 5461 SEQ ID 1578 cagtcatgtagaaaaactt 4421 4440 1 4 NO: )EQ ID NO: 576 ctgttaatttacagctaca 5458 5477 SEQ ID 1579 tgtactggaaaacgtacag 6380 6399 14 NO: 3EQ ID NO: 577 ttacagctacagccctatt 5466 5485 SEQ ID 1580 aatattgatcaatttgtaa 6417 6436 1 4 NO: SEQ ID NO: 578 tctggtaactactttaaac 5486 5505 SEQ ID 1581 gtttgaaaaacaaagcaga 11812 118311 4 NO: 3EQ ID NO: 579 tttaaacagtgacctgaaa 5498 5517 SEQ ID 1582 tttcatttgaaagaataaa 7024 7043 1 4 NO: 3EQ ID NO: 580 ttaaacagtgacctgaaat 5499 5518 SEQ ID 1583 atttcaagcaagaacttaa 10426 10445 1 4 NO: 3EQ ID NO:581 cagtgacctgaaatacaat 5504 5523 SEQ ID 1584 attggcgtggagcttactg 6123 6142 1 4 NO: 3EQ ID NO: 582 tgtggctggtaacctaaaa 5576 5595 SEQ ID 1585 ttttgctggagaagccaca 10757 10776 1 4 NO: EQ ID NO: 583 ttatcagcaagctataaag 5649 5668 SEQ ID 1586 ctttgcactatgttcataa 12756 127751 4 NO: )EQ ID NO: 584 ggttcagggtgtggagttt 5684 5703 SEQ ID 1587 aaacacctaagagtaaacc 9006 9025 1 4 NO: 3EQ ID NO: 585 attcagactcactgcattt 5767 5786 SEQ ID 1588 aaatgctgacatagggaat 8429 8448 1 4 NO: 3EQ ID NO: 586 ttcagactcactgcatttc 5768 5787 SEQ ID 1589 gaaatattatgaacttgaa 13304 13323 1 4 NO: 3EQ ID NO: 587 tacaaatggcaatgggaaa 5840 5859 SEQ ID 1590 tttcctaaagctggatgta 11168 11187 14 NO: 3EQ ID NO: 588 gctgtatagcaaattcctg 5888 5907 SEQ ID 1591 caggtccatgcaagtcagc 10911 10930 1 4 NO: 3EQ ID NO: 589 tgagcagacaggcacctgg 6035 6054 SEQ ID 1592 ccagcttccccacatctca 8333 8352 1 4 NO: 3EQ ID NO: 590 ggcacctggaaactcaaga 6045 6064 SEQ ID 1593 tcttcgtgtttcaactgcc 112.13 11232 1 4 NO: 3EQ ID NO: 591 tgaatacagccaggacttg 6080 6099 SEQ ID 1594 caagtaagtgctaggttca 9372 9391 1 4 NO: 3EQ ID NO: 592 gaatacagccaggacttgg 6081 6100 SEQ ID 1595 ccaacacttacttgaattc 10660 10679 1 4 NO: 3EQ ID NO: 593 ctggacgaactctggctga 6139 6158 SEQ ID 1596 tcagaaagctaccttccag 7931 7950 1 4 NO: 3EQ ID NO: 594 ttttactcagtgagcccat 6193 6212 SEQ ID 1597 atggacttcttctggaaaa 8870 8889 1 4 266 W0 2004/091515, -...... .- - PCT/US2004/011255 NO: SEQ ID NO:595 gatgagagatgccgttgag 6233 6252 SEQ ID 1598 ctcatctcctttcttcatc 10201 10220 14 NO: SEQ ID NO: 596 aattgttgcttttgtaaag 6269 6288 SEQ ID 1599 cttttctaaacttgaaatt 9056 9075 1 4 NO: SEQ ID NO: 597 cttttgtaaagtatgataa 6277 6296 SEQ ID 1600 ttatgaacttgaagaaaag 13310 13329 14 NO: SEQ ID NO: 598 tttgtaaagtatgataaaa 6279 6298 SEQ ID 1601 ttttcacattagatgcaaa 8413 8432 14 NO: SEQ ID NO: 599 tccattaacctcccatttt 6312 6331 SEQ ID 1602 aaaattgatgatatctgga 10719 10738 14 NO: SEQ ID NO: 600 ccattaacctcccattttt 6313 6332 SEQ ID 1603 aaaagggtcatggaaatgg 8885 8904 14 NO: SEQ ID NO: 601 cttgcaagaatattttgag 6338 6357 SEQ ID 1604 ctcaattttgattttcaag 8520 8539 14 NO: SEQ ID NO: 602 agaatattttgagaggaat 6344 6363 SEQ ID 1605 attccctccattaagttct 11700 117191 4 NO: SEQ ID NO: 603 attatagttgtactggaaa 6372 6391 SEQ ID 1606 tttcaagcaagaacttaat 10427 10446 14 NO: SEQ ID NO: 604 gaagcacatcaatattgat 6407 6426 SEQ ID 1607 atcagttcagataaacttc 7991 8010 1 4 NO: SEQ ID NO: 605 acatcaatattgatcaatt 6412 6431 SEQ ID 1608 aattccctgaagttgatgt 1147911498 1 4 NO: SEQ ID NO:606 gaaaactcccacagcaagc 6457 6476 SEQ ID 1609 gctttctcttccacatttc 10052 10071 14 NO: SEQ ID NO: 607 ctgaattcattcaattggg 6486 6505 SEQ ID 1610 cccatttacagatcttcag 11363 11382 1 4 NO: SEQ ID NO: 608 tgaattcattcaattggga 6487 6506 SEQ ID 1611 tcccatttacagatcttca 11362 11381 1 4 NO: SEQ ID NO:609 aactgactgctctcacaaa 6532 6551 SEQ ID 1612 tttgaggattccatcagtt 7979 7998 14 NO: SEQ ID NO:610 aaaagtatagaattacaga 6550 6569 SEQ ID 1613 tctggctccctcaactttt 9042 9061 14 NO: SEQ ID NO: 611 atcaactttaatgaaaaac 6603 6622 SEQ ID 1614 gtttattgaaaatattgat 6803 6822 1 4 NO: SEQ ID NO:612 tgatttgaaaatagctatt 6686 6705 SEQ ID 1615 aatattattgatgaaatca 6708 6727 14 NO: SEQ ID NO: 613 atttgaaaatagctattgc 6688 6707 SEQ ID 1616 gcaagaacttaatggaaat 104331045214 NO: SEQ ID NO: 614 attgctaatattattgatg 6702 6721 SEQ ID 1617 catcacactgaataccaat 10151 101701 4 NO: SEQ ID NO: 615 gaaaaattaaaaagtcttg 6729 6748 SEQ ID 1618 caagagcttatgggatttc 11153 11172 14 NO: SEQ ID NO: 616 actatcatatccgtgtaat 6754 6773 SEQ ID 1619 attactttgagaaattagt 7273 7292 1 4 NO: SEQ ID NO: 617 tattgattttaacaaaagt 6815 6834 SEQ ID 1620 acttgacttcagagaaata 11396 1141514 ______NO: SEQ ID NO: 618 ctgcagcagcttaagagac 6906 6925 SEQ ID 1621 gtcttcagtgaagctgcag 10691 1071014 NO: SEQ ID NO: 619 aaaacaacacattgaggct 6965 6984 SEQ ID 1622 agcctcacctcttactttt 10563 10582 14 NO: SEQ ID NO: 620 ttgagcatgtcaaacactt 7051 7070 SEQ ID 1623 aagtagctgagaaaatcaa 7096 7115 14 ______NO: SEQ ID NO: 621 tttgaagtagctgagaaaa 7092 7111 SEQ ID 1624 ttttcacattagatgcaaa 8413 8432 14 1 NO: SEQ ID NO: 622 ttagtagagttggcccacc 7191 7210 SEQ ID 1625 ggtggactcttgctgctaa 7768 7787 14 267 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO:623 tgaaggagactattcagaa 7219 7238 SEQ ID 1626 ttctcaattttgattttca 8518 8537 1 4 NO: SEQ ID NO: 624 gagactattcagaagctaa 7224 7243 SEQ ID 1627 ttagccacagctctgtctc 10293 10312 1 4 NO: SEQ ID NO: 625 aattagttggatttattga 7285 7304 SEQ ID 1628 tcaagaagcttaatgaatt 7312 7331 1 4 NO: SEQ ID NO: 626 gcttaatgaattatctttt 7319 7338 SEQ ID 1629 aaaacgagcttcaggaagc 13201 13220 1 4 NO: SEQ ID NO:627 ttaacaaattccttgacat 7357 7376 SEQ ID 1630 atgtcctacaacaagttaa 7246 7265 1 4 NO: SEQ ID NO: 628 aaattaaagtcatttgatt 7386 7405 SEQ ID 1631 aatcctttgacaggcattt 9715 9734 1 4 NO: SEQ ID NO: 629 gactcaatggtgaaattca 7456 7475 SEQ ID 1632 tgaaattcaatcacaagtc 9068 9087 14 NO: SEQ ID NO: 630 gaaattcaggctctggaac 7467 7486 SEQ ID 1633 gttctcaattttgattttc 8517 8536 1 4 NO: SEQ ID NO: 631 actaccacaaaaagctgaa 7484 7503 SEQ ID 1634 ttcaggaactattgctagt 10637 106561 4 NO: SEQ ID NO: 632 ccaaaataaccttaatcat 7570 7589 SEQ ID 1635 atgatttccctgaccttgg 10942 109611 4 NO: SEQ ID NO: 633 aaataaccttaatcatcaa 7573 7592 SEQ ID 1636 ttgaagtaaaagaaaattt 10741 10760 1 4 , NO: SEQ ID NO:634 tttaagttcagcatctttg 7607 7626 SEQ ID 1637 caaatctggatttcttaaa 9472 9491 14 NO: SEQ ID NO: 635 caggtttatagcacacttg 7731 7750 SEQ ID 1638 caagggttcactgttcctg 7857 7876 1 4 NO: SEQ ID NO: 636 gttcactgttcctgaaatc 7862 7881 SEQ ID 1639 gattctcagatgagggaac 8914 8933 1 4 NO: SEQ ID NO: 637 cactgttcctgaaatcaag 7865 7884 SEQ ID 1640 cttgaacacaaagtcagtg 6000 6019 1 4 NO: SEQ ID NO: 638 actgttcctgaaatcaaga 7866 7885 SEQ ID 1641 tcttgaacacaaagtcagt 5999 6018 14 NO: SEQ ID NO: 639 gcctgcctttgaagtcagt 7901 7920 SEQ ID 1642 actgttgactcaggaaggc 12572 12591 1 4 NO: SEQ ID NO: 640 taacagatttgaggattcc 7972 7991 SEQ ID 1643 ggaagcttctcaagagtta 13214 13233 14 NO:I SEQ ID NO: 641 gttttccacaccagaattt 8042 8061 SEQ ID 1644 aaatttctctgctggaaac 9410 9429 14 NO: SEQ ID NO: 642 tcagaaccattgaccagat 8128 8147 SEQ ID 1645 atctgcagaacaatgctga 12430 12449 1 4 NO: SEQ ID NO: 643 tagcgagaatcaccctgcc 8218 8237 SEQ ID 1646 ggcagcttctggcttgcta 12293 12312 14 NO: SEQ ID NO: 644 ccttaatgattttcaagtt 8291 8310 SEQ ID 1647 aactgttgactcaggaagg 12571 12590 14 NO: SEQ ID NO: 645 acataccagaattccagct 8320 8339 SEQ ID 1648 agctgccagtccttcatgt 10018 10037 1 4 NO: SEQ ID NO: 646 aatgctgacatagggaatg 8430 8449 SEQ ID 1649 cattaatcctgccatcatt 9997 10016 1 4 NO: SEQ ID NO: 647 atgctgacatagggaatgg 8431 8450 SEQ ID 1650 ccatttgagatcacggcat 9237 9256 1 4 NO: SEQ ID NO: 648 aaccacctcagcaaacgaa 8450 469 SEQ ID 1651 ttcgttttccattaaggtt 9283 9302 14 NO: SEQ ID NO: 649 agcaggtatcgcagcttcc 8468 8487 SEQ ID 1652 ggaagtggccctgaatgct 10964 10983 14 NO: I SEQ ID NO: 650 tgcacaactctcaaaccct 8543 8562 SEQ ID 1653 agggaaagagaagattgca 13493 13512 1 4 268 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 651 aggagtcagtgaagttctc 8584 8603 SEQ ID 1654 gagaacttactatcatcct 13780 13799 1 4 NO: SEQ ID NO:652 tttttggaaatgccattga 8644 8663 SEQ ID 1655 tcaatgaatttattcaaaa 13186 132051 4 NO: SEQ ID NO: 653 aatggagtgattgtcaaga 8721 8740 SEQ ID 1656 tcttttcagcccagccatt 9223 9242 1 4 NO: SEQ ID NO: 654 gtcaagataaacaatcagc 8733 8752 SEQ ID 1657 gctgactttaaaatctgac 4811 4830 1 4 NO: SEQ ID NO: 655 tccacaaattgaacatccc 8779 8798 SEQ ID 1658 gggatttcctaaagctgga 11164 11183 1 4 NO: SEQ ID NO: 656 ttgaacatccccaaactgg 8787 8806 SEQ ID 1659 ccagtttccagggactcaa 12595 126141 4 NO: SEQ ID NO: 657 acatccccaaactggactt 8791 8810 SEQ ID 1660 aagtcgattcccagcatgt 9082 9101 1 4 NO: SEQ ID NO: 658 acttctctagtcaggctga 8806 8825 SEQ ID 1661 tcagatggaaaaatgaagt 11002 110211 4 NO: SEQ ID NO: 659 tgaatcacaaattagtttc 8936 8955 SEQ ID 1662 gaaagtccataatggttca 12809 12828 1 4 NO: SEQ ID NO: 660 agaaggacccctcacttcc 8960 8979 SEQ ID 1663 ggaagaagaggcagcttct 12284 12303 1 4 NO: SEQ ID NO: 661 ttggactgtccaataagat 8980 8999 SEQ ID 1664 atctaaatgcagtagccaa 11626 11645 1 4 NO: SEQ ID NO: 662 actgtccaataagatcaat 8984 9003 SEQ ID 1665 attgataaaaccatacagt 13883 139021 4 NO: 3EQ ID NO: 663 ctgtccaataagatcaata 8985 9004 SEQ ID 1666 tattgataaaaccatacag 13882 13901 14 NO: 3EQ ID NO: 664 gtttatgaatctggctccc 9033 9052 SEQ ID 1667 gggaatctgatgaggaaac 12247 1226614 NO: 3EQ ID NO: 665 atgaatctggctccctcaa 9037 9056 SEQ ID 1668 ttgagttgcccaccatcat 11659 11678 1 4 NO: 3EQ ID NO: 666 ctcaacttttctaaacttg 9051 9070 SEQ ID 1669 caagatcgcagactttgag 11645 11664 1 4 NO: 3EQ ID NO: 667 ctaaaggcatggcactgtt 9121 9140 SEQ ID 1670 aacagaaacaatgcattag 9741 9760 14 NO: 3EQ ID NO: 668 aaggcatggcactgtttgg 9124 9143 SEQ ID 1671 ccaagaaaaggcacacctt 11069 110881 4 NO: 3EQ ID NO: 669 atccacaaacaatgaaggg 9254 9273 SEQ ID 1672 ccctaacagatttgaggat 7969 7988 14 NO: 3EQ ID NO: 670 ggaatttgaaagttcgttt 9271 9290 SEQ ID 1673 aaacaaacacaggcattcc 9647 9666 14 NO: 'EQ ID NO: 671 aataactatgcactgtttc 9324 9343 SEQ ID 1674 gaaatactgttttcctatt 12828 12847 1 4 NO: 'EQ ID NO: 672 gaaacaacgagaacattat 9424 9443 SEQ ID 1675 ataaactgcaagatttttc 13600 13619 14 NO: EQ ID NO: 673 ttcttgaaaacgacaaagc 9591 9610 SEQ ID 1676 gctttccaatgaccaagaa 11057 11076 1 4 NO: EQ ID NO: 674 ataagaaaaacaaacacag 9640 9659 SEQ ID 1677 ctgtgctttgtgagtttat 9682 9701 14 I__ _ NO: EQ ID NO:675 aaaacaaacacaggcattc 9646 9665 SEQ ID 1678 gaatttgaaagttcgtttt 9272 9291 14 NO: EQ ID NO: 676 gcattccatcacaaatcct 9659 9678 SEQ ID 1679 aggaagtggccctgaatgc 10963 10982 1 4 NO: EQ ID NO: 677 tttgaaaaaaacagaaaca 9732 9751 SEQ ID 1680 tgttgaaagatttatcaaa 12925 129441 4 NO: EQ ID NO:1678 caatgcattagattttgtc 9749 9768 SEQ ID 1681 gacaagaaaaaggggattg 10271 10290 1 4 269 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 679 caaagctgaaaaatctcag 9809 9828 SEQ ID 1682 ctgagaacttcatcatttg 11430 11449 14 NO: SEQ ID NO: 680 cctggatacactgttccag 9855 9874 SEQ ID 1683 ctggacttctctagtcagg 8802 8821 14 NO: SEQ ID NO: 681 gttgaagtgtctccattca 9882 9901 SEQ ID 1684 tgaatctggctccctcaac 9038 9057 14 NO: SEQ ID NO: 682 tttctccatcctaggttct 9956 9975 SEQ ID 1685 agaatccagatacaagaaa 6885 6904 14 NO: SEQ ID NO: 683 ttctccatcctaggttctg 9957 9976 SEQ ID 1686 cagaatccagatacaagaa 6884 6903 1 4 NO: SEQ ID NO: 684 tcattagagctgccagtcc 1001110030 SEQ ID 1687 ggacagtgaaatattatga 13297 13316 1 4 NO: SEQ ID NO: 685 tgctgaactttttaaccag 10169101881SEQ ID 1688 ctggatgtaaccaccagca 11178 11197 14 NO: SEQ ID NO:'686 ctcctttcttcatcttcat 1020610225 SEQ ID 1689 atgaagcttgctccaggag 13764 13783 14 NO: SEQ ID NO: 687 tgtcattgatgcactgcag 1022610245 SEQ ID 1690 ctgcgctaccagaaagaca 12072 12091 1 4 NO: SEQ ID NO: 688 tgatgcactgcagtacaaa 1023210251 SEQ ID 1691 tttgagttgcccaccatca 11658 11677 1 4 NO: SEQ ID NO: 689 agctctgtctctgagcaac 1030110320 SEQ ID 1692 gttgaccacaagcttagct 10539 10558 1 4 NO: SEQ ID NO: 690 agccgaaattccaattttg 1040010419'SEQ ID 1693 caaagctggcaccagggct 13963 13982 14 NO: SEQ ID NO: 691 ttgagaatgaatttcaagc 1041610435SEQ ID 1694 gcttcaggaagcttctcaa 13208 13227 1 4 NO: SEQ ID NO: 692 aaacctactgtctcttcct 1046110480 SEQ ID 1695 aggaaggccaagccagttt 12583 12602 1 4 NO: SEQ ID NO: 693 tacttttccattgagtcat 10575105941SEQ ID 1696 atgattatgtcaacaagta 12355 123741 4 NO: SEQ ID NO: 694 tcaggtccatgcaagtcag 1091010929SEQ ID 1697 ctgacatcttaggcactga 4993 5012 1 4 NO: _ _ _ SEQ ID NO: 695 atgcaagtcagcccagttc 1091810937SEQ ID 1698 gaactcagaaggatggcat 13994 14013 1 4 NO: SEQ ID NO: 696 tgaatgctaacactaagaa 1097510994SEQ ID 1699 ttctcaattttgattttca 8518 8537 1 4 NO: SEQ ID NO:697 agaagatcagatggaaaaa 1099611015SEQ ID 1700 ttttctaaatggaacttct 1216512184 14 NO: SEQ ID NO: 698 ggctattcattctccatcc 1125611275 SEQ ID 1701 ggatctaaatgcagtagcc 11624 11643 1 4 NO: SEQ ID NO:699 aaagttttggctgataaat 11280112991SEQ ID 1702 atttcttaaacattccttt 9481 9500 14 NO: SEQ ID NO: 700 agttttggctgataaattc 1128211301 SEQ ID 1703 gaatctggctccctcaact 9039 9058 1 4 INO: 3EQ ID NO: 701 ctgggctgaaactaaatga 1130811327 SEQ ID 1704 tcattctgggtctttccag 11027 110461 4 ______ NO:_ _ _ 3EQ ID NO: 702 cagagaaatacaaatctat 1140511424 SEQ ID 1705 atagcatggacttcttctg 8865 8884 14 NO: 3EQ ID NO: 703 gaggtaaaattccctgaag 1147211491 SEQ ID 1706 cttctggcttgctaacctc 12298 123171 4 NO: 3EQ ID NO: 704 cttttttgagataaccgtg 1153711556 SEQ ID 1707 cacggagttactgaaaaag 13715137341 4 _ _ NO: 3EQ ID NO: 705 gctggaattgtcattcctt 1172711746 SEQ ID 1708 aaggcatctccacctcagc 12094 12113 1 4 NO: 3EQ ID NO: 706 gtgtataatgccacttgga 11787118061SEQ ID 1709 tccaagatgagatcaacac 130961311514 270 WO 2004/091515. PCT/US2004/011255 NO: SEQ ID NO: 707 attccacatgcagctcaac 1185111870 SEQ ID 1710 gttgagaagccccaagaat 6246 6265 1 4 NO: SEQ ID NO: 708 tgaagaagatggcaaattt 1198412003 SEQ ID 1711 aaattctcttttcttttca 9212 9231 1 4 NO: SEQ ID NO: 709 atcaaaagcccagcgttca 1204212061 SEQ ID 1712 tgaaagtcaagcatctgat 12661 1268014 NO: SEQ ID NO:710 gtgggcatggatatggatg 1213512154 SEQ ID 1713 catccttaacaccttccac 8063 8082 14 NO: SEQ ID NO: 711 aaatggaacttctactaca 1217112190 SEQ ID 1714 tgtaccataagccatattt 10080 10099 14 NO: SEQ ID NO:712 aaaaactcaccatattcaa 1221112230 SEQ ID 1715 ttgatgttagagtgctttt 6985 7004 14 NO: SEQ ID NO:713 ctgagaagaaatctgcaga 1242012439 SEQ ID 1716 tctgcacagaaatattcag 13439 13458 14 NO: SEQ ID NO: 714 acaatgctgagtgggttta 1243912458 SEQ ID 1717 taaatggagtctttattgt 14078 14097 14 NO: SEQ ID NO: 715 caatgctgagtgggtttat 12440124591SEQ ID 1718 ataaatggagtctttattg 14077 140961 4 NO: SEQ ID NO:716 ttaggcaaattgatgatat 1246912488 SEQ ID 1719 atattgtcagtgcctctaa 13384 13403 14 NO: SEQ ID NO:717 ataaactaatagatgtaat 1288912908SEQ ID 1720 attactatgaaaaatttat 13633 13652 14 NO: SEQ ID NO:718 ccaactaatagaagataac 1303113050SEQ ID 1721 gttattttgctaaacttgg 14044 14063 14 NO: SEQ ID NO:719 ttaattatatccaagatga 1308713106SEQ ID 1722 tcatcctctaattttttaa 13792 138111 4 NO: SEQ ID NO:720 tttaaattgttgaaagaaa 13143131621SEQ ID 1723 tttcatttgaaagaataaa 7024 7043 l 4 NO: SEQ ID NO: 721 aagttcaatgaatttattc 1318213201 SEQ ID 1724 gaataccaatgctgaactt 10160 10179 I4 NO: SEQ ID NO: 722 ttgaagaaaagatagtcag 1331813337 SEQ ID 1725 ctgagagaagtgtcttcaa 12399 124181 4 NO: SEQ ID NO: 723 acttccattctgaatatat 13369133881SEQ ID 1726 atatctggaaccttgaagt 10729 10748 1 4 NO: SEQ ID NO: 724 cacagaaatattcaggaat 1344313462 SEQ ID 1727 attccctgaagttgatgtg 11480 114991 4 | INO: 3EQ ID NO: 725 ccattgcgacgaagaaaat 1355213571 SEQ ID 1728 atttttattcctgccatgg 1009510114 1 4 NO: EQ ID NO: 726 tataaactgcaagattttt 13599136181SEQ ID 1729 aaaattcaaactgcctata 13865 13884114 NO: 3EQ ID NO: 727 tctgattactatgaaaaat 1362913648 SEQ ID 1730 atttgtaagaaaatacaga 6428 6447 1 4 NO: 3EQ ID NO: 728 ggagttactgaaaaagctg 1371813737 SEQ ID 1731 cagcatgcctagtttctcc 9944 9963 1 4 NO: 3EQ ID NO: 729 tgaagottgctccaggaga 1376513784 SEQ ID 1732 tctcctttcttcatcttca 10205 10224 1 4 NO: 3EQ ID NO: 730 tgaactggacctgcaccaa 1394713966 SEQ ID 1733 ttggtagagcaagggttca 7848 7867 1 4 NO: 3EQ ID NO:731 ttgctaaacttgggggagg 1405014069 SEQ ID 1734 cctcctacagtggtggcaa 4222 4241 1 4 NO: 3EQ ID NO:732 gattcgaatatcaaattca 4404 4423 SEQ ID 1735 tgaaaacgacaaagcaatc 9595 9614 33 NO: 1 EQ ID NO:733 atttgtttgtcaaagaagt 543 4562 SEQ ID 1736 acttttctaaacttgaaat 9055 9074 33 EQ ID NO: 734 tctcggttgctgccgctga 5 44 SEQ ID 1737 tcagcccagccatttgaga 9228 9247 2 3 271 WO 2004/091515 . .- ..- PCT/US2004/011255 NO: SEQ ID NO: 735 gctgaggagcccgcccagc 39 58 SEQ ID 1738 gctggatgtaaccaccagc 11177 11196 2 3 NO: SEQ ID NO: 736 ctggtctgtccaaaagatg 219 238 SEQ ID 1739 catcagaaccattgaccag 8126 8145 23 NO: SEQ ID NO: 737 ctgagagttccagtggagt 283 302 SEQ ID 1740 actcaatggtgaaattcag 7457 7476 23 NO: SEQ ID NO:738 cagtgcaccctgaaagagg 396 15 SEQ ID 1741 cctcacttcctttggactg 8969 8988 23 NO: SEQ ID NO:739 ctctgaggagtttgctgca 464 483 SEQ ID 1742 tgcaaacttgacttcagag 11391 11410 2 3 NO: SEQ ID NO: 740 acatcaagaggggcatcat 574 593 SEQ ID 1743 atgacgttcttgagcatgt 7042 7061 23 NO: SEQ ID NO:741 ctgatcagcagcagccagt 822 841 SEQ ID 1744 actggacttctctagtcag 8801 8820 23 S___ NO: SEQ ID NO: 742 ggacgctaagaggaagcat 857 876 SEQ ID 1745 atgcctacgttccatgtcc 11346 113652 3 1 INO: SEQ ID NO:743 agctgttttgaagactctc 1079 1098 SEQ ID 1746 gagaagtgtcttcaaagct 12403 12422 23 _______ ~~~NO: _________ SEQ ID NO: 744 tgaaaaaactaaccatctc 1105 1124 SEQ ID 1747 gagatcaacacaatcttca 13104 13123 23 INO: SEQ ID NO: 745 ctgagctgagaggcctcag 1168 1187 SEQ ID 1748 ctgaattactgcacctcag 3027 3046 23 INO: SEQ ID NO: 746 tgaaacgtgtgcatgccaa 1303 1322 SEQ ID 1749 ttggtagagcaagggttca 7848 7867 23 NO: SEQ ID NO: 747 ccttgtatgcgctgagcca 1432 1451 SEQ ID 1750 tggcactgtttggagaagg 9130 9149 23 NO: SEQ ID NO: 748 aggagctgctggacattgc 1492 1511 SEQ ID 1751 gcaagtcagcccagttcct 10920 10939 23 NO: SEQ ID NO: 749 atttgattctgcgggtcat 1567 1586 SEQ ID 1752 atgaaaccaatgacaaaat 7420 7439 2 3 NO: SEQ ID NO:750 tccagaactcaagtcttca 1619 1638 SEQ ID 1753 tgaaatacaatgctctgga 5512 5531 23 NO: SEQ ID NO: 751 ggttcttcttcagactttc 1736 1755 SEQ ID 1754 gaaataccaagtcaaaacc 10447 10466 2 3 NO: SEQ ID NO: 752 gttgatgaggagtcctica 1802 1821 SEQ ID 1755 tgaaaaagctgcaatcaac 13726 13745 2 3 NO: SEQ ID NO: 753 tccaagatctgaaaaagtt 1933 1952 SEQ ID 1756 aactgcttctccaaatgga 3544 3563 23 NO: _________ SEQ ID NO: 754 agttagtgaaagaagttct 1948 1967 SEQ ID 1757 agaattcataatcccaact 8267 8286 23 NO: SEQ ID NO: 755 gaagggaatcttatatttg 2076 2095 SEQ ID 1758 caaaacctactgtctcttc 10459 10478 2 3 ___ NO: SEQ ID NO: 756 ggaagctctttttgggaag 2213 2232 SEQ ID 1759 cttcacataccagaattcc 8316 8335 23 NO:I SEQ ID NO: 757 tggaataatgctcagtgtt 2366 2385 SEQ ID 1760 aacaaacacaggcattcca 9648 9667 23 ___ NO: SEQ ID NO: 758 gatttgaaatccaaagaag 2400 2419 SEQ ID 1761 cttcatgtccctagaaatc 10029 100482 3 ___ NO: SEQ ID NO: 759 tccaaagaagtcccggaag 2409 2428 SEQ ID 1762 cttcagcctgctttctgga 4943 4962 23 NO: 3EQ ID NO: 760 aggaagggctcaaagaatg 2562 2581 SEQ ID 1763 cattagagctgccagtcct 10012 100312 23 ____ ____ ___NO: 3EQ ID NO: 761 agaatgacttttttcttca 2575 594 SEQ ID 1764 tgaagatgacgacttttct 12152 12171 2 3 NO: 3EQ ID NO: 762 tttgtgacaaatatgggca 2757 2776 SEQ ID 1765 tgccagtttgaaaaacaaa 11807 11826 2 3 272 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 763 ctgaggctaccatgacatt 3244 3263 SEQ ID 1766 aatgtcagctcttgttcag 10895 10914 2 3 NO: SEQ ID NO: 764 gtagataccaaaaaaatga 3660 3679 SEQ ID 1767 tcatttgccctcaacctac 11442 11461 2 3 NO: SEQ ID NO: 765 aaatgacttccaatttccc 3673 3692 SEQ ID 1768 gggaactgttgaaagattt 12919 12938 2 3 NO: SEQ ID NO: 766 atgacttccaatttccctg 3675 3694 SEQ ID 1769 caggagaacttactatcat 13777 13796 2 3 NO: SEQ ID NO: 767 atctgccatctcgagagtt 4096 4115 SEQ ID 1770 aactcctccactgaaagat 9539 9558 23 NO: SEQ ID NO: 768 atttgtttgtcaaagaagt 4543 4562 SEQ ID 1771 acttccgtttaccagaaat 8239 8258 23 1_____ ___NO: III SEQ ID NO: 769 gcagagcttggcctctctg 5127 5146 SEQ ID 1772 cagagctttctgccactgc 1351013529 2 3 NO: SEQ ID NO: 770 atatgctgaaatgaaattt 5345 5364 SEQ ID 1773 aaattcaaactgcctatat 13866 13885 2 3 NO: SEQ ID NO: 771 tcaaaacttgacaacattt 5412 5431 SEQ ID 1774 aaatacttccacaaattga 8772 8791 23 NO: SEQ ID NO: 772 cagtgacctgaaatacaat 5504 5523 SEQ ID 1775 attgaacatccccaaactg 8786 8805 2 3 NO: SEQ ID NO: 773 tacaaatggcaatgggaaa 5840 5859 SEQ ID 1776 tttcaactgcctttgtgta 11221 11240 2 3 NO: SEQ ID NO: 774 cttttgtaaagtatgataa 6277 6296 SEQ ID 1777 ttattgctgaatccaaaag 13648 13667 2 3 NO: SEQ ID NO: 775 ttgtaaagtatgataaaaa 6280 6299 SEQ ID 1778 ttttcaagcaaatgcacaa 8531 8550 23 NO: SEQ ID NO: 776 tccattaacctcccatttt 6312 6331 SEQ ID 1779 aaaagaaaattttgctgga 10748 107672 3 NO: SEQ ID NO: 777 gattatctgaattcattca 6480 6499 SEQ ID 1780 tgaagtagaccaacaaatc 7154 7173 23 NO: SEQ ID NO: 778 aattgggagagacaagttt 6498 6517 SEQ ID 1781 aaactaaatgatctaaatt 11316 1133512 3 NO: SEQ ID NO: 779 atttgaaaatagctattgc 6688 6707 SEQ ID 1782 gcaatttctgcacagaaat 13433 13452 2 3 NO: SEQ ID NO: 780 tgagcatgtcaaacacttt 7052 7071 SEQ ID 1783 aaagccattcagtctctca 12963 12982 2 3 NO: SEQ ID NO: 781 ttgaagatgttaacaaatt 7348 7367 SEQ ID 1784 aattccatatgaaagtcaa 12652 12671 2 3 NO: SEQ ID NO: 782 acttgtcacctacatttct 7745 7764 SEQ ID 1785 agaatattttgatccaagt 13268 13287 2 3 _ 1 NO: SEQ ID NO: 783 gttttccacaccagaattt 8042 8061 SEQ ID 1786 aaatctggatttcttaaac 9473 9492 23 NO: SEQ ID NO: 784 ataagtacaaccaaaattt 9397 9416 SEQ ID 1787 aaataaatggagtctttat 14075 14094 2 3 NO: 3EQ ID NO: 785 cgggacctgcggggctgag 0 19 SEQ ID 1788 ctcagttaactgtgtcccg 11563 11582 1 3 NO: 3EQ ID NO:786 agtgcccttctcggttgct 17 36 SEQ ID 1789 agcatctgattgactcact 12670 126891 3 NO: 3EQ ID NO: 787 gctgaggagcccgcccagc 39 58 SEQ ID 1790 gctgattgaggtgtccagc 1217 1236 13 NO: 3EQ ID NO: 788 gaggagcccgcccagccag 42 61 SEQ ID 1791 ctggatcacagagtccctc 3744 3763 1 3 NO: 3EQ ID NO: 789 gggccgcgaggccgaggcc 64 83 SEQ ID 1792 ggccctgatccccgagccc 1355 1374 1 3 NO: I 3EQ ID NO: 790 ccaggccgcagcccaggag 81 100 SEQ ID 1793 ctcccggagccaaggctgg 2674 2693 1 3 273 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 791 ggagccgccccaccgcagc 96 115 SEQ ID 1794 gctgttttgaagactctcc 1080 1099 13 NO: SEQ ID NO:792 gaagaggaaatgctggaaa 192 211 SEQ ID 1795 tttcaagttcctgaccttc 8301 8320 1 3 NO: SEQ ID NO: 793 caaaagatgcgacccgatt 229 248 SEQ ID 1796 aatcttattggggattttg 7077 7096 1 3 NO: SEQ ID NO: 794 attcaagcacctccggaag 245 264 SEQ ID 1797 cttccacatttcaaggaat 10059 10078 1 3 NO: SEQ ID NO: 795 gttccagtggagtccctgg 289 308 SEQ ID 1798 ccagcaagtacctgagaac 8602 8621 1 3 1___ _ NO: SEQ ID NO: 796 gactgctgattcaagaagt 308 327 SEQ ID 1799 acttgaagaaaagatagtc 13316 133351 3 NO: SEQ ID NO: 797 gtgccaccaggatcaactg 325 344 SEQ ID 1800 cagtgaagctgcagggcac 10696 107151 3 NO: SEQ ID NO: 798 gatcaactgcaaggttgag 335 354 SEQ ID 1801 ctcacctccacctctgatc 4740 4759 1 3 NO: I SEQ ID NO: 799 actgcaaggttgagctgga 340 359 SEQ ID 1802 tccactcacatcctccagt 1281 1300 1 3 NO: SEQ ID NO: 800 ccagctctgcagcttcatc 365 384 SEQ ID 1803 gatgtggtcacctacctgg 1335 1354 1 NO: SEQ ID NO: 801 agcttcatcctgaagacca 375 394 SEQ ID 1804 tggtgctggagaatgagct 5104 5123 13 NO: SEQ ID NO: 802 cttcatcctgaagaccagc 377 396 SEQ ID 1805 gctggagtaaaactggaag 2688 2707 13 NO: SEQ ID NO: 803 ccagccagtgcaccctgaa 391 410 SEQ ID 1806 ttcaagatgactgcactgg 1531 1550 1 3 NO: SEQ ID NO: 804 cagtgcaccctgaaagagg 396 415 SEQ ID 1807 cctcacagagctatcactg 5222 5241 1 3 NO: SEQ ID NO: 805 tggcttcaaccctgagggc 419 438 SEQ ID 1808 gcccactggtcgcctgcca 3525 3544 1 3 NO: SEQ ID NO: 806 cttcaaccctgagggcaaa 422 441 SEQ ID 1809 tttgagccaacattggaag 2199 2218 13 NO: SEQ ID NO: 807 ttcaaccctgagggcaaag 423 442 SEQ ID 1810 ctttgacaggcattttgaa 9719 9738 13 ___ NO: SEQ ID NO: 808 cttgctgaagaaaaccaag 443 462 SEQ ID 1811 cttgaaattcaatcacaag 9066 9085 1 3 NO: SEQ ID NO: 809 tgctgaagaaaaccaagaa 445 464 SEQ ID 1812 ttctgctgccttatcagca 5639 5658 13 ___ NO: SEQ ID NO: 810 ttgctgcagccatgtccag 475 494 SEQ ID 1813 ctggtcagtttgcaagcaa 2996 3015 1 3 NO: SEQ ID NO: 811 tgctgcagccatgtccagg 476 495 SEQ ID 1814 cctggtcagtttgcaagca 2995 3014 1 3 NO: SEQ ID NO: 812 agccatgtccaggtatgag 482 501 SEQ ID 1815 ctcacatcctccagtggct 1285 1304 1 3 NO: SEQ ID NO: 813 agctcaagctggccattcc 499 518 SEQ ID 1816 ggaactaccacaaaaagct 7481 7500 1 3 1 1 NO: SEQ ID NO: 814 agaagggaagcaggttttc 518 537 SEQ ID 1817 gaaatcttcaatttattct 13813138321 3 NO: SEQ ID NO: 815 aagggaagcaggttttcct 520 539 SEQ ID 1818 aggacaccaaaataacctt 7564 7583 13 _______NO: SEQ ID NO: 816 agaaagatgaacctactta 547 566 SEQ ID 1819 taagaactttgccacttct 4844 4863 13 NO: SEQ ID NO: 817 atcctgaacatcaagaggg 567 586 SEQ ID 1820 ccctaacagatttgaggat 7969 7988 1 3 NO: SEQ ID NO: 818 tcctgaacatcaagagggg 568 587 SEQ ID 1821 cccctaacagatttgagga 7968 7987 1 3 274 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO:819 ctgaacatcaagaggggca 570 589 SEQ ID 1822 tgcctgcctttgaagtcag 7900 7919 1 3 NO: SEQ ID NO:820 aacatcaagaggggcatca 573 592 SEQ ID 1823 t gataaaaaccaagatgtt 6290 6309 1 3 NO: SEQ ID NO: 821 acatcaagaggggcatcat 574 593 SEQ ID 1824 atgataaaaaccaagatgt 6289 6308 1 3 NO: SEQ ID NO: 822 tcatttctgccctcctggt 589 608 SEQ ID 1825 accaccagtttgtagatga 7405 7424 13 _______NO: SEQ ID NO: 823 ttcccccagagacagaaga 607 626 SEQ ID 1826 tcttccacatttcaaggaa 10058 10077 13 NO: SEQ ID NO: 824 gaagaagccaagcaagtgt 621 640 SEQ ID 1827 acaccttccacattccttc 8071 8090 13 _____ _ ___NO: SEQ ID NO:825 ttgtttctggataccgtgt 639 658 SEQ ID 1828 acactaaatacttccacaa 8767 8786 1 3 NO: SEQ ID NO: 826 tgtatggaaactgctccac 655 674 SEQ ID 1829 gtggaggcaacacattaca 2920 2939 13 NO: SEQ ID NO: 827 aaactgctccactcacttt 662 681 SEQ ID 1830 aaagaaacagcatttgttt 4532 4551 13 NO: SEQ ID NO:828 actcactttaccgtcaaga 672 691 SEQ ID 1831 tcttacttttccattgagt 1057210591 13 NO: SEQ ID NO:829 ctttaccgtcaagacgagg 677 696 SEQ ID 1832 cctccagctcctgggaaag 2483 2502 13 _______NO: SEQ ID NO: 830 ttaccgtcaagacgaggaa 679 698 SEQ ID 1833 ttcctaaagctggatgtaa 11169 11188 13 NO: SEQ ID NO:831 acgaggaagggcaatgtgg 690 709 SEQ ID 1834 ccacaagtcatcatctcgt 5956 5975 13 NO: SEQ ID NO:832 cgaggaagggcaatgtggc 691 710 SEQ ID 1835 gccagaagtgagatcctcg 3507 3526 13 NO: SEQ ID NO: 833 gaggaagggcaatgtggca 692 711 SEQ ID 1836 tgccagtctccatgacctc 2468 2487 1 3 NO: 3EQ ID NO:834 ggaagggcaatgtggcaac 694 713 SEQ ID 1837 gttgctcttaaggacttcc 13356 1337513 NO: SEQ ID NO: 835 gaagggcaatgtggcaaca 695 714 SEQ ID 1838 tgttgatgaggagtccttc 1801 1820 1 3 NO: 3EQ ID NO:836 caggcatcagcccacttgc 769 88 SEQID 1839 gcaagtctttcctggcctg 3011 3030 13 NO: 3EQ ID NO: 837 aggcatcagcccacttgct 770 789 SEQ ID 1840 agcaagtctttcctggcct 3010 3029 1 3 NO: 3EQ ID NO: 838. tcagcccacttgctctdat 775 794 SEQ ID 1841 atgaaagtcaagcatctga 12660 126791 3 NO: 3EQ ID NO: 839 gtcaactctgatcagcagc 815 834 SEQ ID 1842 gctgactttaaaatctgac 4811 4830 1 3 NO: 3EQ ID NO: 840 ggacgctaagaggaagcat 857 876 SEQ ID 1843 atgcactgtttctgagtcc 9331 9350 13 NO: )EQ ID NO: 841 aaggagcaacacctcttcc 894 913 SEQ ID 1844 ggaatatcttagcatcctt 13457 134761 3 NO: 3EQ ID NO:842 aggagcaacacctcttcct 895 914 SEQ ID 1845 aggaatatcttagcatcct 13456 1347513 NO: 3EQ ID NO: 843 caacacctcttcctgcctt 900 919 SEQ ID 1846 aaggctgactctgtggttg 4284 4303 13 NO: 3EQ ID NO: 844 aacacctcttcctgccttt 901 920 SEQ ID 1847 aaagcaggccgaagctgtt 1067 1086 1 3 NO: 3EQ ID NO: 845 acaagaataagtatgggat 925 944 SEQ ID 1848 atccatgatctacatttgt 6786 6805 1 3 NO: 3EQ ID NO: 846 caagaataagtatgggatg 926 945 SEQ ID 1849 catcactttacaagccttg 1238 1257 13 275 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 847 tagcacaagtgacacagac 946 965 SEQ ID 1850 gtctcttcgttctatgcta 4584 4603 1 3 NO: SEQ ID NO: 848 agcacaagtgacacagact 947 966 SEQ ID 1851 agtctcttcgttctatgct 4583 4602 1 3 NO: SEQ ID NO: 849 gcacaagtgacacagactt 948 967 SEQ ID 1852 aagtgtagtctcctggtgc 5091 5110 13 _______NO: SEQ ID NO: 850 aacttgaagacacaccaaa 970 989 SEQ ID 1853 tttgaggattccatcagtt 7979 7998 13 NO: SEQ ID NO: 851 gcttctttggtgaaggtac 1000 1019 SEQ ID 1854 gtacctacttttggcaagc 8364 8383 13 NO: SEQ ID NO: 852 ctttggtgaaggtactaag 1004 1023 SEQ ID 1855 cttatgggatttcctaaag 11159 11178 1 NO: SEQ ID NO:853 tactaagaagatgggcctc 1016 1035 SEQ ID 1856 gagggtagtcataacagta 10329103481 3 NO: SEQ ID NO: 854 tttgagagcaccaaatcca 1038 1057 SEQ ID 1857 tggaagtgtcagtggcaaa 10372 10391 1 3 _ NO: SEQ ID NO:855 agagcaccaaatccacatc 1042 1061 SEQ ID 1858 gatggatatgaccttctct 4868 4887 13 NO: SEQ ID NO: 856 agctgttttgaagactctc 1079 1098 SEQ ID 1859 gagaacatactgggcagct 5872 5891 1 3 NO: SEQ ID NO: 857 tgaaaaaactaaccatctc 1105 1124 SEQ ID 1860 gagaaaatcaatgccttca 7104 7123 1 3 NO: SEQ ID NO: 858 gaaaaaactaaccatctct 1106 1125 SEQ ID 1861 agagccaggtcgagctttc 11044 11063 1 3 NO: SEQ ID NO: 859 tctgagcaaaatatccaga 1122 1141 SEQ ID 1862 tctgatgaggaaactcaga 12252 12271 1 3 NO: SEQ ID NO: 860 tctcttcaataagctggtt 1148 1167 SEQ ID 1863 aacctcccattttttgaga 6318 6337 1 3 NO: SEQ ID NO: 861 ctgagctgagaggcctcag 1168 1187 SEQ ID 1864 ctgatccccgagccctcag 1359 1378 13 NO: SEQ ID NO: 862 tgaagcagtcacatctctc 1190 1209 SEQ ID 1865 gagaaaatcaatgccttca 7104 7123 13 NO: SEQ ID NO: 863 aagcagtcacatctctctt 1192 1211 SEQ ID 1866 aagaggcagcttctggctt 12289 12308 1 3 NO: SEQ ID NO:864 ctctcttgccacagctgat 1204 1223 SEQ ID 1867 atcaaaagaagcccaagag 12938 12957 13 NO: SEQ ID NO: 865 tcttgccacagctgattga 1207 1226 SEQ ID 1868 tcaaagttaattgggaaga 12271 12290 1 3 NO: SEQ ID NO: 866 cttgccacagctgattgag 1208 1227 SEQ ID 1869 ctcaattttgattttcaag 8520 8539 1 3 NO: SEQ ID NO:867 tgaggtgtccagccccatc 1223 1242 SEQ ID 1870 gatggaaccctctccctca 4725 4744 1 3 NO: SEQ ID NO: 868 tcagtgtggacagcctcag 1259 1278 SEQ ID 1871 ctgacatcttaggcactga 4993 5012 1 3 NO: SEQ ID NO:869 acatcctccagtggctgaa 1288 1307 SEQ ID 1872 ttcagaagctaagcaatgt 7231 7250 13 NO: SEQ ID NO: 870 gcacagcagctgcgagaga 1377 1396 SEQ ID 1873 tctctgaaagacaacgtgc 12315 12334 13 NO: SEQ ID NO: 871 cagcagctgcgagagatct 1380 1399 SEQ ID 1874 agataacattaaacagctg 13043 13062 1 3 NO: SEQ ID NO: 872 gcgagggatcagcgcagcc 1407 1426 SEQ ID 1875 ggctcaacacagacatcgc 5710 5729 1 3 NO: SEQ ID NO: 873 aagacaaaccctacaggga 1470 1489 SEQ ID 1876 tcccagaaaacctcttctt 3928 3947 1 3 NO: SEQ ID NO:874 caggagctgctggacattg 1491 1510 SEQ ID 1877 caatggagagtccaacctg 4652 4671 1 3 276 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 875 aggagctgctggacattgc 1492 1511 SEQ ID 1878 gcaagggttcactgttcct 7856 7875 1 3 NO: SEQ ID NO:876 ctgctggacattgctaatt 1497 1516 SEQ ID 1879 aattgggaagaagaggcag 12279 122981 3 NO: SEQ ID NO: 877 gattacacctatttgattc 1557 1576 SEQ ID 1880 gaatattttgagaggaatc 6345 6364 1 3 _______NO: SEQ ID NO:878 atttgattctgcgggtcat 1567 1586 SEQ ID 1881 atgaagtagaccaacaaat 7153 7172 13 NO: SEQ ID NO: 879 tctgcgggtcattggaaat 1574 1593 SEQ ID 1882 atttgtaagaaaatacaga 6428 6447 1 3 NO: SEQ ID NO: 880 aaccatggagcagttaact 1601 1620 SEQ ID 1883 agtttctccatcctaggtt 9954 9973 1 3 NO: SEQ ID NO: 881 ggagcagttaactccagaa 1607 1626 SEQ ID 1884 ttctgaaaatccaatctcc 8392 8411 1 3 NO: SEQ ID NO:882 actccagaactcaagtctt 1617 1636 SEQ ID 1885 aagatcgcagactttgagt 1164611665 13 NO: SEQ ID NO:883 tccagaactcaagtcttca 1619 1638 SEQID 1886 tgaactcagaagaattgga 1912 1931 13 NO: SEQ ID NO: 884 aagtacaaagccatcactg 1655 1674 SEQ ID 1887 cagtcatgtagaaaaactt 4421 4440 1 3 NO: SEQ ID NO: 885 gccatcactgatgatccag 1664 1683 SEQ ID 1888 ctggaactctctccatggc 1087510894 13 NO: SEQ ID NO: 886 ccatcactgatgatccaga 1665 1684 SEQ ID 1889 tctgaactcagaaggatgg 13991 140101 3 NO: SEQ ID NO: 887 atccagaaagctgccatcc 1677 1696 SEQ ID 1890 ggatttcctaaagctggat 11165 111841 3 NO: SEQ ID NO: 888 cagaaagctgccatccagg 1680 1699 SEQ ID 1891 cctgaaatacaatgctctg 5510 5529 1 3 NO: SEQ ID NO: 889 acaaggaccaggaggttct 1723 1742 SEQ ID 1892 agaaacagcatttgtttgt 4534 4553 1 3 NO: SEQ ID NO: 890 aggaccaggaggttcttct 1726 1745 SEQ ID 1893 agaagctaagcaatgtcct 7234 7253 1 3 NO: SEQ ID NO: 891 accaggaggttcttcttca 1729 1748 SEQ ID 1894 tgaaggctgactctgtggt 4282 4301 1 3 NO: SEQ ID NO:892 tcttcagactttccttgat 1742 1761 SEQID 1895 atcaggaagggctcaaaga 2559 2578 13 NO: SEQ ID NO: 893 ttcagactttccttgatga 1744 1763 SEQ ID 1896 tcattactcctgggctgaa 112991113181 3 NO: SEQ ID NO:894 gttgatgaggagtccttca 1802 1821 SEQ ID 1897 tgaatctggctccctcaac 9038 9057 1 3 NO: SEQ ID NO:895 cttcacaggcagatattaa 1816 1835 SEQ ID 1898 ttaatcgagaggtatgaag 7140 7159 1 3 NO: SEQ ID NO: 896 ttcacaggcagatattaac 1817 1836 SEQID 1899 gttaatcgagaggtatgaa 7139 7158 13 NO: SEQ ID NO: 897 ggcagatattaacaaaatt 1823 1842 SEQ ID 1900 aattgcattagatgatgcc 6581 6600 1 3 NO: SEQ ID NO: 898 atattaacaaaattgtcca 1828 1847 SEQ ID 1901 tggagtttgtgacaaatat 2752 2771 1 3 NO: SEQ ID NO: 899 acaaaattgtccaaattct 1834 1853 SEQ ID 1902 agaaacagcatttgtttgt 4534 4553 1 3 NO: SEQ ID NO: 900 gagcaagtgaagaactttg 1869 1888 SEQ ID 1903 caaatgacatgatgggctc 5326 5345 1 3 NO: SEQ ID NO:901 gtgaagaactttgtggctt 1875 1894 SEQ ID 1904 aagcatctgattgactcac 12669 12688 1 3 NO: SEQ ID NO: 902 agaactttgtggcttccca 1879 1898 SEQ ID 1905 tgggcctgccccagattct 8901 8920 1 3 277 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 903 tttgtggcttcccatattg 1884 1903 SEQ ID 1906 caataagatcaatagcaaa 8990 9009 1 3 NO: SEQ ID NO: 904 tggcttcccatattgccaa 1888 1907 SEQ ID 1907 ttggctcacatgaaggcca 7623 7642 1 3 NO: SEQ ID NO: 905 ttcccatattgccaatatc 1892 1911 SEQ ID 1908 gatatacactagggaggaa 12737 127561 3 NO: SEQ ID NO: 906 tcccatattgccaatatct 1893 1912 SEQ ID 1909 agatcaaagttaattggga 12268 122871 3 NO: SEQ ID NO: 907 ttgccaatatcttgaactc 1900 1919 SEQ ID 1910 gagtcccagtgcccagcaa 9344 9363 1 3 NO: SEQ ID NO: 908 ttggatatccaagatctga 1926 1945 SEQ ID 1911 tcagtataagtacaaccaa 9392 9411 1 3 NO: SEQ ID NO: 909 tccaagatctgaaaaagtt 1933 1952 SEQ ID 1912 aacttccaactgtcatgga 1978 1997 1 3 NO: SEQ ID NO: 910 tgaaaaagttagtgaaag 1941 1960 SEQ ID 1913 ctttgaagtcagtcttcag 7907 7926 1 3 NO: SEQ ID NO: 911 agttagtgaaagaagttct 1948 1967 SEQ ID 1914 agaatctcaacttccaact 1970 1989 1 3 NO: SEQ ID NO: 912 aatctcaacttccaactgt 1972 1991 SEQ ID 1915 acaggggtcctttatgatt 12342 12361 1 3 NO: SEQ ID NO:913 gtcatggacttcagaaaat 1989 2008 SEQ ID 1916 atttgaaagaataaatgac 7028 7047 1 3 NO: SEQ ID NO: 914 tcaactctacaaatctgtt 2021 2040 SEQ ID 1917 aacacattgaggctattga 6970 6989 1 3 NO: SEQ ID NO:915 aactctacaaatctgtttc 2023 2042 SEQ ID 1918 gaaaaaggggattgaagtt 10276 102951 3 NO: SEQ ID NO: 916 aaatagaagggaatcttat 2071 2090 SEQ ID 1919 ataagcaaactgttaattt 5449 5468 1 3 ___1__NO: SEQ ID NO: 917 agaagggaatcttatattt 2075 2094 SEQ ID 1920 aaatgcactgctgcgttct 4892 491 1 1 3 NO: SEQ ID NO: 918 gaagggaatcttatatttg 2076 2095 SEQ ID 1921 caaaaacattttcaacttc 5279 5298 1 3 NO: SEQ ID NO:919 tgatccaaataactacctt 2093 2112 SEQ ID 1922 aaggaagaaagaaaaatca 3453 3472 1 3 NO: SEQ ID NO: 920 tggatttgcttcagctgac 2150 2169 SEQ ID 1923 gtcagcccagttccttcca 10924 10943.1 3 NO: SEQ ID NO: 921 tttgcttcagctgacctca 2154 2173 SEQ ID 1924 tgaggaaactcagatcaaa 12257 122761 3 NO: SEQ ID NO:922 cttggaaggaaaaggcttt 2183 2202 SEQ ID 1925 aaagcattggtagagcaag 7842 7861 1 3 NO: SEQ ID NO: 923 tggaaggaaaaggctttga 2185 2204 SEQ ID 1926 tcaagtctgtgggattcca 4078 4097 1 3 NO: SEQ ID NO:924 ggctttgagccaacattgg 2196 2215 SEQ ID 1927 ccaagaggtatttaaagcc 12950 129691 3 NO: __ _ SEQ ID NO: 925 tgagccaacattggaagct 2201 2220 SEQ ID 1928 agctttctgccactgctca 13513 13532 1 3 1 _ _ _ __NO: SEQ ID NO:926 gagccaacattggaagctc 2202 2221 SEQ ID 1929 gagctttctgccactgctc 13512 13531 1 3 NO: SEQ ID NO: 927 aacattggaagctcttttt 2207 2226 SEQ ID 1930 aaaagaaacagcatttgtt 4531 4550 1 3 1_ _ NO: SEQ ID NO:928 tggaagctctttttgggaa 2212 2231 SEQ ID 1931 ttccggcacgtgggttcca 3777 3796 1 3 NO: 3EQ ID NO: 929 ctctttttgggaagcaagg 2218 2237 SEQ ID 1932 ccttactgactttgcagag 7790 7809 1 3 NO: I I 3EQ ID NO: 930 tttttgggaagcaaggatt 2221 2240 SEQ ID 1933 aatcattgaaaaattaaaa 6722 6741 1 3 278 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO: 931 ttttcccagacagtgtcaa 239 2258 SEQ ID 1934 ttgatgaaatcattgaaaa 6715 6734 13 NO: SEQ ID NO: 932 ttggctataccaaagatga 2323 2342 SEQ ID 1935 tcattgctcccggagccaa 2668 2687 13 ____ ___ ____ ___ NO: SEQ ID NO: 933 ataccaaagatgataaaca 2329 2348 SEQ ID 1936 tgttgcttttgtaaagtat 6272 6291 1 ___ NO: SEQ ID NO: 934 gagcaggatatggtaaatg 2349 2368 SEQ ID 1937 catttcagccttcgggctc 4254 4273 13 NO: SEQ ID NO: 935 atggtaaatggaataatgc 2358 2377 SEQ ID 1938 gcatgcctagtttctccat 9946 9965 13 NO: SEQ ID NO: 936 tggtaaatggaataatgct 2359 2378 SEQ ID 1939 agcacagtacgaaaaacca 10801 1082013 NO: SEQ ID NO: 937 taaatggaataatgctcag 2362 2381 SEQ ID 1940 ctgaaagagatgaaattta 13059 13078 1 3 NO: SEQ ID NO: 938 tggaataatgctcagtgtt 2366 2385 SEQ ID 1941 aacagatttgaggattcca 7973 7992 13 NO: SEQ ID NO: 939 tcagtgttgagaagctgat 2377 2396 SEQ ID 1942 atcacaactcctccactga 9534 9553 1 3 NO: SEQ ID NO: 940 cagtgttgagaagctgatt 2378 2397 SEQ ID 1943 aatcacaactcctccactg 9533 9552 1 3 NO: SEQ ID NO: 941 agtgttgagaagctgatta 2379 2398 SEQ ID 1944 taatcacaactcctccact 9532 9551 1 3 NO: SEQ ID NO: 942 gattaaagatttgaaatcc 2393 2412 SEQ ID 1945 ggatactaagtaccaaatc 6866 6885 1 3 NO: SEQ ID NO: 943 gatttgaaatccaaagaag 2400 2419 SEQ ID 1946 cttccgtttaccagaaatc 8240 8259 1 3 NO: SEQ ID NO: 944 atttgaaatccaaagaagt 2401 2420 SEQ ID 1947 acttccgtttaccagaaat 8239 8258 1 3 NO: SEQ ID NO: 945 atccaaagaagtcccggaa 2408 2427 SEQ ID 1948 ttccaatttccctgtggat 3680 3699 1 3 NO: SEQ ID NO: 946 tccaaagaagtcccggaag 2409 2428 SEQ ID 1949 cttccaatttccctgtgga 3679 3698 1 3 NO: SEQ ID NO: 947 agagcctacctccgcatct 2430 2449 SEQ ID 1950 agattaatccgctggctct 8563 8582 1 3 NO: SEQ ID NO: 948 gagcctacctccgcatctt 2431 2450 SEQ ID 1951 aagattaatccgctggctc 8562 8581 1 3 NO: SEQ ID NO: 949 cttgggagaggagcttggt 2447 2466 SEQ ID 1952 accactgggacctaccaag 12519 12538 1 3 NO: SEQ ID NO: 950 ggagcttggttttgccagt 2456 2475 SEQ ID 1953 actggtggcaaaaccctcc 2726 2745 1 3 NO: SEQ ID NO:951 ttggttttgccagtctcca 2461 2480 SEQ ID 1954 tggagaagccacactccaa 10763 10782 1 3 NO: SEQ ID NO: 952 cagtctccatgacctccag 2471 2490 SEQ ID 1955 ctggtcgcctgccaaactg 3530 3549 1 3 ,NO: SEQ ID NO: 953 ctccatgacctccagctcc 2475 2494 SEQ ID 1956 ggagtcattgctcccggag 2664 2683 1 3 NO: SEQ ID NO: 954 ctgggaaagctgcttctga 2493 2512 SEQ ID 1957 tcagaaagctaccttccag 7931 7950 1 3 NO: SEQ ID NO: 955 gaggtcatcaggaagggct 2553 2572 SEQ ID 1958 agccagaagtgagatcctc 3506 3525 1 3 NO: SEQ ID NO: 956 aagaatgacttttttcttc 2574 2593 SEQ ID 1959 gaaggcatctgggagtctt 3827 3846 1 3 NO: SEQ ID NO: 957 cttttttcttcactacatc 2582 2601 SEQ ID 1960 gatgcttacaacactaaag 6099 6118 1 3 NO: SEQ ID NO:1958 catcttcatggagaatgcc 2597 2616 SEQ ID 1961 ggcacttccaaaattgatg 10710 10729 1 3 279 WO 2004/091515 N OF : PCT/US2004/011255 NO: SEQ ID NO: 959 cttcatggagaatgccttt 2600 2619 SEQ ID 1962 aaagttaattgggaagaag 12273 12292 13 NO: SEQ ID NO: 960 aatgcctttgaactcccca 2610 2629 SEQ ID 1963 tgggctggcttcagccatt 5729 5748 13 NO: SEQ ID NO: 961 gcctttgaactccccactg 2613 2632 SEQ ID 1964 cagtctgaacattgcaggc 5375 5394 13 NO: SEQ ID NO: 962 caaggctggagtaaaactg 2684 2703 SEQ ID 1965 cagtgcaacgaccaacttg 5072 5091 1 3 NO: SEQ ID NO: 963 tggagtaaaactggaagta 2690 2709 SEQ ID 1966 tactccaacgccagctcca 3051 3070 1 3 ___ NO: SEQ ID NO: 964 ggaagtagccaacatgcag 2702 2721 SEQ ID 1967 ctgccatctcgagagttcc 4098 4117 1 3 ___ ___NO:__ _ _ _ _ _ _ _ SEQ ID NO:965 tttgtgacaaatatgggca 2757 2776 SEQ ID 1968 tgcctttgtgtacaccaaa 11228 11247 13 NO: SEQ ID NO: 966 tgtgacaaatatgggcatc 2759 2778 SEQ ID 1969 gatgggtctctacgccaca 4377 4396 1 3 ___________NO: SEQ ID NO:967 ggacttcgctaggagtggg 2786 2805 SEQ ID 1970 cccaaggccacaggggtcc 12333 12352 13 NO: SEQ ID NO:968 gtggggtccagatgaacac 2800 2819 SEQ ID 1971 gtgttctagacctctccac 4171 4190 1 3 1_ _ 1 NO: SEQ ID NO:969 ttccacgagtcgggtctgg 2826 2845 SEQ ID 1972 ccagaatctgtaccaggaa 12554 12573 1 3 NO: SEQ ID NO: 970 agtcgggtctggaggctca 2833 2852 SEQ ID 1973 tgagaactacgagctgact 4799 4818 13 NO: SEQ ID NO: 971 tcgggtctggaggctcatg 2835 2854 SEQ ID 1974 catgaaggccaaattccga 7631 7650 13 NO: SEQ ID NO: 972 aaaagctgggaagctgaag 2861 2880 SEQ ID 1975 cttccagacacctgatttt 7943 7962 13 ___ NO: SEQ ID NO:973 aagctgaagtttatcattc 2871 2890 SEQ ID 1976 gaatttacaattgttgctt 6261 6280 13 NO: SEQ ID NO: 974 gagaccagtcaagctgctc 2900 2919 SEQ ID 1977 gagcttcaggaagcttctc 13206 13225 13 NO: SEQ ID NO: 975 gcaacacattacatttggt 2926 2945 SEQ ID 1978 accagtcagatattgttgc 1018310202 1 3 NO: SEQ ID NO:976 acattacatttggtctcta 2931 2950 SEQ ID 1979 tagaatatgaactaaatgt 11881 119001 3 NO: SEQ ID NO: 977 cattacatttggtctctac 2932 2951 SEQ ID 1980 gtagctgagaaaatcaatg 7098 7117 1 3 NO: SEQ ID NO:978 aaacggaggtgatcccacc 2956 2975 SEQ ID 1981 ggtggataccctgaagttt 3197 3216 1 3 NO: SEQ ID NO:979 attgagaacaggcagtcct 2979 2998 SEQ ID 1982 aggaaaagcgcacctcaat 12023 120421 3 NO: SEQ ID NO: 980 tgagaacaggcagtcctgg 2981 3000 SEQ ID 1983 ccagcttccccacatctca 8333 8352 1 3 NO: SEQ ID NO:981 ctgcacctcaggcgcttac 3035 3054 SEQ ID 1984 gtaagaaaatacagagcag 6432 6451 1 3 ______ ___ ___ ~NO:_________ SEQ ID NO:982 tccacagactccgcctcct 3066 3085 SEQ ID 1985 aggacagagccttggtgga 3184 3203 13 NO: SEQ ID NO:983 ctgaccggggacaccagat 3093 3112 SEQ ID 1986 atctgatgaggaaactcag 12251 12270 1 3 NO: SEQ ID NO:984 tagagctggaactgaggcc 3112 3131 SEQ ID 1987 ggcctctctggggcatcta 5136 5155 1 3 1 NO:I I SEQ ID NO: 985 ctatgagctccagagagag 3167 3186 SEQ ID 1988 ctctcacaaaaaagtatag 6541 6560 13 NO: SEQ ID NO:986 cttggtggataccctgaag 3194 3213 SEQ ID 1989 cttcaggaagcttctcaag 13209 13228 13 280 WO 2004/091515 PCT/US2004/011255 NO: SEQ ID NO:987 ttgtaactcaagcagaagg 3214 3233 SEQ ID 1990 ccttacacaataatcacaa 9522 9541 1 3 NO: SEQ ID NO: 988 taactcaagcagaaggtgc 3217 3236 SEQ ID 1991 gcacctagctggaaagtta 6947 6966 1 3 __ NO: SEQ ID NO: 989 gcagaaggtgcgaagcaga 3225 3244 SEQ ID 1992 tctgtgggattccatctgc 4083 4102 1 3 NO: SEQ ID NO:990 cagaaggtgcgaagcagac 3226 3245 SEQ ID 1993 gtctgtgggattccatctg 4082 4101 13 NO: SEQ ID NO: 991 gtatgaccttgtccagtga 3280 3299 SEQ ID 1994 tcaccaacggagaacatac 10843 10862 13 _____ ___ ____ ____NO: SEQ ID NO: 992 tatgaccttgtccagtgaa 3281 3300 SEQ ID 1995 ttcaccaacggagaacata 10842 10861 13 NO: SEQ ID NO: 993 gaagtccaaattccggatt 3297 3316 SEQ ID 1996 aatctcaagctttctcttc 10044 10063 13 NO: SEQ ID NO: 994 gagggcaaaacgtcttaca 3363 3382 SEQ ID 1997 tgtacaactggtccgcctc 4207 4226 1 3 NO: SEQ ID NO: 995 agggcaaaacgtcttacag 3364 3383 SEQ ID 1998 ctgttaggacaccagccct 4054 4073 1 3 NO: SEQ ID NO:996 gactcaccctggacattca 3382 3401 SEQ ID 1999 tgaaattcaatcacaagtc 9068 9087 1 3 NO: SEQ ID NO: 997 ctggacattcagaacaaga 3390 3409 SEQ ID 2000 tcttttcttttcagcccag 9218 9237 1 3 NO: SEQ ID NO: 998 tcatgggcgacctaagttg 3427 3446 SEQ ID 2001 caactgcagacatatatga 6627 6646 1 3 NO: SEQ ID NO: 999 tgggcgacctaagttgtga 3430 3449 SEQ ID 2002 tcactccattaacctccca 6308 6327 1 3 NO: SEQ ID NO: 1000 agttgtgacacaaaggaag 3441 3460 SEQ ID 2003 cttcttttccaattgaact 13830 13849 1 3 NO: SEQ ID NO: 1001 tgacacaaaggaagaaaga 3446 3465 SEQ ID 2004 tcttcatcttcatctgtca 10212 10231 1 3 NO: SEQ ID NO:1002 gacacaaaggaagaaagaa3447 3466 SEQ ID 2005 ttcttcatcttcatctgtc 10211 10230 1 3 NO: SEQ ID NO: 1003 ggaagaaagaaaaatcaag 3455 3474 SEQ ID 2006 cttgtcatgcctacgttcc 11340 11359 1 3 NO: SEQ ID NO: 2007 aaaaagcgatggccgggtc 3947 3966SEQ ID NO:2313gaccttgcaagaatatttt 6335 6354 1 3 SEQ ID NO: 2008gtcaaatataccttgaaca 3963 3982SEQ ID NO:2314tgttaacaaattccttgac 7355 7374 1 3 SEQ ID NO: 2009tgaacaagaacagtttgaa 3976 3995SEQ ID NO:2315 tcaagttcctgaccttca 8302 8321 1 3 SEQ ID NO: 201oagtttgaaaattgagattc 3987 4006SEQ ID NO:2316gaatctggctccctcaact 9039 9058 1 3 SEQ ID NO: 2011gtttgaaaattgagattcc 3988 4007SEQ ID NO:2317ggaaataccaagtcaaaac 10446 10465 1 3 SEQ ID NO: 2012ttgaaaattgagattcctt 3990 4009SEQ ID NO:2318aaggaaaagcgcacctcaa 12022 12041 1 3 SEQ ID NO: 2013ctaaagatgttagagactg 4038 4057SEQ ID NO:2319cagttgaccacaagcttag 10537 10556 1 3 SEQ ID NO: 2014atgttagagactgttagga 4044 4063SEQ ID NO:2320tccttaacaccttccacat 8065 8084 1 3 SEQ ID NO: 2015cagccctccacttcaagtc 4066 4085SEQ ID NO:2321 gacttctctagtcaggctg 8805 8824 1 3 SEQ ID NO: 2016agccctccacttcaagtct 4067 4086SEQ ID NO:2322agacatcgctgggctggct 5720 5739 13 SEQ ID NO: 2017ccatctgccatctcgagag 4094 4113SEQ ID NO:2323ctctcaaatgacatgatgg 5322 5341 1 3 SEQ ID NO: 2018attcccaagttgtatcaac 4134 4153SEQ ID NO:2324gttgagaagccccaagaat 6246 6265 1|3 SEQ ID NO: 2019tcaactgcaagtgcctctc 4148 4167SEQ ID NO:2325gagatcaagacactgttga 8835 8854 1 3 SEQ ID NO: 2020ggtgttctagacctctcca 4170 4189SEQ ID NO:2326tggaaccctctccctcacc 4727 4746 1 3 SEQ ID NO: 2021 ctccacgaatgtctacagc 4184 4203 SEQ ID NO:2327gctggtaacctaaaaggag 5580 5599 1 3 SEQ ID NO: 2022cacgaatgtctacagcaac 4187 4 2 06SEQ ID NO:2328gttgcccaccatcatcgtg 11663 11682 1 3 SEQ ID NO: 2023acgaatgtctacagcaact 4188 4207SEQ ID NO:2329agttgcccaccatcatcgt 11662 11681 1 3 SEQ ID NO: 2024 cctacagtggtggcaaca 4224 4243SEQ ID NO:2330tgttagttgctcttaagga 13351 13370 1 3 SEQ ID NO: 2025cgttaccacatgaaggctg 4272 4291,SEQ ID NO:2331 cagcaagtacctgagaacg 8603 8622 1 3 281 -WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2026gaaggctgactctgtggtt 4283 4 3 0 2SEQ ID NO:2332aacctatgccttaatcttc 13161 13180 13 SEQ ID NO: 2027tgtggttgacctgctttcc 4295 43 14SEQ ID NO:2333ggaaagttaaaacaacaca 6957 6976 1 3 SEQ ID NO: 2028cctgctttcctacaatgtg 4304 4 323SEQ ID NO:2334cacaccttgacattgcagg 11080 11099 1 3 SEQ ID NO: 2029 ctgctttcctacaatgtgc 4305 4 324SEQ ID NO:2335gcacaccttgacattgcag 11079 11098 1 3 SEQ ID NO: 2030 tcctacaatgtgcaaggat 4311 4 3 30SEQ ID NO:2336atccgctggctctgaagga 8569 8588 1 3 SEQ ID NO: 2031 tatgaccacaagaatacgt 4344 4 3 6 3 SEQ ID NO:2337acgtccgtgtgccttcata 9976 9995 1 3 SEQ ID NO: 2032atgaccacaagaatacgtc 4345 4 3 64SEQ ID NO:2338gacgtccgtgtgccttcat 9975 9994 1 3 SEQ ID NO: 2033gaatacgtctacactatca 4355 4 3 7 4SEQ ID NO:2339 tgattatctgaattcattc 6479 6498 1 3 SEQ ID NO: 2034tttctagattcgaatatca 4398 4 4 17SEQ ID NO:2340 tgatttacatgatttgaaa 6677 6696 1 3 SEQ ID NO: 2035gattcgaatatcaaattca 4404 4 4 2 3 SEQ ID NO:2341 gaagtagctgagaaaatc 7094 7113 1 3 SEQ ID NO: 2036gaaacaacccagtctcaaa 4441 44601SEQ ID NO: 2342 tttgaaaaattctcttttc 9206 9225 1 3 SEQ ID NO: 2037cccagtctcaaaaggttta 4448 4 4 6 7|SEQ ID NO:2343taaattcattactcctggg 11294 11313 1 3 SEQ ID NO: 2038ctcaaaaggtttactaata 4454 4 4 7 3SEQ ID NO:2344tattcaaaactgagttgag 12223 12242 1 3 SEQ ID NO: 2039 caaaaggtttactaatat 4455 4 4 74SEQ ID NO:2345atattcaaaactgagttga 12222 12241 1 3 SEQ ID NO: 2040aaaaggtttactaatattc 4457 44761SEQ ID NO:2346 gaatttgaaagttcgtttt 9272 9291 1 3 SEQ ID NO: 2041 gaaacagcatttgtttgtc 4535 4 554SEQ ID NO:2347gacagcatcttcgtgtttc 11206|11225 1 3 SEQ ID NO: 2042atttgtttgtcaaagaagt 4543 4 5 6 2 SEQ ID NO:2348|acttaaaaaatataaaaat 8014 8033 1 3 SEQ ID NO: 2043 caagattgatgggcagtt 4561 4 580SEQ ID NO:2349aactctcaagtcaagttga 13414|13433 13 SEQ ID NO: 2044tcagagtctcttcgttct 4578 4597SEQ ID NO:2350agaagatggcaaatttgaa 11987 12006 1 :3 SEQ ID NO: 20451cagagtctcttcgttctat 4580 4 5991SEQ ID NO:2351 atagcatggacttcttctg 8865 8884 1 3 SEQ ID NO: 2046atgctaaaggcacatatgg 4597 4 6161SEQ ID NO:2352ccatttgagatcacggcat 9237 9256 1 3 SEQ ID NO: 2047gcacatatggcctgtcttg 4606 4 62 5SEQ ID NO:2353caagttggcaagtaagtgc 9364 9383 1 3 SEQ ID NO: 2048gagtccaacctgaggttta 4659 4678SEQ ID NO:2354 taaagtgccacttttactc 6182 6201 1 3 SEQ ID NO: 2049agtccaacctgaggtttaa 4660 4 679SEQ ID NO:2355ttaacagggaagatagact 9300 9319 1 3 SEQ ID NO: 2050cctacctccaaggcaccaa 4684 4 703SEQ ID NO:2356,ttggcaagtaagtgctagg 9368 9387 1 3 SEQ ID NO: 2051 gaagatggaaccctctccc 4722 4741 SEQ ID NO:2357gggaagaagaggcagcttc 12283,12302 1 3 SEQ ID NO: 2052tgatctgcaaagtggcatc 4754 4 7 7 3 SEQ ID NO:2358gatgaggaaactcagatca 12255|12274 1 3 SEQ ID NO: 2053gatctgcaaagtggcatca 4755 4 774SEQ ID NO:2359tgatgaggaaactcagatc 12254 12273 1 3. SEQ ID NO: 2054gcttccctaaagtatgaga 4785 4804SEQ ID NO:2360 tctcgtgtctaggaaaagc 5969 5988 1 3 SEQ ID NO: 2055gtatgagaactacgagctg 4796 4 8 15SEQ ID NO:2361 cagcttaagagacacatac 6912 6931 1 3 SEQ ID NO: 2056 tctaacaagatggatatga 4860 4879SEQ ID NO:2362 cattttccaactaataga 13024|13043 1 3 SEQ ID NO: 2057ctgctgcgttctgaatatc 4899 4 9 18SEQ ID NO:2363gatacaagaaaaactgcag 6893 6912 1 3 3EQ ID NO: 2058tcattgaggttcttcagcc 4932 4951 SEQ ID NO:2364ggctcatatgctgaaatga 5340 5359 1 3 3EQ ID NO: 2059 ctggatcactaaattcc 4955 4 9 74SEQ ID NO:2365ggaaggacaaggcccagaa 12541 12560 1 3 3EQ ID NO: 2060ccatggtcttgagttaaat 4973 4 9 9 2 SEQ ID NO: 366atttttattcctgccatgg 10095 10114 1 3 3EQ ID NO: 2061 tcttaggcactgacaaaat 4999 5018SEQ ID NO: 367 attttttgcaagttaaaga 14011 14030 1 3 3EQ ID NO: 2062acaaggcgacactaaggat 5032 5051 SEQ ID NO:2368atccatgatctacatttgt 6786 6805 13 EQ ID NO: 2063tgcaacgaccaacttgaag 5075 50 9 4 SEQ ID NO:2369cttcagggaacacaatgca 5177 5196 13 3EQ ID NO: 2064caacttgaagtgtagtctc 5084 5103SEQ ID NO:2370gagatgagagatgccgttg 6231 6250 13 SEQ ID NO: 2065gctggagaatgagctgaat 5108 5127SEQ ID NO:2371 attctcttttcttttcagc 9214 9233 T3 3EQ ID NO: 20661gcagagctggcctctctg 5127 5146SEQ ID NO:2372cagatacaagaaaaactgc 6891 6910 1 3 3EQ ID NO: 2067tctctggggcatctatgaa 5140 5159SEQ ID NO: 2373ttcattcaattgggagaga 6491 6510 13 'EQ ID NO: 2068tctggggcatctatgaaat 5142 5161 SEQ ID NO: 2374atttgtaagaaaatacaga 6428 6447 1 3 )EQ ID NO: 2069aacacaatgcaaaattcag 5185 5204SEQ ID NO:2375ctgaagcattaaaactgtt 7498 7517 1 3 EQ ID NO: 2070ctcacagagctatcactgg 5223 5 2 4 2SEQ ID NO:2376ccagatgctgaacagtgag 8141 8160 1 3 EQ ID NO: 2071 tgggaagtgcttatcaggc 5239 5258|SEQ ID NO:2377gcctacgttccatgtccca 11348 11367 1 3 EQ ID NO: 2072ttcaaggtcagtcaagaag 5295 5314SEQ ID NO:2378cttcagtgcagaatatgaa 11969 11988 1|3 EQ ID NO: 2073aatgacatgatgggctcat 5328 5 3 4 7SEQ ID NO:2379atgattatctgaattcatt 6478 6497 1|3 EQ ID NO: 2074gctcatatgctgaaatgaa 5341 5 3 6 0SEQ ID NO:2380ttcagccattgacatgagc 5738 5757 1 3 EQ ID NO: 2075atatgctgaaatgaaattt 5345 5 3 6 4 SEQ ID NO:2381 aaatagctattgctaatat 6694 6713 1 3 EQ ID NO: 2076 tctgaacattgcaggctta 5378 5 3 9 7SEQ ID NO:2382taagaaccagaagatcaga 10988 11007 1 3 EQ ID NO:|2o77gaacattgcaggcttatca 5381 5400SEQ ID NO:2383tgatatcgacgtgaggttc 12482 12501 1 3 282 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2078tgcaggcttatcactggac 5387 5 4 0 6SEQ ID NO:2384gtcctggattccacatgca 11844 11863 1 3 SEQ ID NO: 2079tcaaaacttgacaacattt 5412 5431 SEQ ID NO:2385aaattccttgacatgttga 7362 7381 1 3 SEQ ID NO: 2080atttacagctctgacaagt 5427 5 4 4 6 SEQ ID NO:2386acttaaaaaatataaaaat 8014 8033 7 3 SEQ ID NO: 2081 ctctgacaagttttataag 5435 5 4 5 4SEQ ID NO:2387cttacttgaattccaagag 10666 10685 1 3 SEQ ID NO: 2082gttaatttacagctacagc 5460 5 4 7 9SEQ ID NO:2388gctgcatgtggctggtaac 5570 5589 1 3 SEQ ID NO: 2083ttctctggtaactacttta 5483 5502,SEQ ID NO:23 8 9 taaaagattactttgagaa 7267 7286 1 3 SEQ ID NO: 2084cctaaaaggagcctaccaa 5588 560 7 SEQ ID NO:2 3 9 0 tggcaagtaagtgctagg 9368 9387 1 3 SEQ ID NO: 2085aaaaggagcctaccaaaat 5591 5610 SEQ ID NO:23 9 1 atttacaattgttgctttt 6263 6282 1 3 SEQ ID NO: 2086aggagcctaccaaaataat 5594 5 6 1 3SEQ ID NO:2392attacctatgatttctcct 10119 10138 13 SEQ ID NO: 2087ataatgaaataaaacacat 5608 5 6 2 7SEQ ID NO:2393atgtcaaacactttgttat 7057 7076 1 3 SEQ ID NO: 2o88 aaaacacatctatgccatC 5618 5637SEQ ID NO:2394gatgaagatgacgactttt 1215012169 1 3 SEQ ID NO: 2089tgctaaggttcagggtgtg 5678 5 6 9 7SEQ ID NO:2395cacaagtcgattcccagca 9079 9098 1 3 SEQ ID NO: 2090gagtttagccatcggctca 5697 571 6 SEQ ID NO:23 9 6 tgaggtgactcagagactc 7442 7461 1 3 SEQ ID NO: 2091 gctggcttcagccattgac 5732 5751 SEQ ID NO:2397gtcagtgaagttctccagc 8588 8607 1 3 SEQ ID NO: 2092atttcagcaatgtcttccg 5782 5801 SEQ ID NO:2398cggagcatgggagtgaaat 8620 8639 1 3 SEQ ID NO: 2093tttcagcaatgtcttccgt 5783 5802SEQ ID NO:2399acggagcatgggagtgaaa 8619 8638 1 3 SEQ ID NO: 2094ttcagcaatgtcttccgtt 5784 5803SEQ ID NO:2400aacggagcatgggagtgaa 8618 8637 1 3 SEQ ID NO: 2095cagcaatgtcttccgttct 5786 5805SEQ ID NO:2401 agaagtgtcttcaaagctg 12404 12423 1 3 SEQ ID NO: 2096tgtcttccgttctgtaatg 5792 5811 SEQ ID NO:2402cattcaattgggagagaca 6493 6512 1 3 SEQ ID NO: 2097gtcttccgttctgtaatgg 5793 5812SEQ ID NO:2403ccattcagtctctcaagac 12967 12986 1 3 SEQ ID NO: 2098atgggaaactcgctctctg 5851 5870SEQ ID NO:2404cagataaaaaactcaccat 12205 12224 1 3 SEQ ID NO: 2099ggagaacatactgggcagc 5871 5890SEQ ID NO:2405gctgttttgaagactctcc 1080 1099 1 3 SEQ ID NO: 21 oogttgaaagcagaacctctg 5906 5925SEQ ID NO:24061cagaattcataatcccaac 8266 8285 1 3 SEQ ID NO: 2101 gtctaggaaaagcatcagt 5975 599 4 SEQ ID NO:2407actgcaagatttttcagac 13604 13623 1 3 SEQ ID NO: 2102agcatcagtgcagctcttg 5985 6 0 0 4 SEQ ID NO:2408caagaacctgttagttgct 13343 13362 1 3 SEQ ID NO: 2103ttgaacacaaagtcagtgc 6001 6020SEQ ID NO:2409gcacatcaatattgatcaa 6410 6429 1 3 SEQ ID NO: 2104gcagacaggcacctggaaa 6038 6057SEQ ID NO:2410tttcagatggcattgctgc 11602 11621 1 3 SEQ ID NO: 2105gaaactcaagacccaattt 6053 6072SEQ ID NO:241 1 aaatcccatccaggttttc 8029 8048 1 3 SEQ ID NO: 2106acaatgaatacagccagga 6076 6095SEQ ID NO:2412tcctttggctgtgctttgt 9674 9693 1 3 SEQ ID NO: 2107cttggatgcttacaacact 6095 6114SEQ ID NO:2413agtgaagttctccagcaag 8591 8610 1 3 SEQ ID NO: 2108ttggcgtggagcttactgg 6124 6143SEQ ID NO:2414ccagaattcataatcccaa 8265 8284 1 3 SEQ ID NO: 2109cacttttactcagtgagcc 6190 6209SEQ ID NO:2415ggctattgatgttagagtg 6980 6999 1 3 SEQ ID NO: 2110 tttagagatgagagatgcc 6227 6246SEQ ID NO:2416ggcatgatgCtcatttaaa 9169 9188 1 3 SEQ ID NO: 2111 gagaagccccaagaattta 6249 6268SEQ ID NO:2417taaagccattcagtctctc 12962 12981 1 3 SEQ ID NO: 2112caattgttgcttttgtaaa 6268 6287SEQ ID NO:2418tttaaccagtcagatattg 10179 10198 7 3 SEQ ID NO: 2113 ttttgtaaagtatgataaa 6278 6297SEQ ID NO:2419 ttattgctgaatccaaaa 13647 13666 1 3 SEQ ID NO: 2114ttgtaaagtatgataaaaa 6280 6299SEQ ID NO:2420 ttttgagaggaatcgacaa 6350 6369 1 3 SEQ ID NO: 2115ttcactccattaacctccc 6307 6326SEQ ID NO:2421 gggaaaaaacaggcttgaa 9568 9587 1 3 SEQ ID NO: 2116ttttgagaccttgcaagaa 6329 6348SEQ ID NO:2422ttctctctatgggaaaaaa 9558 9577 13 SEQ ID NO: 2117accttgcaagaatattttg 6336 6355SEQ ID NO:2423caaaagaagcccaagaggt 12940 12959 1 3 SEQ ID NO: 2118tcaatattgatcaatttgt 6415 6434SEQ ID NO:2424acaaagcagattatgttga 1182111840 1 3 SEQ ID NO: 2119 cagagcagccctgggaaaa 6443 6462SEQ ID NO:2425 ttttcagaccaactctctg 13614 13633 1 3 SEQ ID NO: 2120 cctgggaaaactcccacag 6452 6471 SEQ JD NO:2426ctgtctctggtcagccagg 7716 7735 1 3 SEQ ID NO: 2121 actcccacagcaagctaat 6461 6480SEQ ID NO:2427attacacttcctttcgagt 12861 12880 7 3 SEQ ID NO: 2122aattcattcaattgggaga 6489 6508,SEQ ID NO:2428tctcttcctccatggaatt 10471 10490 1 3 SEQ ID NO: 2123ttcaattgggagagacaag 6495 6514SEQ ID NO:2429cttggagtgccagtttgaa 1180011819 13 SEQ ID NO: 2124aggagaaactgactgctct 6526 6545SEQ ID NO:2430agagcttatgggatttcct 1115511174 13 SEQ ID NO: 2125actgactgctctcacaaaa 6533 6552SEQ ID NO:2431 tttggcaagctatacagt 8372 8391 1 3 SEQ ID NO: 2126gactgctctcacaaaaaag 6536 6555SEQ ID NO:2432ctttgtgagtttatcagtc 9687 9706 1 3 SEQ ID NO: 2127cagacatatatgatacaat 6633 6652SEQ ID NO:2433attggatatccaagatctg 1925 1944 1 3 SEQ ID NO: 2128aatttgatcagtatattaa 6649 6668SEQ ID NO:2434 taaaagaaatcttcaatt 13807 13826 7 3 SEQ ID NO: 2129 tatgatttacatgatttga 6675 6694SEQ ID NO:2 4 35 caatgattatatcccata 13120 13139 1 3 283 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2130tttgaaaatagctattgct 6689 67081SEQ ID NO:2436agcacagaaaaaattcaaa 13856 13875 1 3 SEQ ID NO: 2131 ttgaaaatagctattgcta 6690 67091SEQ ID NO:24 3 7 tagcacagaaaaaattcaa 13855 13874 1 3 SEQ ID NO: 2132aatagctattgctaatatt 6695 6714SEQ ID NO:2438aataaatggagtctttatt 14076 14095 1 3 SEQ ID NO: 2133attattgatgaaatcattg 6711 6 7 30SEQ ID NO:2439caataccagaattcataat 8260 8279 1 3 SEQ ID NO: 21341aaagtcttgatgagcacta 6739 6758SEQ ID NO:2440 tagtgattacacttccttt 12856 12875 1 3 SEQ ID NO: 2135aagtcttgatgagcactat 6740 6759SEQ ID NO:2441 atagcaacactaaatactt 8761 8780 13 SEQ ID NO: 2136 tgatgagcactatcatat 6745 6764SEQ ID NO:2442atatccaagatgagatcaa 13093 13112 1 3 SEQ ID NO: 2137taattttagtaaaaacaat 6769 6788SEQ ID NO:2443attgagattccctccatta 11694 11713 1 3 SEQ ID NO: 2138ttttagtaaaaacaatcca 6772 6791 SEQ ID NO:2 4 4 4tggagtgccagtttgaaaa 1180211821 13 SEQ ID NO: 2139acatttgtttattgaaaat 6797 6816SEQ ID NO:2445atttcctaaagctggatgt 11167 11186 1 3 SEQ ID NO: 2140attgattttaacaaaagtg 6816 6835SEQ ID NO:2446cactgttccagttgtcaat 9863 9882 1 3 SEQ ID NO: 2141 attttaacaaaagtggaag 6820 6839SEQ ID NO:2447cttcaaagacttaaaaaat 8006 8025 1 3 SEQ ID NO: 2142aaatcagaatccagataca 6880 6899 SEQ ID NO:2448tgtaccataagccatattt 10080 10099 1 3 SEQ ID NO: 2143gaatccagatacaagaaaa 6886 6 905SEQ ID NO: 2 4 4 9 ttttctaaacttgaaattc 9057 9076 1 3 SEQ ID NO: 2144ttaagagacacatacagaa 6916 6935SEQ ID NO: 2 4 5 0 tcttaaacattcctttaa 9483 9502 1 3 SEQ ID NO: 2145atccagcacctagctggaa 6942 6961 SEQ ID NO: 2451 ttccaatttccctgtggat 3680 3699 1 3 SEQ ID NO: 2146tgagcatgtcaaacacttt 7052 7071 SEQ ID NO:2452 aaagtgccacttttactca 6183 6202 1 3 SEQ ID NO: 2147gagcatgtcaaacactttg 7053 7072 SEQ ID NO:2453caaatgacatgatgggctc 5326 5345 1 3 SEQ ID NO: 2148aaacactttgttataaatc 7062 7081 SEQ ID NO:2454gattatatcccatatgttt 13125 13144 1 3 SEQ ID NO: 2149tgagaaaatcaatgccttc 7103 7122SEQ ID NO:2455gaaggaaaagcgcacctca 12021 12040 1 3 SEQ ID NO: 2150tatgaagtagaccaacaaa 7152 7171 SEQ ID NO:2456 tttgtggagggtagtcata 10323 10342 1 3 SEQ ID NO: 2151aagtagaccaacaaatcca 7156 7175SEQ ID NO:2457 tggatgaagatgacgactt 12148 12167 1 3 SEQ ID NO: 2152aagttgaaggagactattc 7215 7234SEQ ID NO:2458gaataccaatgctgaactt 10160 10179 1 3 SEQ ID NO: 2153acaagttaagataaaagat 7256 7275SEQ ID NO:2459atctaaattcagttcttgt 1132611345 1 3 SEQ ID NO: 2154aagataaaagattactttg 7263 7282 SEQ ID NO:|2460 caaaatagaagggaatctt 2069 2088 1 3 SEQ ID NO: 2155gattactttgagaaattag 7272 7291 SEQ ID NO:2461 ctaaacttgaaattcaatc 9061 9080 1 3 SEQ ID NO: 2156tgagaaattagttggattt 7280 7299SEQ ID NO:2462aaatccgtgaggtgactca 7435 7454 1 3 SEQ ID NO: 2157aaattagttggatttattg 7284 7303SEQ ID NO:2463caattttgagaatgaattt 10411 10430 1 3 SEQ ID NO: 2158tggatttattgatgatgct 7292 7311 SEQ ID NO:|2464agcatgcctagtttctcca 9945 9964 1 3 SEQ ID NO: 2159 tcattgaagatgttaacaa 7345 7 3 6 4 SEQ ID NO:2465 ttgtagatgaaaccaatga 7414 7433 1 3 SEQ ID NO: 2160cattgaagatgttaacaaa 7346 7365SEQ ID NO:2466tttgtagatgaaaccaatg 7413 7432 13 SEQ ID NO: 2161 attgaagatgttaacaaat 7347 7366SEQ ID NO:2467atttaagtatgatttcaat 10487 10506 1 3 SEQ ID NO: 2162ttgaagatgttaacaaatt 7348 7367SEQ ID NO:2468aatttaagtatgatttcaa 10486 10505 1 3 SEQ ID NO: 2163tgaagatgttaacaaattc 7349 7368SEQ ID NO:2469gaatttaagtatgatttca 1048510504 13 SEQ ID NO: 2164acatgttgataaagaaatt 7372 7391 SEQ ID NO: 2470,aattccctgaagttgatgt 11479 11498 1 3 SEQ ID NO: 2165tttgattaccaccagtttg 7398 7 4 17SEQ ID NO:2471 caaattgaacatccccaaa 8783 8802 1 3 SEQ ID NO: 2166caaaatccgtgaggtgact 7433 7452|SEQ ID NO:2472agtcccctaacagatttg 7964 7983 1 3 SEQ ID NO: 2167aaaatccgtgaggtgactc 7434 7453SEQ ID NO:2473gagtgaaatgctgtttttt 8630 8649 1 3 SEQ ID NO: 2168aggtgactcagagactcaa 7444 7463SEQ ID NO: 2474 ttgatgatatctggaacct 10723|10742 1 3 SEQ ID NO: 2169gtgaaattcaggctctgga 7465 7484SEQ ID NO:2475tccaatctcctcttttcac 8401 8420 1 3 SEQ ID NO: 2170gttgcagtgtatctggaaa 7539 7558SEQ ID NO:2476 tttcaagcaaatgcacaac 8532 8551 1 3 SEQ ID NO: 2171 ttaagttcagcatctttgg 7608 7627SEQ ID NO:2477ccaatgctgaactttttaa 10165 10184 1 3 SEQ ID NO: 2172tgaaggccaaattccgaga 7633 765 2 SEQ ID NO:2478tctcctttcttcatcttca 10205|10224 1 3 SEQ ID NO: 2173aatgtatcaaatggacatt 7676 7695SEQ ID NO:2479aatgaagtccggattcatt 11013 11032 1 3 SEQ ID NO: 2174attcagcaggaacttcaac 7692 7711 SEQ ID NO:2480,gttgagaagccccaagaat 6246 6265 1 3 SEQ ID NO: 2175acctgtctctggtcagcca 7714 7733SEQ ID NO:2 4 81 ggcaagtaagtgctaggt 9369 9388 1 3 SEQ ID NO: 2176cctgtctctggtcagccag 7715 7734SEQ ID NO:24821ctggacttctctagtcagg 8802 8821 13 SEQ ID NO: 2177ggtcagccaggtttatagc 7724 7743SEQ ID NO:24831gctaaaggagcagttgacc 10527 10546 13 SEQ ID NO: 2178ccaggtttatagcacactt 7730 7749SEQ ID NO:2484aagtccggattcattctgg 11017 11036 1 3 SEQ ID NO: 2179gtttatagcacacttgtca 7734 7753SEQ ID NO:2485tgacctgtccattcaaaac 13673 13692 13 SEQ ID NO: 2180acttgtcacctacatttct 7745 7764SEQ ID NO:2486agaaaaaggggattgaagt 10275 10294 1 3 SEQ ID NO: 2181 ctgattggtggactcttgc 7762 7781 SEQ ID NO:2487 gcaagttaaagaaaatcag 14018 14037 1 3 284 WO 2004/091515 PCT/US2004/011255 SEQ ID Nd: 28'2atgaaagcattggtagagc 7839 7858|SEQ ID NO:2488gctcatctcctttcttcat 10200 10219 1 3 SEQ ID NO: 2183tgaaagcattggtagagca 7840 7859|SEQ ID NO:2489tgctcatctcctttcttca 10199 10218 1 3 SEQ ID NO: 2184gggttcactgttcctgaaa 7860 7879SEQ ID NO:2490tttcaccatagaaggaccc 8951 8970 13 SEQ ID NO: 2185tcaagaccatccttgggac 7879 7898SEQ ID NO:2491 gtccccctaacagatttga 7965 7984 1 3 SEQ ID NO: 2186ccttgggaccatgcctgcc 7889 7908SEQ ID NO:2492,ggcaccagggctcggaagg 13970 13989 1 3 SEQ ID NO: 2187ttcaggctcttcagaaagc 7921 7940SEQ ID NO:2493gcttgaaggaattcttgaa 9580 9599 1 3 SEQ ID NO: 2188ttcagataaacttcaaaga 7996 8015SEQ ID NO:2494tcttcataagttcaatgaa 13175 13194 1 3 SEQ ID NO: 2189acttcaaagacttaaaaaa 8005 8024SEQ ID NO:2495 tttaacaaaagtggaagt 6821 6840 1 3 SEQ ID NO: 219oatcccatccaggttttcca 8031 8050SEQ ID NO:2496 tggagaagcaaatctggat 9464 9483 1 3 SEQ ID NO: 2191 gaatttaccatccttaaca 8055 8074SEQ ID NO:2497tgttgaagtgtctccattc 9881 9900 1 3 SEQ ID NO: 2192cattccttcctttacaatt 8081 8100SEQ ID NO:2498|aattccaattttgagaatg 10406 10425 13 SEQ ID NO: 2193ttgaccagatgctgaacag 8137 8156SEQ ID NO:2499ctgttgaaagatttatcaa 12924 12943 13 SEQ ID NO: 2194aatcaccctgccagacttc 8225 8244SEQ ID NO:2500gaagttctcaattttgatt 8514 8533 13 SEQ ID NO: 2195tgaccttcacataccagaa 8312 8331 SEQ ID NO:2501 ttcttctggaaaagggtca 8876 8895 13 SEQ ID NO: 2196ttccagcttccccacatct 8331 8350 SEQ ID NO:2502agattctcagatgagggaa 8913 8932 13 SEQ ID NO: 2197aagctatacagtattctga 8379 8398SEQ ID NO:2503tcagatggcattgctgctt 1160411623 1 3 SEQ ID NO: 2198attctgaaaatccaatctc 8391 8410SEQ ID NO:2504gagataaccgtgcctgaat 11544 11563 1 3 SEQ ID NO: 2199tttcacattagatgcaaat 8414 8433SEQ ID NO:|2505attttgaaaaaaacagaaa 9730 9749 1 3 SEQ ID NO: 2200caaatgctgacatagggaa 8428 8447SEQ ID NO:2506ttccatcacaaatcctttg 9662 9681 1 3 SEQ ID NO: 2201 gagagtccaaattagaagt 8500 8 519SEQ ID NO:2507actttacttcccaactctc 13402 13421. 13 SEQ ID NO: 2202agagtccaaattagaagtt 8501 8520SEQ ID NO:2508aactttacttcccaactct 13401 13420 1 3 SEQ ID NO: 2203tctcaattttgattttcaa 8519 8538SEQ ID NO:2509ttgattcccttttttgaga 11529 11548 1 3 SEQ ID NO: 2204caattttgattttcaagca .8522 8541.SEQ ID NO:2510tgctgaatccaaaagattg 13652 13671 1 3 SEQ ID NO: 2205aatgcacaactctcaaacc 8541 8560SEQ ID NO:2511 ggtttatcaaggggccatt 12452 12471 131 SEQ ID NO: 2206agttctccagcaagtacct 8596 8615SEQ ID NO:2512aggttccatcgtgcaaact 11380 11399 1 3 SEQ ID NO: 2207agtacctgagaacggagca 8608 8627SEQ ID NO:2513 tgctccaggagaacttact 13772 13791 1 3 SEQ ID NO: 2208tcaaacacagtggcaagtt 8670 8689SEQ ID NO:2514aactctcaagtcaagttga 13414 13433 1 3 SEQ ID NO: 2209acaatcagcttaccctgga 8743 8762SEQ ID NO:2515tccattctgaatatattgt 13372 13391 1 3 SEQ ID NO: 22loctggatagcaacactaaat 8757 8776SEQ ID NO:2516attttctgaacttccccag 12694 12713 1 3 SEQ ID NO: 2211 ctgacctgcgcaacgagat 8821 8 8 4 0SEQ ID NO:2517atctgatgaggaaactcag 12251 12270 13 SEQ ID NO: 2212agatgagggaacacatgaa 8921 8 9 4 0SEQ ID NO:2518ttcatgtccctagaaatct 10030 10049 1 3 SEQ ID NO: 2213 tcaacttttctaaacttga 9052 9071SEQ ID NO:2519 tcaaggataacgtgtttga 12610 12629 13 SEQ ID NO: 2214ttctaaacttgaaattcaa 9059 9078SEQ ID NO:2520ttgatgatgctgtcaagaa 7300 7319 1 3 SEQ ID NO: 2215gaaattcaatcacaagtcg 9069 9088SEQ ID NO:25211cgacgaagaaaataatttc 13558 13577 1 3 SEQ ID NO: 2216cactgtttggagaagggaa :9133 9152SEQ ID NO:2522 tccagaaagcagccagtg 12498 12517 1 3 SEQ ID NO: 2217actgtttggagaagggaag 9134 915 3 SEQ ID NO:2523cttccccaaagagaccagt 2890 2909 1 3 SEQ ID NO: 2218aattctcttttcttttcag 9213 9232SEQ ID NO:2524ctgattactatgaaaaatt 13630 13649 13 SEQ ID NO: 2219 ttcttttcagcccagccat 9222 9241 SEQ ID NO:2525atggaaaagggaaagagaa 13486 13505 1 3 SEQ ID NO: 2220 tttgaaagttcgttttcca 9275 9294SEQ ID NO: 2526tggaagtgtcagtggcaaa 10372 10391 13 SEQ ID NO: 2221 cagggaagatagacttcct 9304 9323SEQ ID NO:2527aggacctttcaaattcctg 9840 9859 1 3 SEQ ID NO: 2222ataagtacaaccaaaattt 9397 9416SEQ ID NO:2528aaatcaggatctgagttat 1403014049 1 3 SEQ ID NO: 2223acaacgagaacattatgga 9427 9446SEQ ID NO:2529 tccattctgaatatattgt 13372 13391 1 3 SEQ ID NO: 2224aggaataaatggagaagca 9455 9474SEQ ID NO:2530 tgctggaattgtcattcct 11726 11745 1 3 SEQ ID NO: 2225agcaaatctggatttctta 9470 9489SEQ ID NO:|2531 taagttctctgtacctgct 1171111730 1 3 SEQ ID NO: 2226tcctttaacaattcctgaa 9494 9513SEQ ID NO:2532ttcaaaacgagcttcagga 13198 13217 13 SEQ ID NO: 2227tttaacaattcctgaaatg 9497 9516SEQ ID NO:2533catttgatttaagtgtaaa 9613 9632 1 3 SEQ ID NO: 2228acacaataatcacaactcc 9526 9545SEQ ID NO:2534ggagacagcatcttcgtgt 11203 11222 1 3 SEQ ID NO: 2229aagatttctctctatggga 9553 9572SEQ ID NO:2535tcccagaaaacctcttctt 3928 3947 13 SEQ ID NO: 2230gaaaaaacaggcttgaagg 9570 9589SEQ ID NO:2536ccttttacaattcattttc 13013 13032 i 3 SEQ ID NO: 2231 ttgaaggaattcttgaaaa 9582 9601 SEQ ID NO:2537ttttgagaatgaatttcaa 1041410433 13 SEQ ID NO: 2232|tgaaggaattcttgaaaac 9583 9602SEQ ID NO:2538gttttggctgataaattca 11283 11302 1 3 SEQ ID NO: 2233|agctcagtataagaaaaac 9632 9651 SEQ ID NO:2539gtttgataagtacaaagct 9797 98161 13 285 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2234tcaaatcctttgacaggca 9712 9731|SEQ ID NO:2540tgcctgagcagaccattga 11680 11699 1 3 SEQ ID NO: 2235atgaaacaaaaattaagtt 9781 98 00SEQ ID NO:2 54 1 aactttgcactatgttcat 12754 12773 1 3 SEQ ID NO: 2236aattcctggatacactgtt 9851 98 7 0SEQ ID NO:2542aacacatgaatcacaaatt 8930 8949 13 SEQ ID NO: 2237ttccagttgtcaatgttga 9868 988 7SEQ ID NO:25 43 tcaaaacgagcttcaggaa 13199 13218 1 3 SEQ ID NO: 2238aagtgtctccattcaccat 9886 99 05SEQ ID NO:2544atgggaagtataagaactt 4834 4853 13 SEQ ID NO: 2239gtcagcatgcctagtttct 9942 99611SEQ ID NO:2545agaaaaggcacaccttgac 11072 11091 1 SEQ ID NO: 2240ctgccatgggcaatattac 1010510124SEQ ID No:2546gtaagaaaatacagagcag 6432 6451 13 SEQ ID NO: 2241 tgaataccaatgctgaact 1015910178SEQ ID NO:2547agttgaaggagactattca 7216 7235 1 3 SEQ ID NO: 2242tattgttgctcatctcctt 101 93 102121SEQ ID NO:2548aaggaaacataaactaata 12881 12900 1 3 SEQ ID NO: 2243tgttgctcatctcctttct 10 196 1 0 2 1 5SEQ ID NO:2549agaagaaatctgcagaaca 1242312442 1 3 SEQ ID NO: 2244tctgtcattgatgcactgc 10224 1 0243SEQ ID NO:2550gcagtagactataagcaga 13920 13939 13 SEQ ID NO: 2245ccacagctctgtctctgag 1029710 3 16SEQ ID NO:2551,ctcagggatctgaaggtgg 8187 8206 1 SEQ ID NO: 2246atttgtggagggtagtcat 1032210341 SEQ ID NO:2552|atgaagtagaccaacaaat 7153 7172 13 SEQ ID NO: 2247atatggaagtgtcagtggc 1 036 9 10 3 88SEQ ID NO:2553gccacactccaacgcatat 1077010789 1I3 SEQ ID NO: 2248tggaaataccaagtcaaaa 1 0 44 5 1 0464SEQ ID NO:2554ttttacaattcattttcca 13015 13034 13 SEQ ID NO: 2249aagtcaaaacctactgtct 10 4 5510474SEQ ID NO:2555agacctagtgattacactt 12851 12870 13 SEQ ID NO: 2250actgtctcttcctccatgg 1 0 46 7 1 0486SEQ ID NO:2556ccatgcaagtcagcccagt 10916 10935 1 3 SEQ ID NO: 2251 cttcctccatggaatttaa 10 474 10493SEQ ID NO:2557ttaatcgagaggtatgaag 7140 7159 13 SEQ ID NO: 2252attcttcaatgctgtactc 1050410523SEQ ID NO:2558gagttgagggtccgggaat 12234 12253 1 3 SEQ ID NO: 2253ttgaccacaagcttagctt 1054010559SEQ ID NO:2559aagcgcacctcaatatcaa 12028 12047 1 3 SEQ ID NO: 2254cctcacctcttacttttcc 1056510584SEQ ID NO:2560ggaactattgctagtgagg 10641 10660 1 3 SEQ ID NO: 2255agctgcagggcacttccaa 1070210721SEQ ID NO:2561 tgggaagaagaggcagct 12281 12300 1 3 SEQ ID NO: 2256ttccaaaattgatgatatc 1071510734SEQ ID NO:2562,gatatacactagggaggaa 12737 12756 1 3 SEQ ID NO: 2257gagaacatacaagcaaagc 1 085210871SEQ ID NO:2563gcttggttttgccagtctc 2459 2478 1 3 SEQ ID NO: 2258atggcaaatgtcagctctt 1088910908SEQ ID NO:2564aagaggtatttaaagccat 12952 12971 13 SEQ ID NO: 2259tggcaaatgtcagctcttg 1089C1090 9 SEQ ID NO:2565caagaggtatttaaagcca 12951 12970 1 3 SEQ ID NO: 2260 tgttcaggtccatgcaag 1090610925SEQ ID NO:2566cttgggggaggaggaacaa 14058 14077 1 3 SEQ ID NO: 2261 tgttcaggtccatgcaagt 1090710926SEQ ID NO:2567acttgggggaggaggaaca 14057 14076 1 3 SEQ ID NO: 2262agttccttccatgatttcc 1093210951 SEQ ID NO:2568ggaatctgatgaggaaact 12248 12267 1 3 SEQ ID NO: 2263tgctaacactaagaaccag 1097910998SEQ ID NO:2569ctggatgtaaccaccagca 11178 11197 1 3 SEQ ID NO: 2264actaagaaccagaagatca 1098611005SEQ ID NO:2570tgatcaagaacctgttagt 13339 13358 1 3 SEQ ID NO: 2265 taagaaccagaagatcag 1098711006SEQ ID NO:2571 ctgatcaagaacctgttag 13338 13357 13 SEQ ID NO: 2266cagaagatcagatggaaaa 1099511014SEQ ID NO:2572ttttcagaccaactctctg 13614 13633 13 SEQ ID NO: 2267aaaaatgaagtccggattc 1101011029SEQ ID NO:2573gaatttgaaagttcgtttt 9272 9291 1 3 SEQ ID NO: 2268gattcattctgggtctttc 1102411043SEQ ID NO:2574gaaaacctatgccttaatc 13158 13177 13 SEQ ID NO: 2269aagaaaaggcacaccttga 1107111090SEQ ID NO:2575tcaaaacctactgtctctt 10458 10477 1 3 SEQ ID NO: 2270aaggacacctaaggttcct 1110711126SEQ ID NO:2576aggacaccaaaataacctt 7564 7583 1 3 SEQ ID NO: 22711ccagcattggtaggagaca 111911121OSEQ ID NO:2577tgtcaacaagtaccactgg 12362 12381 1 3 SEQ ID NO: 2272ctttgtgtacaccaaaaac 1123111250 SEQ ID NO:2578gtttttaaattgttgaaag 13140 13159 1 3 SEQ ID NO: 2273ccatccctgtaaaagtttt 1126911288SEQ ID NO:2579aaaagggtcatggaaatgg 8885 8904 1 3 SEQ ID NO: 2274tgatctaaattcagttctt 1132411343SEQ ID NO:2580aagatagtcagtctgatca 13326 13345 1 3 SEQ ID NO: 2275aagaagctgagaacttcat 1142411 4 43SEQ ID NO:2581atgagatcaacacaatctt 13102 13121 1 3 SEQ ID NO: 2276 ,ttgccctcaacctaccaa 1144511464SEQ ID NO:2582ttggtacgagttactcaaa 12633 12652 1 3 SEQ ID NO: 2277cttgattcccttttttgag 1152811547SEQ ID NO:2583ctcaattttgattttcaag 8520 8539 1 3 SEQ ID NO: 2278 tcacgcttccaaaaagtg 1158311602SEQ ID NO:2584cactcattgattttctgaa 12685 12704 1 3 SEQ ID NO: 2279 gtttcagatggcattgct 1160011619SEQ ID NO:2585agcagattatgttgaaaca 1182511844 1 3 SEQ ID NO: 228oaatgcagtagccaacaaga 1163111650SEQ ID NO:2586tcttttcagcccagccatt 9223 9242 1 3 SEQ ID NO: 2281 ctgagcagaccattgagat 1168311702SEQ ID NO:2587atctgatgaggaaactcag 1225112270 1 3 SEQ ID NO: 2282 gagcagaccattgagatt 1168411703SEQ ID NO:2588aatctgatgaggaaactca 12250|12269 1 3 SEQ ID NO: 2283 tgagattccctccattaa 1169511714SEQ ID NO:2589 ttaatcttcataagttcaa 13171 13190 13 SEQ ID NO: 2284acttggagtgccagtttga 1179911818SEQ ID NO:2590tcaattgggagagacaagt 6496 6515 1 3 SEQ ID NO: 2285caaatttgaaggacttcag 119961 2 015SEQ ID NO:2591ctgagaacttcatcatttg 11430 11449, 13 286 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2286agcccagcgttcaccgatc 1204812067SEQ ID NO:2592gatccaagtatagttggct 13278 13297 13 SEQ ID NO: 2287cagcgttcaccgatctcca 1205212071 SEQ ID NO:2593tggacctgcaccaaagctg 13952 13971 13 SEQ ID NO: 2288ctccatctgcgctaccaga 12066 12 0 8 5SEQ ID NO:259 4 tctgatatacatcacggag 13703 3722 13 SEQ ID NO: 2289atgaggaaactcagatcaa 1 2 2 5 6 12 2 7 5 SEQ ID NO:2595ttgagttgcccaccatcat 11659 11678 13 SEQ ID NO: 229oaggcagcttctggcttgct 1229212311 SEQ ID NO:2596agcaagtctttcctggcct 3010 3029 1 3 SEQ ID NO: 2291 tgaaagacaacgtgcccaa 123191 2 3 3 8SEQ ID NO:2597ttgggagagacaagtttca 6500 6519 1 3 SEQ ID NO: 2292tatgattatgtcaacaagt 1 2 3 5 4 1 2 3 7 3SEQ ID NO:2598actttgcactatgttcata 1275512774 13 SEQ ID NO: 2293cattaggcaaattgatgat 1 2 4 6 7 1 2 4 86SEQ ID NO:2599atcaacacaatcttcaatg 13107 13126 1 3 SEQ ID NO: 2294ttgactcaggaaggccaag 12576 1 2 5 9 5SEQ ID NO:2600cttggtacgagttactcaa 12632 12651 1 3 SEQ ID NO: 2295gaaacctgggatatacact 1 2 7 2 8 1 2 7 4 7SEQ ID NO:2601jagtgattacacttcctttc 12857 12876 1 3 SEQ ID NO: 2296tcctttcgagttaaggaaa 1 2 8 6 9 1 2 8 8 8SEQ ID NO:2602tttctgccactgctcagga 1351613535 1 3 SEQ ID NO: 2297gccattcagtctctcaaga 12 9 6 6 1 2 9 85SEQ ID NO:2603tcttccgttctgtaatggc 5794 5813 1 3 SEQ ID NO: 2298gtgctacgtaatcttcagg 1299313012SEQ ID NO:2604cctgcaccaaagctggcac 13956 13975 1 3 SEQ ID NO: 2299agctgaaagagatgaaatt 13 05 7 1 3 0 7 6SEQ ID NO:2605aatttattcaaaacgagct 13192 13211 1 3 SEQ ID NO: 2300aatttacttatcttattaa 1307213091 SEQ ID NO:2606ttaaaagaaatcttcaatt 13807 13826 1 3 SEQ ID NO: 2301 ttttaaattgttgaaagaa 1314213161 SEQ ID NO:2607 tctctctatgggaaaaaa 9558 9577 1 3 SEQ ID NO: 2302taatcttcataagttcaat 1317213191SEQ ID NO:2608attgagattccctccatta 11694 11713 13 SEQ ID NO: 2303atattttgatccaagtata 13271|13290SEQ ID NO:2609tataagcagaagcacatat 13929 13948 13 SEQ ID NO: 2304tgaaatattatgaacttga 13303 13322SEQ ID NO:2610 tcaaccttaatgattttca 8287 8306 1 3 SEQ ID NO: 2305caatttctgcacagaaata 13434 13453SEQ ID NO:261 1 attcttcttttccaattg 13826 13845 13 SEQ ID NO: 2306agaagattgcagagtttc 13501 1 3 5 2 0 SEQ ID NO:2612gaaatcttcaatttattct 13813 13832 13 SEQ ID NO: 2307gaagaaaataatttctgat 1356213581 SEQ ID NO:2613atcagttcagataaacttc 7991 8010 13 SEQ ID NO: 2308ttgacctgtccattcaaaa 1367213691 SEQ ID NO:2614ttttgagaatgaatttcaa 10414 10433 13 SEQ ID NO: 2309tcaaaactaccacacattt 13685|13704SEQ ID NO:2615aaattccttgacatgttga 7362 7381 SEQ ID NO: 2310 ttttttaaaagaaatcttc 13803|13822SEQ ID NO:2616gaagtgtcagtggcaaaaa 10374 10393 1 3 SEQ ID NO: 2311 aggatctgagttattttgc 140351405 4 SEQ ID NO:2617gcaagggttcactgttcct 7856 7875 13 SEQ ID NO: 2312tttgctaaacttgggggag 14049114068SEQ ID NO:|2618ctccccaggacctttcaaa 9834 9853 1 3 # Match Number B = Middle Matching Bases 287 WO 2004/091515 PCT/US2004/011255 Table 10. Selected palindromic sequences from human ApoB Source Start IndexEnd Index Match Start IndexEnd Inde B SEQ ID NO: 2619ggccattccagaagggaag 517 53 6 SEQ ID NO:3948cttccgttctgtaatggcc 5803 58221 9 SEQ ID NO: 2620tgccatctcgagagttcca 4107 4 12 6 SEQ ID NO: 39 4 9 tggaactctctccatggca 10884 109031 8 SEQ ID NO: 2621 catgtcaaacactttgtta 7064 7083SEQ ID NO: 39 5 0 taacaaattccttgacatg 7366 73851 8 SEQ ID NO: 2622 tttgttataaatcttattg 7076 7 0 9 5 SEQ ID NO: 3 9 5 1 caataagatcaatagcaaa 8998 90171 8 SEQ ID NO: 2623tctggaaaagggtcatgga 8888 8 9 0 7 SEQ ID NO: 3 9 5 2 tccatgtcccatttacaga 11364 113831 8 SEQ ID NO: 2624cagctctgttcaggtcca 10908 10 9 2 7 SEQ ID NO: 3 9 5 3 tggacctgcaccaaagctg 13960 139791 8 SEQ ID NO: 2625ggaggttccccagctctgc 364 3 8 3 SEQ ID NO:3954gcagccctgggaaaactcc 6455 64741 7 SEQ ID NO: 2626 ctgttttgaagactctcca 1089 1 10 8 1SEQ ID NO: 3 9 5 5 tggagggtagtcataacag 10335 103541 7 SEQ ID NO: 2627agtggctgaaacgtgtgca 1305 1324 SEQ ID NO: 3 9 5 6 tgcagagctttctgccact 13516 135351 7 SEQ ID NO: 2628ccaaaatagaagggaatct 2076 2095SEQ ID NO: 3 9 5 7agattcctttgccttttgg 4008 40271 7 SEQ ID NO: 262 tgaagagaagattgaattt 3628 3647 SEQ ID NO: 3958aaattctcttttettttca 9220 92391 7 SEQ ID NO: 2 6 3 0 1agtggtggcaacaccagca 4238 4 2 57 SEQ ID NO: 3 95 9 tgctagtgaggccaacact 10657 106761 7 SEQ ID NO:2631 aaggctccacaagtcatca 5958 5 9 77 SEQ ID NO: 3 96 0 tgatgatatctggaacctt 10732 107511 7 SEQ ID NO: 2632gtcagccaggtttatagca 7733 7752 SEQ ID NO: 3 96 1 tgctaagaaccttactgac 7789 78081 7 SEQ ID NO: 2633 tgatatctggaaccttgaa 10735 1 0 7 54 SEQ ID NO: 39 6 2 ttcactgttcctgaaatca 7871 78901 7 SEQ ID NO: 2634gtcaagttgagcaatttct 13431 1 34 50SEQ ID NO: 3963agaaaaggcacaccttgac 11080 110991 7 SEQ ID NO: 2 63 5 atccagatggaaaagggaa 13488 1 3 50 7 SEQ ID NO: 39 6 4 tccaatttccctgtggat 3688 37071 7 SEQ ID NO: 2636atttgtttgtcaaagaagt 4551 4 57 0 SEQ ID NO:3965acttcagagaaatacaaat 11409 114284 6 SEQ ID NO: 2637ctggaaaatgtcagcctgg 212 2 3 1 SEQ ID NO: 3966 ccagacttccgtttaccag 8243 82622 6 SEQ ID NO: 26381accaggaggttcttcttca 1737 17 5 6 SEQ ID NO: 39 6 7tgaagtgtagtctcctggt 5097 51162 6 SEQ ID NO: 2 63 9 aaagaagttctgaaagaat 1964 19 8 3 SEQ ID NO:3968ttccatcacaaatccttt 9669 96882 6 SEQ ID NO: 26 4 0 gctacagcttatggctcca 3578 3 5 9 7 SEQ ID NO: 3 9 6 9 tggatctaaatgcagtagc 11631 116502 6 SEQ ID NO: 2641 atcaatattgatcaatttg 6422 6441 SEQ ID NO: 3970 caaagaagtcaagattgat 4561 45802 6 SEQ ID NO: 2 64 2 gaattatcttttaaaacat 7334 7 3 5 3 SEQ ID NO: 3 9 7 1 atgtgttaacaaaatattc 11502 115212 6 SEQ ID NO: 2 64 3 cgaggcccgcgctgctggc 138 15 7 SEQ ID NO:3972gccagaagtgagatcctcg 3515 35341 6 SEQ ID NO: 2644acaactatgaggctgagag 279 2 9 8 SEQ ID NO: 3973ctctgagcaacaaatttgt 10317 103361 6 SEQ ID NO: 2645 gctgagagttccagtggag 290 3 0 9 SEQ ID NO: 3974 ctccatggcaaatgtcagc 10893 109121 6 SEQ ID NO: 2640 gaagaaaaccaagaactc 456 4 75 SEQ ID NO: 3975 gagtcattgaggttcttca 4937 49561 6 SEQIDNO: 647cctacttacatcctgaaca 566 5 85 SEQ ID NO: 3 97 6 tgttcataagggaggtagg 12774 127931 6 SEQ ID NO: 26481ctacttacatcctgaacat 567 5 86 SEQ ID NO: 3 97 atgttcataagggaggtag 12773 127921 6 SEQ ID NO: 2 6 4 9 1gagacagaagaagccaagc 623 642 SEQ ID NO: 3978 gcttggttttgccagtctc 2467 24861 6 SEQ ID NO: 26 5 0cactcactttaccgtcaag 679 6 98 SEQ ID NO:3979cttgaacacaaagtcagtg 6008 60271 6 SEQ ID NO: 2651 ctgatcagcagcagccagt 830 84 9 SEQ ID NO: 39 8 0 actgggaagtgcttatcag 5245 52641 6 SEQ ID NO: 2652actggacgctaagaggaag 862 881 SEQ ID NO: 39 8 1 cttccccaaagagaccagt 2898 29171 6 SEQ ID NO: 2653agaggaagcatgtggcaga 873 8 9 2 SEQ ID NO: 39 8 2 tctggcatttactttctct 5929 59481 6 SEQ ID No: 26541tgaagactctccaggaact 1095 1114 SEQ ID NO: 3983 agttgaaggagactattca 7224 72431 6 SEQID NO: 2655ctctgagcaaaatatccag 1129 1 14 8 SEQ ID NO:3984ctggttactgagctgagag 1169 11881 6 SEQ ID NO: 2656 atgaagcagtcacatctct 1197 12 16 SEQ ID NO:3985agagctgccagtccttcat 10024 100431 6 SEQ ID NO: 265 gccacagctgattgagg 1217 12 3 6 SEQ ID NO:3986cctcctacagtggtggcaa 4230 42491 6 SEQ ID NO: 26 58 1agctgattgaggtgtccag 1224 12 4 3 SEQ ID NO: 3 9 8 7 ctggattccacatgcagct 11855 118741 6 SEQ ID NO: 2659 gctccactcacatcctcc 1286 13 0 5 SEQ ID NO: 3988 ggaggctttaagttcagca 7609 76281 6 SEQ ID NO: 2660 gaaacgtgtgcatgccaa 1311 13 3 0 SEQ ID NO: 3 9 89 tgggagagacaagtttca 6508 65271 6 3EQ ID NO: 2661 gacaftgctaatacctga 1511 15 3 0 SEQ ID NO: 3 9 90 tcagaagctaagcaatgtc 7240 72591 6 SEQ ID NO: 2662 tcttcttcagactttcct 1746 17 6 5 SEQ ID NO: 3 9 9 1 aggagagtccaaattagaa 8506 85251 SEQ ID NO: 2663 ccaatatcttgaactcaga 1911 19 3 0 SEQ ID NO: 3 99 2 ctgaattcattcaattgg 6493 65121 6 3EQ ID NO: 2664 aaagttagtgaaagaagtt 1954 19 73 1SEQ ID NO:13993 aactaccctcactgccttt 2140 21591 6 288 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2665aagttagtgaaagaagttc 1955 1 9 74 SEQ ID NO:3994gaacctctggcatttactt 5924 59431 6 SEQ ID No: 2666 aaagaagftctgaaagaat 1964 1983SEQ ID NO:3995attctctggtaactacttt 5490 55091 6 SEQ ID NO: 2667 tttggctataccaaagatg 2330 2 3 49 SEQ ID NO:3996catctaggcactgacaaa 5005 50241 6 SEQlDNo:2668tgtigagaagctgattaaa 2389 24 0 8

SEQIDNO:

3 9 9 7 tttagccatcggctcaaca 5708 57271 6 SEQ ID NO: 2669caggaagggctcaaagaat 2569 2 5 88 SEQ ID NO:3998attcctttaacaattcctg 9500 95191 6 SEQ ID NO: 26701aggaagggctcaaagaatg 2570 2 5 89 SEQ ID NO:3999cattcctttaacaattcct 9499 95181 6 SEQ ID NO: 26711gaagggctcaaagaatgac 2572 2591 SEQ ID NO: 400gtcagtcttcaggctcttc 7922 79411 6 SEQ ID NO: 2672 caaagaatgacttttitct 2580 2 5 9 9 SEQ ID NO: 4001 agaaggatggcattttttg 14008 140271 6 SEQ ID NO: 26731catggagaatgccittgaa 2611 2 6 3 0 SEQ ID NO: 4002 ttcagagccaaagtccatg 7127 71461 6 SEQ ID NO: 2674ggagccaaggctggagtaa 2687 2706SEQ ID NO:4003ttactccaacgccagctcc 3058 30771 6 SEQ ID NO: 2675tcattccttccccaaagag 2892 2911 SEQID NO: 4004ctctctggggcatctatga 5147 51661 6 SEQ ID NO: 2676acctatgagctccagagag 3173 3 1 9 2 SEQ ID NO:4005ctctcaagaccacagaggt 12984 130031 6 SEQ ID NO: 2677gggcaaaacgtcttacaga 3373 3 3 9 2 SEQ ID NO:4006tctgaaagacaacgtgccc 12325 123441 6 SEQ ID NO: 267 8 accctggacattcagaaca 3395 3 4 14 SEQ ID NO:4007tgttgctaaggttcagggt 5683 57021 61 SEQ ID NO: 2679atgggcgacctaagttgtg 3437 3 4 5 6 SEQ ID NO:4008cacaaattagtttcaccat 8949 89681 6 SEQ ID NO: 2680gatgaagagaagattgaat 3626 3 6 45 SEQ ID NO:4009attccagettccccacatc 8338 83571 6 SEQ ID NO: 2681 caatgtagataccaaaaaa 3664 3 6 83SEQ ID NO:4010 ttggaaatgccattg 8651 86701 6 SEQ ID NO: 2 6 8 2 gtagataccaaaaaaatga 3668 3 6 87 SEQ ID NO: 4011 tcatgtgatgggtctctac 4379 43981 6 SEQ ID NO: 2683gcttcagttcatttggact 4517 4 5 36 SEQ ID NO:4012agtcaagaaggacttaagc 5312 53311 6 SEQ ID NO: 2684tttgtttgtcaaagaagtc 4552 4571 SEQ ID NO:4O13gacttcagagaaatacaaa 11408 114271 6 SEQ ID NO: 2685tgtttgtcaaagaagtca 4553 4 5 7 2 SEQ ID NO:4014tgacttcagagaaatacaa 11407 114261 6 SEQ ID NO: 2686tggcaatgggaaactcgct 5854 5873 SEQ ID NO:4015agcgagaatcaccctgcca 8227 82461 6 SEQ ID NO: 2687aacctctggcatttacttt 5925 5944 SEQ ID NO:4016aaaggagatgtcaagggtt 10607 106261 6 SEQ ID NO: 2688catttactttctctcatga 5934 5 9 5 3 SEQ ID NO: 4017tcatttgaaagaataaatg 7034 70531 6 SEQ ID NO: 2689aaagtcagtgccctgcfta 6017 6 0 3 6 SEQ ID NO: 4018 taagaaccttactgacttt 7792 78111 6 SEQ ID NO: 2690 cCcattttttgagacctt 6330 6349 SEQ ID NO:4019aaggacttcaggaatggga 12012 120311 6 SEQ ID NO: 2691 catcaatattgatcaattt 6421 6440 SEQ ID NO: 4020 aaattaaaaagtcttgatg 6740 67591 6 SEQ ID NO: 2692 taaagatagttatgattta 6673 6692 SEQ ID NO: 4021 taaaccaaaacttggttta 9027 90461 6 SEQ ID NO: 2693 tattgatgaaatcattgaa 6721 6740 SEQ ID NO: 4022 caaagacttaaaaaata 8015 80341 6 SEQ ID NO: 26 9 4 atgatctacatttgtttat 6798 6817 SEQ ID NO: 4023 ataaagaaattaaagtcat 7388 74071 6 SEQ ID NO: 2695agagacacatacagaatat 6927 6946SEQ ID NO: 4024atatattgtcagtgcctct 13390 134091 6 SEQ ID NO: 2 696,gacacatacagaatataga 6930 6949 SEQ ID NO: 4025 tctaaattcagttcttgtc 11335 113541 6 SEQ ID NO: 2697agcatgtcaaacacttigt 7062 7081 SEQ ID NO: 4026 acaaagtcagtgccctgct 6015 60341 6 SEQ ID NO: 2698 agaggaaaccaagg 7523 7 54 2 SEQ ID NO: 4027cctttgtgtacaccaaaaa 11238 112571 6 SEQ ID NO: 2699tagaggaaaccaaggc 7524 7543 SEQ ID NO: 4028gcctttgtgtacaccaaaa 11237 112561 6 SEQ ID NO: 2700 ggaagatagacttcctgaa 9315 9334 SEQ ID NO: 4029 ftcagaaatactgttttcc 12832 12851 1 6 SEQ ID NO: 2701 cactgtttctgagtcccag 9342 9361 SEQ ID NO: 4030ictgggacctaccaagagtg 12531 125501 6 SEQ ID NO: 2 7 0 2 cacaaatcctttggctgtg 9676 9695 SEQ ID NO: 4031 cacatttcaaggaattgtg 10071 100901 6 SEQ ID NO: 2703-cctggatacactgttcc 9861 9880SEQ ID NO:4032ggaactgttgactcaggaa 12577 125961 6 SEQ ID NO: 2704gaaatctcaagctttctct 10050 10 0 6 9 SEQ ID NO: 4033agagccaggtcgagotttG 11052 110711 6 SEQ ID NO: 2705 cttcatcttcatctgt 10218 10 2 3 7 SEQ ID NO: 4034acagctgaaagagatgaaa 13063 130821 6 SEQ ID NO: 2706 tctaccgctaaaggagcag 10529 10548 SEQ ID NO:4035ctgcacgctttgaggtaga 11769 117881 6 SEQ ID NO: 2707 ctaccgctaaaggagcagt 10530 10 5 4 9 SEQ ID NO: 4036 actgcacgctttgaggtag 11768 117871 6 SEQ ID NO: 2708agggcctctttitcaccaa 10839 10858SEQ ID NO: 4037ttggccaggaagtggccct 10965 109841 6 SEQ ID NO: 2709 1ctccatccctgtaaaag 11273 1 1 2 92 SEQ ID NO: 4038 ctttttcaccaacggagaa 10846 108651 6 SEQ ID NO: 2710 gaaaaacaaagcagattat 11824 1 1 8 43 1SEQ ID NO: 4039ataaactgcaagatttttc 13608 136271 6 SEQ ID NO: 2711 actcactcattgattttct 12690 12709 SEQ ID NO: 4040 agaaaatcaggatctgagt 14035 140541 6 289 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2712 taaactaatagatgtaatc 12898 12 9 1 7 SEQ ID NO:4041lgattaccaccagcagttta 13586 136051 6 SEQ ID NO: 2713caaaacgagcttcaggaag 13208 132 2 7 SEQ ID NO:4042cttcgtgaagaatattttg 13268 132871 6 SEQ ID NO: 2714tggaataatgctcagtgtt 2374 2 39 3 SEQ ID NO:4043aacacttacttgaattcca 10670 106893 SEQ ID NO: 271 5 gatttgaaatccaaagaag 2408 24 2 7 SEQ ID NO: 4044cttcagagaaatacaaatc 11410 114293 5 SEQ ID NO: 2716 atttgaaatccaaagaagt 2409 2428 SEQ ID NO:4045 acttcagagaaatacaaat 11409 114283 5 SEQ ID NO: 271 atcaacagccgcttctttg 998 1017 SEQ ID NO: 4046caaagaagtcaagattgat 4561 4580 5 SEQ ID NO: 2718 tgttttgaagactctccag 1090 1 10 9 SEQ ID NO: 4047ctggaaagttaaaacaaca 6963 69822 5 SEQ ID NO: 2719cccttctgatagatgtggt 1332 1351 SEQ ID NO:4048accaaagctggcaccaggg 13969 139882 5 SEQ ID NO: 2720 tgagcaagtgaagaacttt 1876 1895 SEQ ID NO: 4049 aaagccattcagtctctca 12971 129902 5 SEQ ID NO: 2721 atttgaaatccaaagaagt 2409 2428 SEQ ID NO:4050 acttttctaaacttgaaat 9063 90822 5 SEQ ID NO: 2722atccaaagaagtcccggaa 2416 2 4 3 5 SEQ ID NO: 4051 ttccggggaaacctgggat 12729 127482 5 SEQ ID NO: 2723 agagcctacctccgcatct 2438 2 4 5 7 SEQ ID NO:4052agatggtacgttagcctct 11929 119482 5 SEQ ID NO: 2 72 4 aatgcctttgaactcccca 2618 2637 SEQ ID NO:4053tgggaactacaatttcatt 7020 70392 5 SEQ ID NO: 2725 gaagtccaaattccggatt 3305 3324 SEQ ID NO: 4054aatcttcaatttattcttc 13823 138422 5 SEQ ID NO: 2726 tgcaagcagaagccagaag 3504 3523 SEQ ID NO:4055 cttcaggttccatcgtgca 11384 11403 5 SEQ ID NO: 2727gaagagaagattgaatttg 3629 3648 SEQ ID NO:4056caaaacctactgtctcttc 10467 104862 5 SEQ ID NO: 2728atgctaaaggcacatatgg 4605 4624 SEQ ID NO: 4057ccatatgaaagtcaagcat 12664 12683 5 SEQ ID NO: 2729 tcctcacctccacctctg 4745 4764 SEQ ID NO: 4058 cagattctcagatgaggga 8920 89392 5 SEQ ID NO: 27309atttacagctctgacaagt 5435 5454SEQ ID NO: 4059acttttctaaacttgaaat 9063 90822 5 SEQ ID NO: 2731 aggagcctaccaaaataat 5602 5621 SEQ ID NO: 40601attatgttgaaacagtcct 11838 118572 5 SEQ ID NO: 2732aaagctgaagcacatcaat 6409 64 2 8 SEQ ID NO: 4061lattgttgctcatctccttt 10202 102212 5 SEQ ID NO: 2733ctgctggaaacaacgagaa 9426 94 4 5 SEQ ID NO:4062ttctgattaccaccagcag 13582 136012 5 SEQ ID NO: 2734 gaaggaattcttgaaaa 9590 9609 SEQ ID NO: 4063 ttttaaaagaaatcttcaa 13813 138322 5 SEQ ID NO: 2 7 3 5 gaagtaaaagaaaattttg 10751 1 0 77 0 SEQ ID NO:4064caaaacctactgtctcttc 10467 104862 5 SEQ ID NO: 2736 gaagaagatggcaaattt 11992 12 0 1 1 SEQ ID NO: 4065aaatgtcagctcttgttca 10902 109212 5 SEQ ID NO: 273 aggatctgagttattttgc 14043 14 0 6 2 SEQ ID NO: 4066,gcaagtcagcccagttcct 10928 109472 5 SEQ ID NO: 2 738 9tgcccttctcggttgctg 26 4 5 SEQ ID NO: 406 cagccattgacatgagcac 5748 57671 5 SEQ ID NO: 2739ggcgctgcctgcgctgctg 154 17 3 SEQ ID NO: 4068 cagctccacagactccgcc 3070 30891 5 SEQ ID NO: 2740ctgcgctgctgctgctgct 162 18 1 SEQ ID NO: 4069 agcagaaggtgcgaagcag 3232 32511 5 SEQ ID NO: 2741 gctgctggcgggcgccagg 178 197 SEQ ID NO: 070 cctggattccacatgcagc 11854 118731 5 SEQ ID NO: 2742 aagaggaaatgctggaaaa 201 22 0 SEQ ID NO: 071 tttcactacatett 2592 26111 5 SEQ DNO: 2 74 3 tggaaaatgtcagcctgg 212 2 3 1 SEQ ID NO: 4072 ccagacttccacatcccag 3923 39421 5 SEQ ID NO: 2744 tggagtccctgggactgct 304 32 3 SEQ ID NO: 4073,agcatgcctagtttctcca 9953 99721 5 SEQ ID NO:2 7 4 5 ggagtccctgggactgctg 305 32 4 SEQ ID NO: 4074 cagcatgcctagtttctcc 9952 99711 5 SEQ ID NO: 2746 tgggactgctgattcaaga 313 3 32 SEQ ID NO: 4075 tcttccatcacttgaccca 2050 20691 5 SEQ ID NO: 2747 ctgctgattcaagaagtgc 318 33 7 SEQ ID NO: 4076gcacaccttgacattgcag 1108 111061 5 SEQIDNO:2748tgccaccaggatcaactgc 334 35 3 SEQ ID NO:4077gcaggctgaactggtggca 2725 27441 5 SEQ ID NO: 2749 gccaccaggatcaactgca 335 354SEQ ID NO:4078tgcaggctgaactggtggc 2724 27431 5 SEQ ID NO: 2750 tgcaaggttgagctggagg 350 36 9 SEQ ID NO: 4079 Gctccacctctgatctgca 4752 47711 5 SEQ ID NO: 2751 caaggttgagctggaggtt 352 37 1 SEQ ID NO: 4080aacccctacatgaagcttg 13763 137821 5 SEQ ID NO: 27521ctctgcagcttcatcctga 377 3 9 6 1SEQ ID NO: 4081 tcaggaagcttctcaagag 13219 132381 5 SEQ ID NO: 27 5 3 cagcttcatcctgaagacc 382 401 SEQ ID NO: 4082 ggtcttgagttaaatgctg 4985 50041 5 SEQ ID NO: 2754 gcttcatcctgaagaccag 384 4 0 3 SEQ ID NO: 4083 ctggacgCtaagaggaagc 863 8821 5 SEQ ID NO: 2755 tcatcctgaagaccagcca 387 4 0 6 SEQ ID NO: 4084 tggcatggcattatgatga 3612 36311 5 SEQ ID NO: 2756 gaaaaccaagaactctgag 460 4 7 9 SEQ ID NO: 4085ctcaaccttaatgattttc 8294 83131 5 SEQ ID NO: 2757,agaactctgaggagtttgc 468 4 8 7 1SEQ ID NO: 4086gcaagctatacagtattct 8385 84041 5 EQ ID NO: 2758 ctgaggagtttgctgcag 473 4 92 SEQ ID NO: 4087 ctgcaggggatcccccaga 2534 25531 5 290 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2759 gctgcagccatgtcca 482 501 SEQ ID NO: 088 tggaagtgtcagtggcaaa 10380 103991 5 SEQ ID NO: 2760 caagaggggcatcatttct 586 6 0 5 SEQ ID NO:4089agaataaatgacgttcttg 7043 70621 5 SEQ ID NO: 2761 cactttaccgtcaagacg 682 701 SEQ ID NO:4090cgtctacactatcatgtga 4368 43871 5 SEQ ID NO: 2762 accgtcaagacgagga 686 70 5 SEQ ID NO: 4091 tccttgacatgttgataaa 7374 73931 5 SEQ ID NO: 2763cactggacgctaagaggaa 861 8 8 0 SEQ ID NO: 4092 ttccagaaagcagccagtg 12506 125251 5 SEQ ID NO: 764aggaagcatgtggcagaag 875 8 94 SEQ ID NO: 4093cttcatacacattaatcct 9996 100151 5 SEQ ID NO: 2765caaggagcaacacctcttc 901 9 20 SEQ ID NO: 4094gaagtagtactgcatcttg 6843 68621 5 SEQ ID NO: 2766 acagactttgaaacttgaa 967 986 SEQ D NO: 4095 caattcttcaatgctgt 10508 105271 5 SEQIDNO:2767tgatgaagcagtcacatct 1195 1 2 14 SEQ ID NO: 4096agatttgaggattccatca 7984 80031 5 SEQ ID NO: 27681agcagtcacatctctcttg 1201 12 2 0 SEQ ID NO: 4097caaggagaaactgactgct 6532 6551 1 5 SEQ ID NO: 2769CCagCCCCatcacftt2ca 1239 12 5 8 SEQ ID NO:4098tgtagtctcctggtgctgg 510 51211 5 SEQIDNO:2770ctccactcacatcctccag 1288 13 0 7 SEQ ID NO: 4099ctggagcttagtaatggag 8717 87361 5 SEQ ID NO: 2771 catgccaaccccctctga 1322 1341 SEQ ID NO: 4100 cagatgagggaacacatg 8927 89461 5 SEQ ID NO: 2772 gagagatcttcaacatggc 1398 14 17 SEQ ID NO: 4101 gccaccctggaactctctc 10877 108961 5 SEQ ID NO: 2773 tcaacatggcgagggatca 1407 14 2 6 SEQ ID NO: 4102 gatcccacctctcattga 2973 29921 5 3EQ ID No: 2774caccttgtatgcgctgag 1437 14 5 6 SEQ ID NO: 4103ctcagggatctgaaggtgg 8195 82141 5 SEQ ID NO: 2775gtcaacaactatcataaga 1463 14 8 2 SEQ ID NO: 4104 cttgagttaaatgctgac 4987 50061 5 3EQ ID NO: 2776 ggacattgctaattacct 1509 1528SEQ ID NO:4105aggtatattegaaagtcca 12807 128261 5 SEQID NO: 2777ggacattgctaattacctg 1510 152 9 SEQ ID NO:4lO6caggtatattcgaaagtcc 12806 128251 5 3EQ ID NO: 2778 ctgcgggtcattggaaa 1581 1600 SEQ ID NO: 107 cacatgccaaggagaa 6522 6541 1 5 EQ ID NO: 277gccagaactcaagtcttcaa 1628 16 4 7 SEQ ID NO: 4108 ttgaagtgtagtctcctgg 5096 51151 5 EQ ID NO: 278Cagtcttcaatcctgaaatg 1638 16 5 7 SEQ ID NO:4109catttctgattggtggact 7765 77841 5 ;EQ ID NO: 2781 gagcaagtgaagaacttt 1876 18 9 5 SEQ ID NO: 11 0aaagtgccacttttactca 6191 62101 5 EQ ID NO: 2782agcaagtgaagaactttgt 1878 18 9 7 SEQ ID NO: 111|acaaagtcagtgccctgct 6015 60341 5 EQ ID NO: 2783 ctgaaagaatctcaactt 1972 1991 SEQ ID NO: 112|aagtccataatggttcaga 12819 128381 5 EQ ID NO: 2784actgtcatggacttcagaa 1994 2 0 13 SEQ ID NO: 113 ctgaatatattgtcagt 13384 134031 5 EQ ID NO: 2785acttgacccagcctcagcc 2059 2 07 8 SEQ ID NO: 114ggctcaccotgagagaagt 12399 124181 5 EQ ID NO: 2786|ccaaataactaccttcct 2104 2 12 3 SEQ ID NO: 115aggaagatatgaagatgga 4720 47391 5 EQ ID NO: 2787actaccctcactgcctttg 2141 2 16 0 SEQ ID NO: 116caaatttgtggagggtagt 10327 103461 5 EQ ID NO: 2788 tggatttgcttcagtga 2157 2 1 7 6 SEQ ID NO: 11 cagtataagtacaaccaa 9400 94191 5 EQ ID NO: 2789 ttggaagctctttttggga 2219 2238 SEQ ID NO: 118 cccgattcacgcttccaa 11585 116041 5 EQ ID NO: 2790ggaagctctttttgggaag 2221 2 24 0 SEQ ID NO: 119cttcagaaagctaccttcc 7937 79561 5 EQ ID NO: 2791 tcccagacagtgtca 2246 2265 SEQ ID NO: 120 gaccttctctaagcaaaa 4884 49031 5 EQ ID NO: 27921agacagtgtcaacaaagct 2254 2 2 7 3 SEQ ID NO: 121 agcttggttttgccagtct 2466 24851 5 EQ ID NO: 27931ctttggctataccaaagat 2329 2 3 4 8 SEQ ID NO: 122atctcgtgtctaggaaaag 5976 59951 5 EQ ID NO: 2794 caaagatgataaacatgag 2341 2 3 6 0 SEQ ID NO: 123 ctcaaggataacgtgtttg 12617 126361 5 EQ ID NO: 2795 gatatggtaaatggaataa 2363 2 3 82 SEQ ID NO: 124 atcttattaattatatc 13087 131061 5 EQ ID NO: 2796ggaataatgctcagtgtg 2375 2 3 94 SEQ ID NO: 125caacacttacttgaattcc 10669 106881 5 EQ ID NO: 2797 tlgaaatccaaagaagtc 2410 24 2 5SEQ ID NO: 126 acttcagagaaatacaaa 11408 114271 5 EQ ID NO: 27981gatcccccagatgattgga 2542 2561 SEQ ID NO: 127 ccaatttccctgtggatc 3689 37081 5 EQ ID NO: 2799cagatgattggagaggtca 2549 2568 SEQ ID NO: 128 gaccacacaaacagtctg 5371 53901 5 QID NO: 20agaatgacttttttcttca 2583 2602 SEQ ID NO: 4129 gaagtccggattcattct 11023 110421 5 EQID NO: 2801 gaactccccactggagctg 2627 2646 SEQ ID NO: 4130cagctcaaccgtacagttc 11869 118881 5 =Q ID NO: 2802 atatcttcatctggagtca 2660 2679 SEQ ID NO: 131 gacttcagtgcagaatat 11974 119931 5 QIDNO:2803gtcattgctcccggagcca 2675 2694SEQ ID NO:4132 ggccccgtttaccatgac 5817 58361 5 EQ ID NO: 2804gctgaagtttatcattcct 2881 2 90 0 SEQ ID NO:4133aggaggctttaagttcagc 7608 76271 5 EQ ID NO: 2805attccttccccaaagagac 2894, 2 9 1 3 SEQ ID NO:4134gtctcttcctccatggaat 10478 104971 5 291 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2806ctcattgagaacaggcagt 2984 3 0 0 3 SEQ ID NO:4135actgactgcacgctttgag 11764 117831 5 SEQIDNO: 2807tgagcagtattctgtcag 3150 3 16 9 SEQ ID NO: 4136ctgagagaagtgtcttcaa 12407 124261 5 SEQ ID NO: 2808accttgtccagtgaagtcc 3293 3 3 12 SEQ ID NO:4137ggacggtactgtcccaggt 12792 128111 5 SEQ ID NO: 2809ccagtgaagtccaaattcc 3300 3319SEQ ID NO:4138ggaaggcagagtttactgg 9156 91751 5 SEQ ID NO: 2810acattcagaacaagaaaat 3402 3421,SEQ ID NO:4139atttcctaaagctggatgt 11175 111941 5 SEQ ID NO: 2811 gaaaaatcaagggtgttat 3471 3 4 90 SEQ ID NO:4140ataaactgcaagatttttc 13608 136271 5 SEQ ID NO: 2812aaatcaagggtgtatttc 3474 3493 SEQ ID NO: 4141 gaaacaatgcattagattt 9753 97721 5 SEQ ID NO: 2813 ggcattatgatgaagaga 3617 3 63 6 SEQ ID NO: 4142 tctcccgtgtataatgcca 11789 118081 5 SEQ ID NO: 2814aagagaagattgaatttga 3630 3 64 9 SEQ ID NO:4143tcaaaacctactgtctctt 10466 104851 5 SEQ ID NO: 281 5 aaatgacttccaatttccc 3681 3700SEQ ID NO:4144gggaactacaatttcattt 7021 70401 5 SEQ ID NO: 2816atgacitccaatttccctg 3683 3702 SEQ ID NO: 4145caggctgattacgagtcat 4925 49441 5 SEQ ID NO: 281 acttccaatttccctgtgg 3686 3 7 0 5 SEQ ID NO:4146ccacgaaaaatatggaagt 10368 103871 5 SEQ ID NO: 2 8 18 agttgcaatg agctcatgg 3811 3 8 3 0 SEQ ID NO: 4147 ccatcagttcagataaact 7997 80161 5 SEQ ID NO: 2819 tttgcaagaccacctcaat 3868 3 8 8 7 SEQ ID NO: 4148attgacctgtccattcaaa 13679 136981 5 SEQ ID No: 2820 gaaggagttcaacctccag 3892 3 9 1 1 SEQ ID NO: 4149 ctggaattgtcattcCttc 11736 117551 5 SEQ ID NO: 2821 acttccacatcccagaaaa 3927 3946 SEQ ID NO: 4150 ttaacaaaagtggaagt 6829 68481 5 SEQ ID NO: 28 2 2 1ctcttcttaaaaagcgatg 3947 3 9 66 SEQ ID NO: 4151 catcactgccaaaggagag 8494 85131 5 SEQ ID NO: 2823aaaagcgatggccgggtca 3956 3975 SEQ ID NO: 4152tgactcactcattgatttt 12688 127071 5 SEQ ID NO: 2824tcctttgccttttggtgg 4011 4030 SEQ ID NO:4153ccacaaacaatgaagggaa 9264 92831 5 SEQ ID NO: 28 2 5 caagtctgtgggattccat 4087 4 10 6 SEQ ID NO: 4154atgggaaaaaacaggcttg 9574 95931 SEQ ID NO: 2 82 6 aagtccctacttttaccat 4125 4 14 4 SEQ ID NO: 4155atgggaagtataagaactt 4842 48611 5 SEQID NO:2827gcctctcctgggtgttct 4167 4186 SEQIDNO:41561agaaaaacaaacacaggca 9651 96701 5 SEQ ID NO: 2828accagcacagaccatttca 4250 4269SEQ ID NO:4157tgaagtgtagtctcctggt 5097 51161 5 SEQ ID NO: 2829 ccagcacagaccatttcag 4251 4270 SEQ ID NO: 4158 ctgaaatacaatgctctgg 5519 55381 5 SEQ ID NO: 2830actatcatgtgatgggtct 4375 4 3 94 SEQ ID NO: 4159agacacctgattttatagt 7956 79751 5 SEQ ID NO: 2831 accacagatgtctgcttca 4504 4523 SEQ ID NO: 4160 tgaaggctgactctgtggt 4290 43091 5 SEQ ID NO: 2832ccacagatgtctgcttcag 4505 4524SEQ ID NO:4161 ctgagcaacaaatttgtgg 10319 103381 5 SEQ ID NO: 2833ttggactccaaaaagaaa 4528 4547SEQ ID NO:4162itctctcatgattacaaa 5941 59601 5 SEQ ID NO: 2834 caaagaagtcaagattga 4560 4 5 79 SEQ ID NO: 4163 caaggataacgtgtttga 12618 126371 5 SEQIDNO: 2835atgagaactacgagctgac 4806 4 82 5 SEQ ID NO: 4164gtcagatattgttgctcat 10195 102141 5 SEQ ID NO: 2836ttaaaatctgacaccaatg 4826 4 84 5 SEQ ID NO:4165cattcattgaagatgttaa 7350 73691 5 SEQ 1D NO: 2837jgaagtataagaaCtttgcc 4846 4865SEQ ID NO:4166ggcaaatttgaaggacttc 12002 120211 5 SEQ ID NO: 2838aagtataagaactttgcca 4847 4 86 6 SEQ ID NO: 4167tggcaaatttgaaggactt 12001 120201 5 SEQ ID NO: 2839 cttcagcctgctttctg 4949 4 96 8 SEQ ID NO: 4168cagaatccagatacaagaa 6892 69111 5 SEQ ID NO: 2840 ctggatcactaaattccca 4965 4984SEQ ID NO: 4169 gggtctttccagagccag 11041 11060 1 5 SEQ ID NO: 2841 aaattaatagtggtgctca 5022 5041 SEQ ID NO: 4170 gagaagccccaagaattt 6256 62751 5 SEQ ID NO: 2842 agtgcaacgaccaacttga 5081 5100 SEQ ID NO: 4171 caaattcctggatacact 9856 98751 5 SEQ ID NO: 28431ctgggaagtgcttatcagg 5246 52 6 5 SEQ ID NO: 4172cctgaccttcacataccag 8318 83371 5 SEQ ID NO: 2g44 gcaaaaacattttcaactt 5286 53 0 5 SEQ ID NO: 4173aagtaaaagaaaattttgc 10752 107711 5 SEQ ID NO: 2845 aaaaacattttcaacttca 5288 5 3 0 7 SEQ ID NO: 4174 gaagtaaaagaaaatttt 10750 107691 5 SEQ ID NO: 2846 tcagtcaagaaggacttaa 5310 5 3 2 9 SEQ ID NO: 4175 taaggacttccattctga 13371 133901 5 SEQ ID NO: 2847 caaatgacatgatgggct 5333 5 3 52 SEQ ID NO:41761agcccatcaatatcattga 6213 62321 5 SEQID NO: 24 8 cacacaaacagtctgaaca 5375 5 3 94 SEQ ID NO:4177gtttcaactgcctttgtg 11227 112461 5 SEQ ID NO: 2849 cttcaaaacttgacaaca 5417 5 4 36 SEQ ID NO: 4178 gttttcctatttccaaga 12843 128621 5 SEQ ID NO: 2850,caagttttataagcaaact 5449 5 46 8 SEQ ID NO: 4179agttattttgctaaacttg 14051 140701 5 SEQ ID NO: 2851 ggtaactactttaaacag 5496 5 5 15 SEQ ID NO:4180ctgtttttagaggaaacca 7520 75391 5 SEQ ID NO: 28521aacagtgacctgaaataca 5510 5 52 9 SEQ ID NO:4181 gtatagcaaattcctgtt 5898 759171 292 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 853gggaaactacggctagaac 5552 5571 SEQ ID NO:4182gttccttccatgatttccc 10941 109601 5 SEQ ID NO: 2854aacacatctatgccatctc 5628 5 64 7 SEQ ID NO:4183gagacagcatcttcgtgtt 11212 112311 5 SEQ ID NO: 2855tcagcaagctataaagcag 5660 5679SEQ ID NO:4184ctgctaagaaccttactga 7788 78071 5 SEQIDNO: 2856gcagacactgttgctaagg 5675 5 6 94 SEQ ID NO:4185cctttcaagcactgactgc 11754 117731 5 SEQ ID NO: 2857tctggggagaacatactgg 5874 5 89 3 SEQ ID NO:4186ccaggttttccacaccaga 8046 80651 5 SEQ ID NO: 2858 ttctctcatgattacaaag 5942 5961 SEQ ID NO: 4187ctttttcaccaacggagaa 10846 108651 5 SEQ ID NO: 2859,ctgagcagacaggcacctg 6042 6061 SEQ ID NO:4188caggaggctttaagttcag 7607 76261 5 SEQ ID NO: 2 86 0 caatttaacaacaatgaat 6074 6093 SEQ ID NO: 4189 attccttcCtttacaattg 8090 81091 5 SEQ ID NO: 2861 tggacgaactctggctgac 6148 6 16 7 SEQ ID NO:4190gtcagcccagttccttcca 10932 109511 5 SEQ ID NO: 2 86 2 cttttactcagtgagccca 6200 6219 SEQ ID NO: 4191 tgggctaaacgtatgaaag 7835 78541 5 SEQ ID NO: 2863tcattgatgctttagagat 6225 62 4 4 SEQ ID NO: 4192atcttcataagttcaatga 13182 132011 5 SEQ ID NO: 2864aaaaccaagatgttcactc 6303 6322SEQ ID NO:4193gagtgaaatgctgtttttt 8638 86571 5 SEQ ID NO: 2 86 5 aggaatcgacaaaccatta 6365 6384SEQ ID NO:4194taatgattttcaagttcct 8302 83211 5 SEQ ID NO: 866tagttgtactggaaaacgt 6384 6403SEQ ID NO:4195acgttagcctctaagacta 11936 119551 5 SEQ ID NO: 2 86 7 ggaaaacgtacagagaaag 6394 64 13 SEQ ID NO:4196cttttacaattcattttcc 13022 130411 5 SEQ ID NO: 2 86 8 gaaaacgtacagagaaagc 6395 6414 SEQ ID NO: 419 7etttctcttccacatttc 10060 100791 5 SEQ ID NO: 2 86 9 aaagctgaagcacatcaat 6409 6428SEQ ID NO:4198attgatgttagagtgcttt 6992 70111 5 SEQ ID NO: 287 0 aagctgaagcacatcaata 6410 6429SEQ ID NO:4199tattgatgttagagtgctt 6991 70101 5 SEQIDNO: 2871 tgaagcacatcaatattga 6414 6 4 3 3 SEQID NO:4200tcaaccttaatgattttca 8295 83141 5 SEQ ID NO: 2 8 72 atcaatattgatcaattg 6422 6441 SEQ ID NO: 4201 caaagccatcactgatgat 1668 16871 5 SEQ ID NO: 2873 aatgattatctgaattca 6484 6503SEQ ID NO: 4202 tgaaatcattgaaaaatta 6727 67461 5 SEQ ID NO: 2874gattatctgaattcattca 6488 6507 SEQ ID NO: 4203 tgaagtagctgagaaaatc 7102 71211 5 SEQ ID NO: 2 8 75 aattgggagagacaagttt 6506 6 5 2 5 ,SEQ ID NO: 4204aaacattccttaacaatt 9496 95151 5 SEQ ID NO: 2 8 76 aaaatagctattgctaata 6701 6720 SEQ ID NO: 4205 tattgaaaatattgatttt 6814 68331 5 SEQ ID NO: 2877 aaaattaaaaagtcttgat 6739 6758SEQ ID NO:4206atcatatccgtgtaatttt 6765 67841 5 SEQ ID NO: 2878ttgaaaatattgattttaa 6816 6835SEQ ID NO: 4207 ttaatcttcataagttcaa 13179 131981 5 SEQ ID NO: 2 87 9 agacatccagcacctagct 6946 6965 SEQ ID NO: 4208 agcttggttttgccagtct 2466 24851 5 SEQ ID NO: 2 8 80 caatttcatttgaaagaat 7029 7048 SEQ ID NO: 4209 attccttcctttacaattg 8090 81091 5 SEQIDNO: 2 8 8 1 aggttttaatggataaatt 7182 7201 SEQ ID NO: 4210aattgttgaaagaaaacct 13155 131741 5 SEQ ID NO: 2 8 8 2cagaagctaagcaatgtcc 7241 7260SEQ ID NO:4211 ggacaaggcccagaatctg 12553 125721 5 SEQIDNO: 2 8 8 3taagataaaagattacttt 7270 7 2 8 9 SEQ1D NO:4212aaagaaaacctatgcctta 13163 131821 5 SEQ ID NO: 2 8 84 aaagattactttgagaaat 7277 7296SEQ ID NO:4213atttcttaaacattccttt 9489 95081 5 SEQ ID NO: 288 5 gagaaattagttggattta 7289 7 3 0 8 SEQ ID NO:4214taaagccattcagtctctc 12970 129891 5 SEQ ID NO: 2 8 86 atttattgatgatgctgtc 7303 7322 SEQ ID NO: 4215 acatgttgataaagaaat 7379 73981 5 SEQ ID NO: 2887gaattatcttttaaaacat 7334 7353 SEQ ID NO: 4216 atgtatcaaatggacattc 7685 77041 5 SEQ ID NO: 2888 taccaccagtttgtagat 7411 7430,SEQ ID NO: 4217 atctggaaccttgaagtaa 10739 107581 5 SEQ ID NO: 2889gcagtgtatctggaaag 7548 7567SEQ ID NO: 4218cttttcacattagatgcaa 8420 84391 5 SEQ ID NO: 2890cattcagcaggaacttcaa 7699 7 7 1 8 SEQ ID NO: 4219 ttgaaggacttcaggaatg 12009 120281 5 SEQ ID NO: 2891 acacctgattttatagtcc 7958 7 9 7 7 SEQ ID NO: 4220 ggactcaaggataacgtgt 12614 126331 5 SEQ ID NO: 2892ggattccatcagttcagat 7992 8011 SEQ ID NO: 4221 atcttcaatgattatatcc 13124 131431 5 SEQ ID NO: 2893 ttgtagaaatgaaagtaaa 8112 8131 SEQ ID NO: 4222ttatgattatgtcaacaa 12360 123791 5 SEQ ID NO: 2 8 94 ctgaacagtgagctgcagt 8156 8 17 5 SEQ ID NO: 223actggacttctctagtcag 8809 88281 5 SEQ ID NO: 2895aatccaatctcctcttttc 8407 8 4 2 6 SEQ ID NO:4224gaaaaatgaagtccggatt 11017 110361 5 SEQ ID NO: 2 8 96 attttgattttcaagcaaa 8532 8551 SEQ ID NO: 4225 tttgcaagttaaagaaaat 14023 140421 5 SEQ ID NO: 2897 ttttgattttcaagcaaat 8533 8552SEQ ID NO:4226atttgatttaagtgtaaaa 9622 96411 5 SEQ ID NO: 2898tgattttcaagcaaatgca 8536 8555SEQ ID NO:4227tgcaagttaaagaaaatca 14025 140441 5 SEQ ID NO: 2899 atgctgttttttggaaatg 8645 8664SEQ ID NO:4228,cattggtaggagacagcat 11203 112221 5 293 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2900 gctgttttttggaaatgc 8646 8665 SEQ ID NO: 229gcattggtaggagacagca 11202 112211 5 SEQ ID NO: 2901aaaaaaatacactggagct 8706 8 7 2 5 SEQ ID NO: 230agctagagggcctcttttt 10833 108521 5 SEQ ID NO: 2902 actggagcttagtaatgga 8716 8 7 3 5 SEQ ID NO: 4231 tccactcacatcctccagt 1289 13081 5 SEQID NO: 2903cttctggaaaagggtcatg 8886 8 9 0 5 SEQ ID NO:4232catgaacccctacatgaag 13759 13781 5 SEQIDNO:2904ggaaaagggtcatggaaat 8891 8 9 10 SEQ ID NO:4233atttgaaagttcgttttcc 9282 93011 5 SEQ ID NO: 2905gggcctgccccagattctc 8910 8929SEQ ID NO:4234gagaacattatggaggccc 9440 94591 5 SEQ ID NO: 2906 ctitcagatgagggaacac 8924 8 9 4 3 SEQ ID NO:4235gtgtcttcaaagctgagaa 12416 124351 5 SEQ ID NO: 2907 gatgagggaacacatgaat 8930 8949SEQ ID NO:4236attccagcttccccacatc 8338 83571 5 SEQ ID NO: 290 8 ctttggactgtccaataag 8986 9 0 05 SEQ ID NO:4237cttatgggatttcctaaag 11167 111861 5 SEQ ID NO: 2909gcatccacaaacaatgaag 9260 92 79 SEQ ID NO:4238cttcatctgtcattgatgc 10227 102461 5 SEQ ID NO: 2910 cacaaacaatgaagggaat 9265 92 8 4 SEQ ID NO: 4239attccctgaagttgatgtg 11488 115071 5 SEQ ID NO: 2911 ccaaaatttctctgctgga 9415 9 4 3 4 SEQ ID NO: 4240 tccatcacaaatcctttgg 9671 96901 5 SEQ ID NO: 291 caaaatttctctgctggaa 9416 9435SEQ ID NO: 4241 ttccatcacaaatcctttg 9670 96891 5 SEQ ID NO: 2913tctgctggaaacaacgaga 9425 9 4 44 SEQ ID NO:4242tctcaagagttacagcaga 13229 132481 5 SEQ ID NO: 2914ctgctggaaacaacgagaa 9426 9 4 4 5 SEQ ID NO: 4243 tctcaagagttacagcag 13228 132471 5 SEQ ID NO: 291 5 agaacattatggaggccca 9441 9 4 6 0 SEQ ID NO: 4244 tgggcctgccccagattet 8909 89281 5 SEQ ID NO: 29 16 agaagcaaatctggatttc 9475 9 49 4 SEQ ID NO: 4245gaaatcttcaatttattct 13821 138401 5 SEQ ID NO: 2917 ttctctctatgggaaaaa 9565 9 5 84 SEQ ID NO:4246tgcaagttaaaaaaa 14021 140401 5 SEQ ID NO: 2918 tcagagcatcaaatcctt 9712 9731SEQ ID NO:4247aaagaaaatcaggatctga 14033 140521 5 SEQ ID NO: 291g cagaaacaatgcattagat 9751 9 77 0 SEQ ID NO: 4248atctatgccatctcttctg 5633 56521 5 SEQ ID NO: 2920 acacattaatcctgtccat 10001 1 0 02 0 SEQ ID NO: 4249 atggagtcetttattgtgta 14089 141081 5 SEQ ID NO: 2 9 2 1agtcagatattgttgctca 10194 1 0 2 13 SEQ ID NO: 4250 gagaactacgagctgact 4807 48261 5 SEQ ID NO: 2922ggagggtagtcataacagt 10336 1 0 35 5 SEQ ID NO: 4251actggtggcaaaaccctcc 2734 27531 5 SEQ ID NO: 2923 caaaagccgaattccaat 10404 1 04 23 SEQ ID NO: 4252 attgaagtacctacttttg 8366 83851 5 SEQ ID NO: 292 4 aaaagccgaaaftccaat 10405 1 04 2 4 SEQ ID NO:4253aattgaagtacctactttt 8365 83841 5 SEQ ID NO: 2925ttcaagcaagaacttaatg 10436 10455 SEQ ID NO: 4254cattatggcccttcgtgaa 13258 132771 5 SEQ ID NO: 2926 ctctacttttccattga 10578 10 5 97 SEQ ID NO: 255tcaaaagaagcccaagagg 12947 129661 5 EQID NO: 2927gaggccaacacttacttg 10663 10 6 8 2 5SEQ ID NO: 256caagcatctgattgactca 12676 126951 5 SEQ ID NO: 2928cacttacttgaattccaag 10672 10691 SEQ ID NO: 25 cttgaacacaaagtcagtg 6008 260271 5 SEQ ID NO: 2929 gaagtaaaagaaaattttg 10751 10 7 70 SEQ ID NO: 258 caaaaacattttcaacttc 5287 53061 5 SEQ ID NO: 2930 cctgggactctctccatgg 10882 10 9 01 SEQ ID NO: 4259 ccatttacagatcttcagg 11372 11,3911 5 SEQ ID NO: 293 agctggatgtaaccaccag 11184 1 1 2 03 SEQ ID NO: 4260 tggattccacatgcagct 11855 118741 5 SEQ ID NO: 2932 aaaattccctgaagttgat 11485 1 1 5 04 SEQ ID NO: 4261 atcatatccgtgtaatttt 6765 67841 5 SEQ ID NO: 2933aagatgcatgctct 11613 1 1 6 32 5 SEQ ID NO: 4262 aaagctgagaagaaatctg 12424 124431 5 SEQ ID NO: 29343agatggcattgtgtttg 11614 1 1 6 33 SEQ ID NO:4263caaagctgagaagaaatct 12423 .124421 5 SEQ ID NO: 2935 gttgaaacagtcotggat 11842 11861 SEQ ID NO: 4264atccaagatgagatcaaca 13103 131221 5 SEQ ID NO: 2935atattcaaaactgagtg 12229 1 2 24 8 SEQ ID NO: 4265caactctctgattactatg 13631 13650 1 5 SEQ ID NO: 293 aaagatttatcaaaagaag 12938 12 95 7 SEQ ID NO: 4266 ttcaatttafttcttt 13826 138451 5 SEQ ID NO: 2938attttccaactaatagaag 13034 1 3 05 3 SEQ ID NO: 4267cttcaaagacttaaaaaat 8014 80331 5 SEQ ID NO: 293g8attatatccaagatgaga 13097 13 11 6 SEQ ID NO: 4268 ctcttcctccatggaatt 10479 104981 5 SEQ ID NO: 2940ttcaggaagdtctcaaga 13218 13 2 3 7 SEQ ID NO: 4269 cttcataagttcaatgaa 13183 132021 5 SEQ ID NO: 2941 tgagcaatttctgcacag 13437 13 4 5 6 SEQ ID NO: 4270 tgttgaaagatttatcaa 12932 129511 5 SEQ ID NO: 29402tgattacatcacggagt 13712 13731 SEQ ID NO: 4271 actcaatggtgaaattcag 7465 74841 5 SEQ ID NO: 2943 catcacggagttactgaa 13719 13738 SEQ ID NO: 4272 tcagaagctaagcaatgt 7239 72581 5 SEQ ID NO: 2944 actgcctatattgataaaa 13882 13901 SEQ ID NO: 4273 ttggcaagctatacagt 8380 83991 5 SEQ ID NO: 294 aggatggcattttttgcaa 14011 14 0 3 0 SEQ ID NO: 4274 tgcaagcaagtctttcct 3013 30321 5 SEQ ID NO: 2946 tgcaagttaaagaa 14020 14 0 3 9 SEQ ID NO:4275 ctctctatgggaaaaaa 9566 95851 5 294 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2947tccagaactcaagtcttca 1627 164 6 SEQ ID NO:4276tgaaatgctgttttttgga 8641 86603 4 SEQ ID NO: 2 9 48agttagtgaaagaagttct 1956 197 5 SEQ ID NO:4277agaatctgtaccaggaact 12564 125833 4 SEQ ID NO: 2 9 49 atttacagctctgacaagt 5435 5 45 4 SEQ ID NO: 4278acttcagagaaatacaaat 11409 11428 4 SEQ ID NO: 2 95 0 gattatctgaattcattca 6488 6507 SEQ ID NO:4279tgaaaccaatgacaaaatc 7429 74483 4 SEQ ID NO: 2951,gtgcccttctcggttgctg 26 4 5 SEQ ID NO:4280cagctgagcagacaggcac 6039 60582 4 SEQ ID NO: 2952attcaagcacctccggaag 253 2 72 SEQ ID NO: 4281 cttcataagttcaatgaat 13184 132032 4 SEQ ID NO: 2 95 3 gactgctgattcaagaagt 316 33 5 SEQ ID NO:4282acttccaactctcaagtc 13415 134342 4 SEQ ID NO: 2954tgctgcagccatgtccag 483 50 2 SEQ ID NO:4283ctgggcagctgtatagcaa 5889 59082 4 SEQ ID NO: 2955agaaagatgaacctactta 555 57 4 SEQ ID NO:4284taagtatgatttcaattct 10498 105172 4 SEQ ID NO: 2956tgaagactctccaggaact 1095 1 1 14 SEQ ID NO:4285agttcaatgaatttattca 13191 132102 4 SEQ ID NO: 2957atctctcttgccacagctg 1210 1 22 9 SEQ ID NO:4286cagcccagccatttgagat 9237 92562 4 SEQIDNo:2958tctctcttgccacagctga 1211 12 3 0 SEQ ID NO:4287tcagcccagccatttgaga 9236 92552 4 SEQ ID NO: 2959 tgaggtgtccagccccatc 1231 1250 SEQ ID NO:4288gatgggaaagccgccctca 5216 52352 4 SEQ ID NO: 2 9 6 0 ccagaactcaagteitcaa 1628 1647 SEQ ID NO:4289tgaaagcagaacctctgg 5915 59342 4 SEQ ID NO: 2961 ctgaaaaagttagtgaaag 1949 1 96 8 SEQ ID NO:4290ctttctcgggaatattcag 10631 106502 4 SEQ ID NO: 2962ttttcccagacagtgtca 2246 2265 SEQ ID NO: 4291 tgacaggcattttgaaaaa 9730 9749 4 SEQ ID NO: 2963 cCccagacagtgtcaa 2247 2256 SEQ ID NO:4292ttgacaggcattttgaaaa 9729 97482 4 SEQ ID NO: 29 6 4 cattcagaacaagaaaatt 3403 34 2 2 SEQ ID NO:4293aattccaattttgagaatg 10414 104332 4 SEQ ID NO: 2965tgaagagaagattgaattt 3628 3647SEQ ID NO:4294 aaatgtcagctcttgttca 10902 109212 4 SEQIDNO: 2966 tgaatggaacacaggca 3644 36 6 3 SEQ ID NO:4295tgccagtttgaaaaacaaa 11815 118342 4 SEQ ID NO: 2967ctagattcgaatatcaa 4407 4426SEQ ID NO:4296tgacatgttgataaagaa 7377 73962 4 SEQ ID NO: 2968gattcgaatatcaaattca 4412 4431 SEQ ID NO:4297tgaagtagaccaacaaatc 7162 71812 4 SEQD NO:2969gcaacgaccaacttgaag 5083 5 102 SEQID NO: 4298cttcaggttccatcgtgca 11384 114032 4 SEQ ID NO: 2970 aagctctcaaatgacat 5325 5344 SEQ ID NO: 4299 atgttgataaagaaattaa 7382 74012 4 SEQ ID NO: 2971 caatttaacaacaatgaat 6074 6093 SEQ ID NO: 4300attcaaactgcctatattg 13876 138952 4 SEQ ID NO: 2972 gaatacagccaggactg 6088 6107 SEQ ID NO: 4301 caagagcacacggtcttca 10687 107062 4 SEQ ID NO: 29731catcaatattgatcaattt 6421 6 44 0 SEQ ID NO:4302aaattccctgaagttgatg 11486 115052 4 SEQ ID NO: 2974tgagcatgtcaaacactt 7059 7 0 78 SEQ ID NO: 4303aagtaagtgctaggttcaa 9381 94002 4 SEQ ID NO: 2975tgaaggagactattcagaa 7227 7246 SEQ ID NO: 4304 tctgcacagaaatattca 13446 134652 SEQ ID NO: 2976Pcaggctcttcagaaagc 7929 7948 SEQ ID NO: 4305 cttgctaacctctctgaa 12312 123312 4 SEQ ID NO: 2977ccacaaattgaacatccc 8787 8806 SEQ ID NO: 4306 ggacctaccaagagtgga 12533 125522 4 SEQ ID NO: 2978 gaataccaatgctgaact 10167 10186 SEQ ID NO: 4307 agttcaatgaatttattca 13191 132102 4 SEQ ID NO: 2979 aaactaatagatgtaatc 12898 12917SEQ ID NO: 4308 gattactatgaaaaattta 13640 136592 4 SEQ ID NO: 2980 gacctgtccattcaaaa 13680 13 69 9 SEQ ID NO: 4309 aaaagaaatcttcaa 13813 138322 4 SEQIDNo:2981gggctgagtgcccttctcg 19 38 SEQDNO:4310 cgaggccaggccgcagccc 84 1031 4 SEQ ID No: 2 9 8 2 ggctgagtgcccttctgg 20 39 SEQ ID NO: 4311 ccgaggccaggccgcagcc 83 1021 4 SEQ ID NO: 29831ctgagtgcccttctcggtt 22 41 SEQ ID NO: 4312aaccgtgcctgaatctcag 11557 115761 4 SEQ ID NO: 2984 ctcggttgctgccgctga 33 52 SEQ ID NO: 4313 tcagctgacctcatcgaga 2168 21871 4 SEQ ID NO: 2 9 8 caggccgcagcccaggagc 90 1 09 SEQ ID NO: 4314gCtctgcagcttcatcctg 376 3951 4 SEQ ID NO: 2986gctggcgctgcctgcgctg 151 17 0 SEQ ID NO:4315cagcacagaccatttcagc 4252 42711 4 SEQ ID NO: 298 gctgctggcgggcgccag 177 19 6 SEQ ID NO: 4316ctggatgtaaccaccagca 11186 112051 4 SEQ ID NO: 2988 ctggtctgtccaaaagatg 227 2 4 6 SEQ ID NO: 4317 catcctgaagaccagccag 388 4071 4 SEQ ID NO: 298gictgagagttccagtggagt 291 3 10 SEQ ID NO: 4318actcaccctggacattcag 3391 34101 4 SEQ ID NO: 2990 tccagtggagtccctggga 299 3 18 SEQ ID NO:4319tcccggagccaaggotgga 2683 27021 4 SEQ ID NO: 2991 aggttgagctggaggttcc 354 3 7 3 SEQ ID NO:4320ggaaccotctccctcacct 4736 47551 4 SEQDNO: 2992tgagctggaggttccccag 358 3 7 7 SEQ ID NO: 4321 ctgggaggcatgatgctca 9171 91901 4 295 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 2993 ctgcagcttcatcctgaa 378 39 7 SEQ ID NO:4322 tcaaatataatcggcaga 3269 32881 4 SEQ ID NO: 2 9 g 4 gccagtgcaccctgaaaga 402 421 SEQ ID NO:4323tcttccgttctgtaatggc 5802 58211 4 SEQ ID NO: 2995ctctgaggagtttgctgca 472 491 SEQ ID NO: 4324 tgcaagaatattttgagag 6348 63671 4 SEQ ID NO: 29 9 6 aggtatgagctcaagctgg 500 5 19 SEQ ID NO:4325ccagtttccggggaaacct 12724 127431 4 SEQ ID NO: 2997cctttacccggagaaaga 543 5621SEQ ID NO:4326tctttttgggaagcaagga 2227 22461 4 SEQ ID NO: 2998catcaagaggggcatcatt 583 60 2 SEQ ID NO:4327aatggtcaagttcctgatg 2285 23041 4 SEQ ID NO: 2999cctggttcccccagagac 609 62 8 SEQ ID NO:4328gtctctgaactcagaagga 13996 140151 4 SEQ ID NO: 30 0 0 aagaagccaagcaagtgtt 630 64 9 SEQ ID NO:4329aacaaataaatggagtctt 14080 140991 4 SEQ ID NO: 3001aagcaagtgttgtttctgg 638 65 7 SEQ ID NO:4330ccagagccaggtcgagctt 11050 110691 4 SEQ ID NO: 3002tctggataccgtgtatgga 652 671 SEQ ID NO: 4331 tccatgtcccatttacaga 11364 113831 4 SEQ ID NO: 30 0 3 ccactcactttaccgtcaa 678 69 7 SEQ ID NO:4332ttgattttaacaaaagtgg 6825 68441 4 SEQ ID NO: 30 0 4 aggaagggcaatgtggcaa 701 72 0 SEQ ID NO: 4333ttgcaagcaagtctttcct 3013 30321 4 SEQ ID NO: 30 0 5 gcaatgtggcaacagaaat 708 72 7 SEQ ID NO: 4334atttccataccccgtttgc 3488 35071 4 SEQ ID NO: 30 0 6 caatgtggcaacagaaata 709 72 8 SEQ ID NO: 4335 tattcttcttttccaattg 13834 138531 4 SEQ ID NO: 3007ggcaacagaaatatccac 714 7 3 3 SEQ ID NO: 4336gtggcttcccatattgcca 1895 19141 4 SEQ ID NO: 30 0 8 agagacctgggccagtgtg 737 75 6 SEQ ID NO: 4337cacattacatttggtctct 2938 29571 4 SEQ ID NO: 3009 gtgatcgcttcaagccca 752 7 7 1 SEQ ID NO: 4338 gggaaagccgccctcaca 5218 52371 4 SEQ ID NO: 301 0 gtgategcttcaagcccat 753 7 7 2 SEQ ID NO: 4339atgggaaagccgccctcac 5217 52361 4 SEQ ID NO: 3011 cagcccacttgctctcatc 784 8 0 3 SEQ ID NO: 4340gatgctgaacagtgagctg 8152 81711 4 SEQ ID NO: 301 2 gctctcatcaaaggcatga 794 8 1 3 SEQ ID NO: 4341 tcataacagtactgtgagc 10345 103641 4 SEQ ID NO: 30 13 ccttgtcaactctgatcag 819 8 3 8 SEQ ID NO: 4342ctgagtgggtttatcaagg 12453 124721 4 SEQ ID NO: 301 4 cttgtcaactctgatcagc 820 8 3 9 SEQ ID NO: 4343gctgagtgggtttatcaag 12452 124711 4 SEQ ID NO: 301 5 agccatctgcaaggagcaa 892 911 SEQ ID NO: 4344ttgcaatgagctcatggct 3813 38321 SEQ ID NO: 30 1 6 gccatctgcaaggagcaac 893 9 12 SEQ ID NO: 4345gttgcaatgagctcatggc 3812 38311 4 SEQ ID NO: 301 cttcctgcctttctcctac 916 9 3 5 SEQ ID NO:4346gtaggaataaatggagaag 9461 94801 4 SEQ ID NO: 30 1 8 ctttctcctacaagaataa 924 9 4 3 SEQ ID NO:4347ttattgctgaatccaaaag 13656 136751 4 SEQ ID NO: 3019 atcaacagccgcttcttt 997 10 1 6 SEQ ID NO: 4348aaagccatcactgatgatc 1669 16881 4 SEQ ID NO: 30 2 0 atcaacagccgcttctttg 998 10 1 7 SEQ ID NO: 4349caaagccatcactgatgat 1668 16871 4 SEQ ID NO: 3021 acagccgCttctttggtga 1002 1021 SEQ ID NO: 4350 tcacaaatcctttggctgt 9675 96941 4 SEQ ID NO: 3 0221aagatgggcctcgcatttg 1031 10 5 0 SEQ ID NO: 4351 caaaatagaagggaatctt 2077 2096 1 4 SEQ ID NO: 3023 gttttgaagactctccag 1090 1109 SEQ ID NO: 43521ctggtaactactttaaaca 5495 55141 4 SEQ ID NO: 3024tgaagactctccaggaac 1094 1 113 SEQ ID NO: 4353 gttcaatgaatttattcaa 13192 132111 SEQ ID NO: 30 2 5 aactgaaaaaactaaccat 1110 1 12 9 SEQ ID NO: 4354atggcattttttgcaagtt 14014 140331 4 SEQ ID NO: 30 2 6 ctgaaaaaactaaccatCt 1112 1131 SEQ ID NO: 4355agattgatgggcagttcag 4572 45911 4 SEQ ID NO: 302 aaaactaaccatctctgag 1117 1 136 SEQ ID NO: 4356 ctcaaagaatgactttttt 2578 25971 4 SEQ ID NO: 3028 gagcaaaatatccagaga 1132 1151 SEQ ID NO: 4357 ctccagataaaaaactca 12209 122281 4 SEQ ID NO: 30 2 9 caataagctggttactgag 1162 1181 SEQ ID NO: 4358ctcagatcaaagttaattg 12273 122921 4 SEQ ID NO: 3030 actgagctgagaggcctc 1174 1 193 SEQ ID NO:4359gagggtagtcataacagta 10337 103561 4 SEQ ID NO: 3031 cctcagtgatgaagcagt 1188 12 07 SEQ ID NO: 4360 actgttgactcaggaaggc 12580 125991 4 SEQ ID NO: 3032agtcacatctctcttgcca 1204 1223 SEQ ID NO: 4361 tggccacatagcatggact 8866 88851 4 SEQ ID NO: 30 3 3 atctctcttgccacagctg 1210 12 29 SEQ ID NO: 4362cagctgacctcatcgagat 2169 21881 4 SEQ ID NO: 3034 ctctcttgccacagctga 1211 12 30 SEQ ID NO: 4363 tcagctgacctcatcgaga 2168 21871 4 SEQ ID NO: 3035gccacagctgattgaggt 1218 12 37 SEQ ID NO: 4364acctgcaccaaagctggca 13963 139821 4 SEQ ID NO: 3 0 3 6 gccacagctgattgaggtg 1219 12 38 SEQ ID NO: 4365caccaaaaaccccaatggc 11248 112671 4 SEQ ID NO: 3037 tcactttacaagccttggt 1248 12 67 SEQ ID NO: 4366accagatgctgaacagtga 8148 81671 4 SEQ ID NO: 30 3 8 cccttctgatagatgtggt 1332 1351 SEQ ID NO: 367accacttacagctagaggg 10824 108431 4 SEQ ID NO: 30 3 9gtcacctacctggtggccc 1349 1368 SEQ ID NO: 368gggcgacctaagttgtgac 3439 34581 4 296 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 30 4 0 ccttgtatgcgctgagcca 1440 1459 SEQ ID NO:4369tggctggtaacctaaaagg 5586 56051 4 SEQ ID NO: 3041 gacaaaccctacagggacc 1480 14 9 9 SEQ !D NO:437Oggtcctttatgattatgtc 12355 123741 4 SEQ ID NO: 3042 tgctaattacctgatggaa 1516 1535SEQ ID NO:4371 tcccaaaagcagtcagca 9938 99571 4 SEQ ID NO: 3043 tgactgcactggggatgaa 1546 15 6 5 SEQ ID NO:4372tcaggtccatgcaagtca 10917 109361 4 SEQ ID NO: 3044 actgcactggggatgaaga 1548 15 6 7 SEQ ID NO:4373 tcttgaacacaaagtcagt 6007 60261 4 SEQ ID NO: 30 4 5 latgaagattacacctattt 1560 15 7 9 SEQ ID NO: 4374aaatgaaagtaaagatcat 8118 81371 4 SEQ ID NO: 30 4 6 accatggagcagttaactc 1610 1629 SEQ ID NO: 4375gagtaaaccaaaacttggt 9024 90431 4 SEQ ID NO: 3047gcagttaactccagaactc 1618 16 37 SEQ ID NO: 4376gagttactgaaaaagctgc 13727 137461 4 SEQ ID NO: 30 4 8 cagaactcaagtcttcaat 1629 1 64 8 SEQ ID NO: 4377attggatatccaagatctg 1933 19521 4 SEQ ID NO: 30 4 9 caggctctgcggaaaatgg 1703 1 72 2 SEQ ID NO:4378ccatgacctccagctcctg 2485 25041 4 SEQ ID NO: 30 5 0 ccaggaggttcttcttcag 1738 1 75 7 SEQ ID NO:4379ctgaaatacaatgctctgg 5519 55381' 4 SEQ ID No: 3051 ggttcttcttcagacttic 1744 1 7 63 SEQ ID NO: 4380 gaaaaacttggaaacaacc 4439 44581 4 SEQ ID NO: 3052 ccttgatgatgcttct 1759 1778 SEQ ID NO: 4381 agaatccagatacaagaaa 6893 69121 4 SEQ ID NO: 30 5 3 ggagataagcgactggctg 1781 1 80 0 SEQ ID NO:4382cagcatgcctagtttctcc 9952 99711 4 SEQ ID NO: 3 0 5 4gctgcctatcttatgttga 1796 1 8 15 SEQ ID NO:4383 tcaatatcaaaagcccagc 12045 120641 4 SEQ ID NO: 30 5 5 actttgtggcttcccatat 1890 1 90 9 SEQ ID NO: 4384atatctggaaccttgaagt 10737 107561 4 SEQ ID NO: 30 5 6 1gccaatatcttgaactcag 1910 1 92 9 SEQ ID NO: 4385ctgaactcagaaggatggc 14000 140191 4 SEQ ID NO: 3057aatatcttgaactcagaag 1913 1 93 2 SEQ ID NO: 4386 Ctccattctgaatatatt 13378 133971 4 SEQ ID NO: 3058 ctcagaagaattggatatc 1924 1 94 3 SEQ ID NO: 438 gataaaagattactttgag 7273 72921 4 SEQ ID NO: 3059 aagaattggatatccaaga 1929 1 94 8 SEQ ID NO: 4388 tcttcaatttattcttctt 13825 138441 4 SEQ ID NO: 3060 agaattggatatccaagat 1930 1 94 9 SEQ ID NO: 4389 atcttcaatttattcttct 13824 138431 4 SEQ ID NO: 3061 tggatatccaagatctgaa 1935 1 95 4 SEQ ID NO:4390 ttcacataccagaattcca 8325 83441 4 SEQ ID NO: 30 6 2 atatccaagatctgaaaaa 1938 1 95 7 SEQ ID NO: 4391 taaccagtcagatat 10185 102041 4 SEQ ID NO: 3063tatccaagatctgaaaaag 1939 1 95 8 SEQ ID NO: 4392ctttttaaccagtcagata 10184 102031 4 SEQ ID NO: 30 64 caagatctgaaaaagttag 1943 1 96 2 SEQ ID NO: 4393ctaaattcccatggtcttg 4973 49921 4 SEQ ID NO: 3065 aagatctgaaaaagttagt 1944 1 9 6 3 SEQ ID NO: 4394actaaattcccatggtctt 4972 49911 4 SEQ ID NO: 3066tgaaaaagttagtgaaaga 1950 1 96 9 SEQ ID NO: 4395tctttctcgggaatattca 10630 106491 SEQ ID NO: 3067tccaactgtcatggacttc 1990 2009 SEQ ID NO:4396gaagcacatatgaactgga 13945 139641 4 SEQ ID NO: 3068 cagaaaattctctcggaa 2007 2026 SEQ ID NO: 4397 cctttaacaattcctga 9501 95201 4 SEQ ID NO: 3069 ccatcacttgacccagc 2052 2071 SEQ ID NO: 43981gctgacatagggaatggaa 8441 8460 1 4 SEQ ID NO: 3070 cccagcctcagccaaaata 2065 2084 SEQ ID NO: 4399 attctatccaagattggg 7820 78391 4 SEQ ID NO: 3071 agcctcagccaaaatagaa 2068 2087,SEQ ID NO: 4400tctatccaagattgggct 7822 78411 4 SEQ ID NO: 3 0 72 atettatatttgatccaaa 2091 2 1 10 SEQ ID NO: 4401 tttgaaaaacaaagcagat 11821 118401 4 SEQ ID NO: 3073 cttatatttgatccaaat 2092 2 11 1 SEQ ID NO: 4402 attttttgcaagttaaaga 14019 140381 4 SEQ ID NO: 3 0 74 cttcctaaagaaagcatgc 2117 2 13 6 SEQ ID NO:4403gcatggcattatgatgaag 3614 36331 4 SEQ ID NO: 3 0 75 ctaaagaaagcatgctgaa 2121 2140SEQ ID NO:4404ttcagggtgtggagtttag 5694 57131 4 SEQ ID NO: 3076 aaagaaagcatgctgaaa 2122 2141 SEQ ID NO: 4405 tttcttaaacattccttta 9490 95091 4 SEQIDNO:3077gagattggcttggaaggaa 2183 2 2 02 SEQ ID NO:4406ttccctccattaagttctc 11709 117281 4 SEQ ID NO: 3078 tttgagccaacattggaa 2206 2225 SEQ ID NO: 4407 ttccaatgaccaagaaaag 11068 110871 4 SEQ ID NO: 3 0 79cagacagtgtcaacaaagc 2253 2272 SEQ ID NO: 4408 gcttactggacgaactctg 6142 6161 1 4 SEQ ID NO: 3 0 80 cagtgtcaacaaagctttg 2257 2276 SEQ ID NO: 4409 caaattcctggatacactg 9857 98761 4 SEQ ID NO: 308lagtgtcaacaaagctttgt 2258 2277 SEQ ID NO: 4410 acaagaatacgtctacact 4359 43781 4 SEQ ID NO: 30 82 ctgatggtgtctctaaggt 2298 2 3 17 SEQ ID NO: 4411 acctcggaacaatcctcag 3333 33521 4 SEQ ID NO: 3083tgatggtgtctctaaggtc 2299 2318 SEQ ID NO: 4412gacctgcgcaacgagatca 8831 88501 4 SEQ ID NO: 30 84 aaacatgagcaggatatgg 2351 2370 SEQ ID NO: 4413ccatgatctacatttgttt 6796 68151 4 SEQ ID NO: 3085 gaagctgattaaagatttg 2395 2414 SEQ ID NO: 4414 caaaaacattttcaacttc 5287 5306 1 4 SEQ ID NO: 3086aaagatttgaaatccaaag 2405 2 4 24 1SEQ ID NO: 4415ctttaagttcagcatcttt 7614 763311 4 297 WO 2004/091515 PCT/US2004/011255 EQIDNO:3087gatgggtgcccgcactctg 2518 2 5 3 7 SEQ ID NO:44161cagatttgaggattccatc 7983 80021 4 SEQ ID NO: 30881gggatcccccagatgattg 2540 2 5 59 SEQ ID NO:4417 caatcacaagtcgattccc 9083 91021 4 SEQ ID NO: 3089 ttttCttcactacatcttc 2593 2 6 12 SEQ ID NO: 4418gaagtgtcagtggcaaaaa 10382 104011 4 SEQ ID NO: 3090 tcttcactacatcttcatg 2596 2 6 15 SEQ ID NO:4419catggcattatgatgaaga 3615 36341 4 SEQ ID NO: 3091 acatcttcatggagaatg 2603 2 6 2 2 SEQ ID NO:4420 cattatggaggcccatgta 9445 94641 4 SEQ ID NO: 3092 ttcatggagaatgcctttg 2609 2 6 2 8 SEQ ID NO:4421caaaatcaactttaatgaa 6607 66261 4 SEQ ID NO: 3093 tcatggagaatgcctttga 2610 2 6 2 9 SEQ ID NO:4422 tcaacacaatcttcaatga 13116 131351 4 SEQID NO: 309tgaactccccactggag 2624 2 6 4 3 SEQ ID NO:4423ctccccaggacctttcaaa 9842 98611 4 SEQ ID NO: 3095 tgaactccccactggagc 2625 2644SEQ ID NO:4424 gctccccaggacctttcaa 9841 98601 4 SEQ ID NO: 3096 tgaactccccactggagct 2626 2645SEQ ID NO:44251agctccccaggacctttca 9840 98591 4 SEQ ID NO: 3097 cactggagctggattacag 2635 2654SEQ ID NO:4426 ctgtttctgagtcccagtg 9344 93631 4 SEQ ID NO: 3098actggagctggatacagt 2636 2655SEQ ID NO:4427actgtttctgagtcccagt 9343 93621 4 SEQ ID NO: 3099agttgcaaatatcttcatc 2652 2671 SEQ ID NO:4428gatgatgccaaaatcaact 6599 66181 4 SEQ ID NO: 3100gttgcaaatatcttcatct 2653 2 6 7 2 SEQ ID NO:4429agatgatgccaaaatcaac 6598 66171 4 SEQ ID NO: 3 10 1 aaatatcttcatctggagt 2658 2 6 7 7 SEQ ID NO:4430actcagaaggatggcattt 14004 140231 4 SEQDNO: 3102 aaaactggaagtagccaa 2703 2 7 2 2 SEQ ID NO:4431tggttacaggaggcttta 7600 76191 4 SEQ ID NO: 3103ggctgaactggtggcaaaa 2728 2 7 4 7 SEQ ID NO: 4432 cttttcagcccagcc 9228 92471 4 SEQ ID NO: 3104tgtggagtttgtgacaaat 2758 2777 SEQ ID NO: 4433attttcaagcaaatgcaca 8538 85571 4 SEQ ID NO: 3105tgtgacaaatatgggcat 2766 2785SEQ ID NO: 44341atgcgtctaccttacacaa 9521 95401 4 SEQ ID NO: 3106atgaacaccaacttcttcc 2819 2 8 38 SEQ ID NO: 4435ggaagctgaagtttatcat 2877 28961 4 SEQ ID NO: 310 cttccacgagtcgggtctg 2833 2 85 2 SEQ ID NO: 4436cagagctatcactgggaag 5235 52541 4 SEQ ID NO: 310g gagtcgggtctggaggctc 2840 2859 SEQ ID NO: 4437 gagcttactggacgaactc 6140 61591 4 SEQ ID NO: 3 10 gcctaaaagctgggaagctg 2866 2 88 5 SEQ ID NO:4438cagcctccccagccgtagg 12120 121391 4 SEQ ID NO: 3110 agctgggaagctgaagttt 2872 2891 SEQ ID NO: 4439 aaactgttaatttacagct 5463 54821 4 EQ ID NO: 3111 ccagattagagctggaact 3114 3 13 3 1SEQ ID NO: 4440 agtttccggggaaacctgg 12726 127451 4 SEQ ID NO: 3112 ggataccctgaagtttgta 3208 3 2 2 7 SEQ ID NO: 4441 acagtattctgaaaatcc 8393 84121 4 SEQID NO: 31 1 3ctgaggctaccatgacatt 3252 3271 SEQ ID NO: 4442 aatgagctcatggcttcag 3817 38361 4 3EQ ID NO: 3114 gtccagtgaagtccaaat 3297 3316SEQ ID NO: 4443attttgagaggaatcgaca 6357 63761 4 SEQ ID NO: 3115aattccggattttgatgtt 3313 3 3 32 SEQ ID NO:4444aacacatgaatcacaaatt 8938 89571 4 SEQ ID NO: 3116 itccggattttgatgttga 3315 3334 SEQ ID NO: 4445 tcaaaacgagcttcaggaa 13207 132261 4 SEQ ID NO: 3117 cggaacaatcctcagagtt 3337 3356 SEQ ID NO: 4446aacttgtacaactggtccg 4211 42301 4 SEQ ID NO: 3118 cctcagagttaatgatga 3345 3 3 64 SEQ ID NO: 444 catcaattggttacagga 7593 76121 4 SEQ ID NO: 3119 ctcaccctggacattcaga 3392 34 1 1 SEQ ID NO: 4448tctgcagaacaatgctgag 12439 124581 4 SEQ ID NO: 3120 cattcagaacaagaaaatt 3403 34 2 2 ,SEQ ID NO: 4449aattgactttgtagaaatg 8104 81231 4 SEQ ID NO: 3121 actgaggtcgccctcatgg 3422 3441 SEQ ID NO: 4450 coatgcaagtcagcccagt 10924 109431 4 SEQ ID NO: 3122 atttccataccccgttt 3486 3 5 0 5 SEQ ID NO: 4451 aaactgcctatattgataa 13880 138991 4 SEQ ID NO: 31231gtttgcaagcagaagccag 3501 3 5 2 0 SEQ ID NO: 4452ctggacttctcttcaaaac 5408 54271 4 SEQ ID NO: 3124 gcaagcagaagccaga 3502 3521 SEQ ID NO: 4453 ctgggtgtcgacagcaaa 5272 52911 4 EQ ID NO: 3125 tgcaagcagaagccagaa 3503 3 5 2 2 SEQ ID NO: 4454 ttctgggtgtcgacagcaa 5271 52901 4 SEQ ID NO: 3126ctgctctccaaatggact 3554 3 5 7 3 SEQ ID NO:4455agtcaagattgatgggcag 4567 45861 4 SEQ ID NO: 3127 gctacagcttatggctcc 3577 3596SEQ ID NO:4456ggaggctttaagttcagca 7609 76281 4 SEQ ID NO: 3128 acagcttatggctccacag 3581 3 6 0 0 SEQ ID NO: 457 ctgtatagcaaattcctgt 5897 59161 4 SEQID NO: 3129 ttccaagagggtggcatg 3600 3 6 19 SEQ ID NO: 4458catggacttcttctggaaa 8877 88961 4 SEQ ID NO: 3130,caagagggtggcatggca 3603 3 62 2 SEQ ID NO: 4459 gcccagcaagcaagttgg 9361 93801 4 3EQ ID NO: 3131 9tggcatggcattatgatg 3611 3630 SEQ ID NO: 4460 catccttaacaccttccac 8071 80901 4 3EQ 1D NO: 3132tgatgaagagaagattgaa 3625 36 4 4 SEQ ID NO: 461tcactgttcctgaaatca 7871 78901 4 3EQ ID NO: 3133gaagagaagattgaatttg 3629 36 4 8 1SEQ ID NO: 4462 caaaaacattttcaactc 5287 53061 4 298 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3134gagaagattgaatttgaat 3632 3651SEQ ID NO:4463attcataatcccaactctc 8278 82971 4 SEQ ID NO: 3135tttgaatggaacacaggca 3644 36631SEQ ID NO:4464tgcctttgtgtacaccaaa 11236 112551 4 SEQ ID NO: 3 1 3 6 aggcaccaatgtagatacc 3658 3 6 7 7 SEQ ID NO: 4465ggtaacctaaaaggagcct 5591 56101 4 SEQ ID NO: 3137caaaaaaatgacttccaat 3676 3695SEQ ID NO:4466attgaagtacctacttttg 8366 83851 4 SEQ ID NO: 3138aaaaaaatgactccaatt 3677 3696SEQ ID NO:4467aattgaagtacctactttt 8365 83841 4 SEQ ID NO: 3139aaaaaatgacttccaattt 3678 3 6 9 7 SEQ ID NO:4468aaatccaatctcctctttt 8406 84251 4 SEQ ID NO: 3 1 4 0 cagagtccctcaaacagac 3760 3779SEQ ID NO:4469gtctgtgggattccatctg 4090 41091 4 SEQ ID NO: 314 1 aaattaatagttgcaatga 3803 3 8 2 2 SEQ ID NO:4470tcataagttcaatgaattt 13186 132051 4 SEQ ID NO: 3142tcaacctccagaacatgg 3899 3918 SEQ ID NO: 4471 ccattgaccagatgctgaa 8142 81611 4 SEQ ID NO: 3143tgggattgccagacttcca 3915 3934SEQ ID NO: 4472tggaaatgggcctgcccca 8903 89221 4 SEQ ID NO: 3 14 4 cagtttgaaaattgagatt 3994 4 0 1 3 SEQ ID NO:4473aatcacaactcctccactg 9541 95601 4 SEQ ID No: 314 5 gaaaattagattccttig 4000 4 0 1 9 SEQ ID NO: 4474caaaactaccacacatttc 13694 137131 4 SEQ ID NO: 3146 gccttttggtggcaaa 4015 4034 SEQ ID NO: 4475 tttgagaggaatcgacaaa 6359 63781 4 SEQ ID NO: 3147ctccagagatctaaagatg 4036 4 0 5 5 SEQ ID NO:4476catcaattggttacaggag 7594 76131 4 SEQ ID NO: 3148tctaaagatgttagagact 4045 4064SEQ ID NO:4477agtccttcatgtccctaga 10033 100521 4 SEQ ID NO: 3 14 gctgtgggattCCatctgcc 4092 4111 SEQ ID NO: 4478ggcattttgaaaaaaacag 9735 97541 4 SEQ ID NO: 3 1 50atctgccatctcgagagtt 4104 4123SEQ ID NO:4479aactctcaaaccctaagat 8556 85751 4 SEQ ID NO: 3151totcgagagttccaagtcc 4112 4131 SEQ ID NO:4480ggacattcctctagcgaga 8215 82341 4 SEQ ID NO: 3 1 52 agtcctacttttaccatt 4126 4 14 5 SEQ ID NO: 4481aatgaatacagccaggact 6086 61051 4 SEQ ID NO: 3 1 53 acttttaccattcccaagt 4133 4152 SEQ ID NO: 4482actttgtagaaatgaaagt 8109 81281 4 SEQIDNo:3154cattcccaagttgtatcaa 4141 4 1 60 SEQD NO:4483tgaaggacttcaggaatg 12009 120281 4 SEQ ID NO: 3 1 5 5 accacatgaaggctgactc 4284 4303SEQ ID NO:4484gagtaaaccaaaacttggt 9024 90431 4 SEQ ID NO: 3156 tttcctacaatgtgcaagg 4317 43361SEQ ID NO:4485cctttaacaattcctgaaa 9503 95221 4 SEQ ID NO: 3 1 5 7 ctggagaaacaacatatga 4338 4 3 57 SEQ ID NO:4486tcattctgggtctttccag 11035 110541 4 SEQ ID NO: 31 5 8 latcatgtgatgggtctcta 4378 4397 SEQ ID NO: 4487tagaattacagaaaatgat 6565 65841 4 SEQ ID NO: 3 15 9 catgtgatgggtctctacg 4380 4 3 99 SEQ ID NO:4488cgtaggcaccgtgggcatg 12133 121521 4 SEQ ID NO: 3 1 60 1ttctagattcgaatatcaa 4407 4 42 6 SEQ ID NO: 4489 tgatgatgctgtcaagaa 7308 73271' 4 SEQ ID NO: 3161 tggggaccacagatgtctg 4499 4 5 18 SEQ ID NO: 4490cagaattccagcttcccca 8334 83531 4 SEQ ID NO: 3 16 2ctaacactggccggctcaa 4644 4663 SEQ ID NO: 4491 ttgaggctattgatgttag 6984 70031 4 SEQ ID NO: 3163 taacactggccggctcaat 4645 4664 SEQ ID NO: 4492attgaggctattgatgtta 6983 70021 4 SEQ ID NO: 3 1 64aacactggccggctcaatg 4646 4665 SEQ ID NO: 4493 cattgaggctattgatgtt 6982 7001 1 4 SEQ ID NO: 3165ctggccggctcaatggaga 4650 4669 SEQ ID NO: 4494 ctccatctgcgctaccag 12073 120921 4 SEQ ID NO: 3 16 6 agataacaggaagatatga 4713 4 73 2 SEQ ID NO:4495 tcatctcctttcttcatct 10210 102291 4 SEQ ID NO: 3167tccctcacctccacctctg 4745 4 76 4 SEQ ID NO: 4496cagatatatatctcaggga 8184 82031 4 SEQ ID NO: 3 16 8 agctgactttaaaatctga 4818 4837 SEQ ID NO: 4497 tcaggctcttcagaaagct 7930 79491 4 SEQ ID NO: 31 6 gctgactttaaaatctgaca 4820 4839SEQ ID NO: 4498tgtcaagataaacaatcag 8740 87591 4 SEQ ID NO: 3170caagatggatatgaccttc 4873 4892SEQ ID NO:4499gaagtagtactgcatcttg 6843 68621 4 SEQ ID NO: 3171 ctgcgttctgaatatcag 4909 4928SEQ ID NO:4500ctgagtcccagtgcccagc 9350 93691 4 SEQ ID NO: 31 7 2 cgttctgaatatcaggctg 4913 4932 SEQ ID NO: 4 5 0 1 cagcaagtacctgagaacg 8611 86301 4 SEQ ID NO: 31 7 3 aattcccatggtcttgagt 4976 4 99 5 SEQ ID NO:4502actcagatcaaagttaatt 12272 122911 4 SEQ ID NO: 3174tggtcttgagttaaatgct 4984 5003SEQ ID NO:4503 agcacagtacgaaaaacca 10809 108281 4 SEQ ID NO: 3 17 5 1cttgagttaaatgctgaca 4988 5007 SEQ ID NO: 4504 gtccctagaaatctcaag 10042 100611 SEQID NO:3176tgagttaaatgctgacat 4989 5 00 8 SEQ ID NO: 4505 atgtccctagaaatctcaa 10041 100601 4 SEQ ID NO: 3177tgagttaaatgctgacatc 4990 5009 SEQ ID NO: 4506gatggaaccctctccctca 4733 47521 4 SEQ ID NO: 3 17 8 acttgaagtgtagtCtCCt 5094 5 1 13 SEQ ID NO: 4507aggaaactcagatcaaagt 12267 122861 4 SEQ ID NO: 31 7 9 agtgtagtctcctggtgct 5100 5 1 19 SEQ ID NO: 4508agcagccagtggcaccact 12514 125331 4 SEQDNO: 31 8 0 gtgctggagaatgagctga 5114 5 13 3 SEQ ID NO:4509tcagccaggtttatagcac 7734 77531 4 299 WO 2004/091515 PCT/US2004/011255 EQ ID NO: 3181 ctggggcatctatgaaatt 5151 5 1 70 SEQ ID NO: 4510aatttctgattaccaccag 13579 135981 4 SEQID NO: 3182atggccgctcagggaaca 5178 5 19 7 SEQ ID NO: 4511 tgttttttggaaatgccat 8649 86681 4 EQDNO: 3183ttcagtctggatgggaaag 5207 52 2 6 SEQ ID NO:4512ctttgacaggcattttgaa 9727 97461 4 SEQ ID NO: 3184 ccatgattctgggtgtcga 5265 5 2 8 4 SEQ ID NO: 4513 tcgatgcacatacaaatgg 5838 58571 4 SEQ ID NO: 3185aaaacatttcaacftcaa 5289 5 3 0 8 SEQ ID NO 514 ttgatgttagagtgCtttt 6993 70121 4 SEQ ID NO: 318 cttaagctctcaaatgaca 5324 5 3 4 3 SEQ ID NO: 4515 tgtcctacaacaagttaag 7255 72741 4 SEQ ID NO: 3187 aagctctcaaatgacat 5325 5 34 4 SEQ ID NO: 4516atgtcctacaacaagttaa 7254 72731 4 SEQ ID NO: 3188catgatgggctcatatgct 5341 5 3 60 SEQ ID NO: 4517agcatctttggctcacatg 7624 76431 4 EQIDNO: 3189gggctcatatgctgaaat 5346 5 36 5 SEQ ID NO: 4518atttatcaaaagaagccca 12942 129611 4 SEQ ID NO: 3190actggacttcttcaaaa 5407 54 2 6 SEQ ID NO: 4519 ggcaagctatacagt 8380 83991 4 SEQ ID NO: 3191 acttctctcaaaacttga 5412 5431 SEQ ID NO: 4520 caattgggagagacaagt 6504 65231 4 SEQ ID NO: 3192ctgacaagttttataagca 5445 5 4 64 SEQIDNO:4521'gctttgtgagtttatcag 9693 97121 4 SEQ ID NO: 3193aagttttataagcaaactg 5450 5469 SEQ ID NO: 4522cagtcatgtagaaaaactt 4429 44481 4 SEQ ID NO: 3194ctgttaatttacagctaca 5466 5485 SEQ ID NO: 4523tgtactggaaaacgtacag 6388 64071 4 SEQ ID NO: 3195 ttacagctacagccctatt 5474 5493 SEQ ID NO: 4524aatattgatcaatttgtaa 6425 64441 4 SEQ ID NO: 3196tctggtaactactttaaac 5494 5 5 13 SEQ ID NO: 4525gtttgaaaaacaaagcaga 11820 118391 4 SEQ ID NO: 3197 tttaaacagtgacctgaaa 5506 5525 SEQ ID NO: 4526 tttcatttgaaagaataaa 7032 70511 4 SEQ ID NO: 3198 ttaaacagtgacctgaaat 5507 5526 SEQ ID NO: 527atttcaagcaagaacttaa 10434 104531 4 SEQ ID NO: 3199cagtgacctgaaatacaat 5512 5531 SEQ ID NO: 4528attggcgtggagcttactg 6131 61501 4 SEQ ID NO: 3200tgtggctggtaacctaaaa 5584 5 6 03 SEQ ID NO: 4529tgctggagaagccaca 10765 107841 4 SEQ ID NO: 3201 ttatcagcaagctataaag 5657 5676 SEQ ID NO: 4530 ctttgcactatgttcataa 12764 127831 4 SEQ ID NO: 3202ggttcagggtgtggagttt 5692 5 7 1 1 SEQ ID NO: 4531 aaacacctaagagtaaacc 9014 90331 4 SEQ ID NO: 3203 attcagactcactgcattt 5775 5794 SEQ ID NO: 4532 aaatgctgacatagggaat 8437 84561 4 EQDNO:3204ttcagactcactgcatttc 5776 5795SEQ ID NO:4533gaaatattatgaacttgaa 13312 133311 4 SEQ ID NO: 3205tacaaatggcaatgggaaa 5848 5867SEQ ID NO: 4534tttcctaaagctggatgta 11176 111951 4 SEQID NO: 3206gctgtatagcaaatcctg 5896 5 9 15 SEQ ID NO: 435caggtccatgcaagtcagc 10919 109381 4 SEQ ID NO: 3207tgagcagacaggcacctgg 6043 6 0 62 SEQ ID NO: 4536ccagcttccccacatctca 8341 83601 4 SEQ ID NO: 3208 ggcacctggaaactcaaga 6053 6 0 72 SEQ ID NO: 4537 cttcgtgtttcaactgcc 11221 112401 4 SEQ ID NO: 3209 tgaatacagccaggacttg 6088 6 1 07 SEQ ID NO: 4538 caagtaagtgctaggttca 9380 93991 4 SEQIDNo:3210gaatacagccaggacttgg 6089 6 10 8 SEQ ID NO: 539ccaacacttacttgaattc 10668 106871 4 3EQ ID NO: 3211 ctggacgaactctggctga 6147 6166 SEQ ID NO: 4540 tcagaaagctaccttccag 7939 79581 4 3EQ ID NO: 3212tactcagtgagcccat 6201 6220SEQ ID NO:4541latggacttcttctggaaaa 8878 88971 4 3EQID NO: 3213gatgagagatgccgttgag 6241 62 6 0 SEQ ID NO:4542ctcatctcctttcttcatc 10209 102281 4 3EQ ID NO: 3214 aattgttgcttttgtaaag 6277 6 2 9 6 SEQ ID NO: 4543cttttctaaacttgaaatt 9064 90831 4 EQ ID NO: 3215cttttgtaaagtatgataa 6285 6304 SEQ ID NO: 4544tatgaactgaagaaaag 13318 133371 4 EQ ID NO: 3216 gtaaagtatgataaaa 6287 6306 SEQ ID NO: 4545 tttcacattagatgcaaa 8421 84401 4 EQ ID NO: 3217tccattaacctcccatttt 6320 6 33 9 SEQ ID NO:4S46aaaattgatgatatctgga 10727 107461 4 EQ ID NO: 3218 ccattaacctcccattttt 6321 6 34 0 SEQ ID NO: 4547 aaaagggtcatggaaatgg 8893 89121 4 EQ ID NO: 3219cttgcaagaatattttgag 6346 63 6 5 SEQ ID NO: 548ctcaattttgattttcaag 8528 85471 4 EQ ID NO: 32201agaatattttgagaggaat 6352 6371 SEQ ID NO: 549 attccctccattaagttct 11708 117271 4 EQ ID NO: 3221 attatagttgtactggaaa 6380 6 3 9 9 SEQ ID NO: 4550 tttcaagcaagaacttaat 10435 104541 4 EQIDNO: 32229aagcacatcaatattgat 6415 6 4 3 4 SEQ ID NO: 551atcagttcagataaacttc 7999 80181 4 EQ ID NO: 3223acatcaatattgatcaatt 6420 6 4 3 9 SEQ ID NO: 552aattccctgaagttgatgt 11487 115061 4 EQ ID NO: 3224gaaaactcccacagcaagc 6465 6 4 84 SEQIDNO:4553gctttctcttccacatttc 10060 100791 4 EQ ID NO: 3225 ctgaatcatcaattggg 6494 6 5 13 SEQ ID NO: 554 occatttacagatctcag 11371 113901 4 EQ ID NO: 3226 tgaattcattcaattggga 6495 6 5 14 SEQ ID NO: 555 cccatttacagatcttca 11370 113891 4 EQID NO:3227aactgactgctctcacaaa 6540 65591SEQ ID NO:. 556tgaggattccatcagtt 7987 80061 4 300 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3228aaaagtatagaattacaga 6558 6577SEQ ID NO:4557tctggctccctcaactttt 9050 90691 SEQ ID NO: 3229 atcaacttaatgaaaaac 6611 6 6 3 0 SEQ ID NO: 4558gtttattgaaaatattgat 6811 68301 4 SEQ ID NO: 3230 tgatttgaaaatagctatt 6694 6 7 13 SEQ ID NO: 4559aatattattgatgaaatca 6716 67351 4 SEQ ID NO: 3231 atttgaaaatagctattgc 6696 6 7 15 SEQ ID NO:4560gcaagaacttaatggaaat 10441 104601 4 SEQ ID NO: 3232attgctaatattattgatg 6710 6 72 9 1SEQ ID NO: 4561 catcacactgaataccaat 10159 101781 4 SEQ ID No: 3233gaaaaattaaaaagtcttg 6737 6 75 6 SEQ ID NO:4562caagagcttatgggatttc 11161 111801 4 SEQ ID NO: 3234actatcatatccgtgtaat 6762 6781 SEQ ID NO:4563attactttgagaaattagt 7281 73001 4 SEQ ID NO: 3235 attgattttaacaaaagt 6823 6842 SEQ ID NO: 4564acttgacttcagagaaata 11404 114231 4 SEQID No: 3236ctgcagcagcttaagagac 6914 6 9 3 3 SEQ ID NO:4565gtcttcagtgaagotgcag 10699 107181 4 SEQ ID NO: 3237aaaacaacacattgaggct 6973 6 9 9 2 SEQ ID NO: 4566agcctcacctcttactttt 10571 105901 4 SEQ ID NO: 3238 gagcatgtcaaacactt 7059 7078 SEQ ID NO:4567aagtagctgagaaaatcaa 7104 71231 4 SEQ ID NO: 3239gaagtagctgagaaaa 7100 7 11 9 SEQ ID NO: 4568 ttttcacattagatgcaaa 8421 84401 4 SEQIDNO: 3240tagtagagttggcccacc 7199 7 2 1 8 SEQID NO:4569gtggactcttgotgctaa 7776 77951 4 SEQ ID NO: 3241 gaaggagactattcagaa 7227 7 24 6 SEQ ID NO: 4570 ttctcaattttgattttca 8526 85451 4 SEQ ID NO: 3242gagactattcagaagctaa 7232 7251 SEQ ID NO: 4571 tagccacagctctgtctc 10301 103201 4 SEQ ID NO: 32 4 3aattagttggattattga 7293 7312SEQ ID NO:4572 caagaagcttaatgaatt 7320 73391 4 SEQ ID NO: 3244 gcttaatgaattatctttt 7327 7 34 6 SEQ ID NO: 4573aaaacgagcttcaggaagC 13209 132281 4 SEQ ID NO: 3245 ttaacaaattccttgacat 7365 7 3 84SEQ ID NO:4574atgtcctacaacaagttaa 7254 72731 4 SEQ ID NO: 32 4 6 aaaftaaagtcatttgatt 7394 74 13 SEQ ID NO:4575aatcctttgacaggcattt 9723 97421 4 SEQ ID NO: 32 4 7 gactcaatggtgaaattca 7464 7483SEQ ID NO:4576 gaaattcaatcacaagtc 9076 90951 4 SEQ ID NO: 32 4 8 gaaattcaggctctggaac 7475 7494SEQ ID NO:4577gttctcaattttgattttc 8525 85441 4 SEQ ID NO: 32 4 9 actaccacaaaaagctgaa 7492 7 5 1 1 SEQ ID NO: 4578ttcaggaactattgctagt 10645 106641 4 SEQ ID NO: 3 250 ccaaaataaccttaatcat 7578 75 9 7 SEQ ID NO: 4579atgatttccctgacctgg 10950 109691 4 SEQ ID NO: 3251 aaataaccttaatcatcaa 7581 7600 SEQ ID NO: 4580 ttgaagtaaaagaaaattt 10749 107681 4 SEQ ID NO: 3252 tttaagttcagcatCtttg 7615 7634SEQ ID NO: 4581 caaatctggatttcttaaa 9480 94991 4 SEQ ID NO: 32 5 3 caggtttatagcacacttg 7739 7758 SEQ ID NO: 458 caagggttcactgttcctg 7865 78841 4 SEQ ID NO: 3254gttcactgttcctgaaatc 7870 7889 SEQ ID NO: 4583 gattctcagatgagggaac 8922 89411 SEQ ID NO: 3255cactgttcctgaaatcaag 7873 7 8 92 SEQ ID NO:45841cttgaacacaaagtcagtg 6008 60271 4 SEQ ID NO: 3 2561actgttcctgaaatcaaga 7874 7893 SEQ ID NO: 458 cttgaacacaaagtcagt 6007 60261 4 SEQ ID NO: 3 2 5 7 gcctgcctttgaagtcagt 7909 7928 SEQ ID NO: 4586 actgttgactcaggaaggc 12580 125991 4 SEQ ID NO: 3258 taacagatttgaggattcc 7980 7 9 99 SEQ ID NO: 458 ggaagcttctcaagagtta 13222 132411 4 SEQ ID NO: 3 259 gttttccacaccagaattt 8050 8069 SEQ ID NO: 4588aaatttctctgctggaaac 9418 94371 4 SEQ ID NO: 3260tcagaaccattgaccagat 8136 8155SEQ ID NO:4589atctgcagaacaatgctga 12438 124571 4 SEQIDNO: 3261tagcgagaatcaccctgcc 8226 8 24 5 SEQ ID NO:4590ggcagcttctggcttgcta 12301 123201 4 SEQ ID NO: 3262ccttaatgattttcaagtt 8299 8 3 1 8SEQ ID NO: 4591 aactgttgactcaggaagg 12579 125981 4 SEQ ID NO: 3263 acataccagaattccagct 8328 8 34 7 SEQ ID NO: 4592 agctgccagtccttcatgt 10026 100451 4 SEQ ID NO: 3264aatgctgacatagggaatg 8438 84 5 7 SEQ ID NO:4593cattaatcctgccatcatt 10005 100241 4 SEQ ID NO: 3265atgctgacatagggaatgg 8439 8458SEQ ID NO:45941ccatttgagatcacggcat 9245 92641 4 SEQ ID NO: 3266 aaccacctcagcaaacgaa 8458 8 4 7 7 SEQ ID NO: 4595 cgttttccattaaggtt 9291 93101 4 SEQ ID NO: 3267 agcaggtatcgcagCttcc 8476 8 4 9 5 SEQ ID NO: 4596 agaagtggccctgaatgct 10972 109911 4 SEQ ID NO: 3268tgcacaactctcaaaccct 8551 8 5 7 0 SEQ ID NO:4597agggaaagagaagattgca 13501 135201 4 SEQ ID NO: 3 2 6 g aggagtcagtgaagttctc 8592 8611 SEQ ID NO: 4598 gagaacttactatcatcct 13788 138071 4 SEQ ID NO: 3270 tggaaatgccattga 8652 8671 SEQ ID NO: 4599 caatgaatttattcaaaa 13194 132131 4 SEQ ID NO: 3271aatggagtgattgtcaaga 8729 8748SEQ ID NO: 4600 cttttcagcccagccatt 9231 92501 4 EQID NO: 3272tcaagataaacaatcagc 8741 8760SEQ ID NO: 4601gctgactttaaaatctgac 4819 48381 4 SEQ ID NO: 32 7 3 tccacaaattgaacatccc 8787 8 8 0 6 SEQ ID NO: 4602gggatttcctaaagctgga 11172 111911 4 SEQ ID NO: 3274 tgaacatccccaaactgg 8795 8814 SEQ ID NO: 4603 ccagtttccagggactcaa 12603 126221 4 301 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3 2 75 acatccccaaactggactt 8799 8 8 1 8 SEQ ID NO:46041aagtcgattcccagcatgt 9090 91091 4 SEQ ID NO: 3276acttctctagtcaggctga 8814 8 8 3 3 SEQ ID NO: 4605 cagatggaaaaatgaagt 11010 110291 4 SEQ ID NO: 3277 tgaatcacaaattagtttc 8944 8 9 6 3 SEQ ID NO: 4606 gaaagtccataatggttca 12817 128361 4 SEQ ID NO: 3278 agaaggaccctcacitcc 8968 8 9 8 7 SEQ ID NO: 4607 ggaagaagaggcagcttct 12292 123111 4 SEQ ID NO: 3279 ttggactgtccaataagat 8988 9 0 0 7 SEQ ID NO: 4608atctaaatgcagtagccaa 11634 116531 4 SEQ ID NO: 32 8 0actgtccaataagatcaat 8992 9011 SEQ ID NO:4609attgataaaaccatacagt 13891 139101 4 SEQ ID NO: 32 8 1 ctgtccaataagatcaata 8993 9 0 12 SEQ ID NO:4610tattgataaaaccatacag 13890 139091 4 SEQ ID NO: 32 8 2 gtttatgaatctggctccc 9041 9 0 60 SEQ ID NO:4611gggaatctgatgaggaaac 12255 122741 4 SEQ ID NO: 32 8 3 atgaatctggctccctcaa 9045 9 06 4 SEQ ID NO: 4612ftgagttgcccaccatcat 11667 116861 4 SEQ ID NO: 32 8 4 ctcaacttttctaaacttg 9059 9 07 8SEQ ID NO:4613caagatcgcagactttgag 11653 116721 4 SEQIDNO: 3285ctaaaggcatggcactgtt 9129 9 14 8 SEQID NO:4614aacagaaacaagcattag 9749 97681 4 SEQ ID NO: 32 8 6 aaggcatggcactgtttgg 9132 9151 SEQ ID NO:4615,ccaagaaaaggcacacctt 11077 110961 4 SEQ ID NO: 3287atccacaaacaatgaaggg 9262 9281 SEQ ID NO:4616ccctaacagatttgaggat 7977 79961 4 SEQ ID NO: 32 8 8 ggaatttgaaagttcgttt 9279 9298 SEQ ID NO:4617 aaacaaacacaggcattcc 9655 96741 4 SEQ ID NO: 32 8 gaataactatgcactgtttc 9332 9351 SEQ ID NO:4618gaaatactgttttcctatt 12836 128551 4 SEQ ID NO: 32 9 0 gaaacaacgagaacattat 9432 9451 SEQ ID NO: 4619ataaactgcaagatttttc 13608 136271 4 SEQ ID NO: 3291 cttgaaaacgacaaagc 9599 9 6 18 SEQ ID NO:4620gctttccaatgaccaagaa 11065 110841 4 SEQ ID NO: 3292ataagaaaaacaaacacag 9648 9667SEQ ID NO:4621 ctgtgctttgtgagtttat 9690 97091 4 SEQ ID NO: 32 9 3 aaaacaaacacaggcattc 9654 9 67 3 SEQ ID NO:4622gaatttgaaagttcgtttt 9280 92991 4 SEQ ID NO: 3294 gcattccatcacaaatcct 9667 9 68 6 SEQ ID NO:4623aggaagtggccctgaatgc 10971 109901 4 SEQ ID NO: 3295tttgaaaaaaacagaaaca 9740 9759SEQ ID NO:4624tgttgaaagatttatcaaa 12933 129521 4 SEQ ID NO: 32 9 6 caatgcattagattttgtc 9757 97 7 6 SEQ ID NO: 4625gacaagaaaaaggggattg 10279 102981 4 SEQ ID NO: 3297caaagctgaaaaatctcag 9817 98 3 6 SEQ ID NO:4626ctgagaacttcatcatttg 11438 114571 4 SEQ ID NO: 3298 ectggatacactgttccag 9863 9882 SEQ ID NO:4627ctggacttctctagtcagg 8810 88291 4 SEQ ID NO: 32 9 ggttgaagtgtctccattca 9890 99 0 9 SEQ ID NO:4628tgaatctggctccctcaac 9046 90651 4 SEQ ID NO: 3300tttctccatcctaggttct 9964 99 8 3 SEQ ID NO:4629agaatccagatacaagaaa 6893 69121 4 SEQ ID NO: 3301 ttctccatcctaggttctg 9965 9984SEQ ID NO:4630cagaatccagatacaagaa 6892 69111 4 SEQ ID NO: 3302tcattagagctgccagtcc 10019 10038SEQ ID NO:4631,ggacagtgaaatattatga 13305 133241 4 SEQ ID NO: 3303tgctgaactttttaaccag 10177 1 0 19 6 SEQ ID NO:4632ctggatgtaaccaccagca 11186 112051 4 SEQ ID NO: 33 04ctcctttcttcatcttcat 10214 10233 SEQ ID NO: 4633atgaagcttgctccaggag 13772 137911 4 SEQ ID NO: 330tgtcattgatgcactgcag 10234 1 02 5 3 SEQ ID NO:4634ctgcgctaccagaaagaca 12080 120991 4 SEQ ID NO: 3306tgatgcactgcagtacaaa 10240 10 2 5 9 SEQ ID NO:4635tttgagttgcccaccatca 11666 116851 4 SEQ ID NO: 3307agctctgtetctgagcaac 10309 10328 SEQ ID NO: 4636gttgaccacaagcttagct 10547 105661 4 SEQ ID No: 3308agccgaaattccaattttg 10408 10 4 2 7 SEQ ID NO:4637caaagctggcaccagggct 13971 139901 4 SEQ ID NO: 3309 gagaatgaatttcaagc 10424 10 4 4 3 SEQ ID NO: 638gcttcaggaagcttctcaa 13216 132351 4 SEQ ID NO: 33 10 aaactactgtctcftcct 10469 10488SEQID NO: 639aggaaggccaagccagttt 12591 126101 4 SEQ ID NO: 3311 acttttccattgagtcat 10583 10 6 02 SEQID NO: 640atgattatgtcaacaagta 12363 123821 4 SEQ ID NO: 3312tcaggtccatgcaagtcag 10918 10 9 3 7 SEQID NO: 641ctgacatcttaggcactga 5001 50201 4 SEQ ID NO: 3313atgcaagtcagcccagttc 10926 10 94 5 SEQ ID NO: 642gaactcagaaggatggcat 14002 140211 4 SEQ ID NO: 3314 gaatgctaacactaagaa 10983 1 10 02 SEQ ID NO: 4643 ctcaattttgattttca 8526 85451 4 SEQIDNO:3315agaagatcagatggaaaaa 11004 1 10 23 SEQID NO: 4644ttctaaatggaacttct 12173 121921 4 SEQIDNO: 3316ggctattcattctccatcc 11264 1 12 83 SEQ ID NO:4645ggatctaaatgcagtagcc 11632 116511 4 SEQ ID NO: 331 aaagttttggctgataaat 11288 1 13 07 SEQ ID NO: 4646 atttcttaaacattccttt 9489 95081 4 SEQ ID NO: 3 3 1 8 agttttggctgataaattc 11290 1 13 09 SEQ ID NO: 4647gaatctggctccctcaact 9047 90661 4 SEQ ID NO: 3 3 1 9 ctgggctgaaactaaatga 11316 1 13 35 SEQ ID NO:4648tcattctgggtctttccag 11035 110541 4 SEQ ID NO: 3320cagagaaatacaaatctat 11413 114321SEQ ID NO:4649atagcatggactctctg 8873 88921 4 S 3321gaggtaaaattccctgaag 11480 1 14 99 SEQ ID NO:4650cttctggcttgctaacctc 12306 123251 4 302 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3322cttttttgagataaccgtg 11545 1 15 6 4 SEQ ID NO:4651cacggagttactgaaaaag 13723 137421 4 SEQ ID NO: 3323gctggaattgtcattcctt 11735 1 17 5 4 SEQ ID NO: 4652aaggcatctccacctcagc 12102 121211 4 SEQ ID NO: 33 2 4 gtgtataatgccacttgga 11795 11814SEQ ID NO:4653tccaagatgagatcaacac 13104 131231 4 SEQID NO: 33 2 5 attccacatgcagctcaac 11859 1 18 7 8 SEQ ID NO:4654gttgagaagccccaagaat 6254 62731 4 SEQ ID NO: 3326 gaagaagatggcaaattt 11992 12011 SEQ ID NO: 4655aaattctcttttcttttca 9220 92391 4 SEQ ID No: 332 atcaaaagcccagcgttca 12050 12069 SEQ ID NO: 4656 tgaaagtcaagcatctgat 12669 126881 4 SEQ ID NO: 3328gtgggcatggatatggatg 12143 12162SEQ ID NO:4657catccttaacaccttccac 8071 80901 4 SEQ ID NO: 33 2 gaaatggaacttctactaca 12179 12198SEQ ID NO:4658tgtaccataagccatattt 10088 101071 4 SEQ ID NO: 333 0 aaaaactcaccatattcaa 12219 12238 SEQ ID NO: 4659 gatgttagagtgctttt 6993 70121 4 SEQ ID NO: 3331 ctgagaagaaatctgcaga 12428 12 44 7 SEQ ID NO: 4660tctgcacagaaatattcag 13447 134661 4 SEQ ID NO: 3332acaatgctgagtgggttta 12447 12466 SEQ ID NO: 4661 taaatggagtctttattgt 14086 141051 4 SEQ ID NO: 33 3 3 caatgctgagtgggtttat 12448 12 46 7 SEQ ID NO: 4662ataaatggagtctttattg 14085 141041 4 SEQ ID NO: 3334taggcaaattgatgatat 12477 12496SEQ ID NO:4663atattgtcagtgcctctaa 13392 134111 4 SEQ ID NO: 333 5 ataaactaatagatgtaat 12897 12 9 16 SEQ ID NO:4664attactatgaaaaatttat 13641 136601 4 SEQ ID NO: 33 3 6 ccaactaatagaagataac 13039 13 05 8 SEQ ID NO: 4665gttattttgctaaacttgg 14052 140711 4 SEQ ID NO: 3337taattatatccaagatga 13095 13 1 14 SEQ ID NO: 4666 tcatcctctaattttttaa 13800 138191 4 SEQ ID NO: 3338taaattgttgaaagaaa 13151 13 17 0 SEQ ID NO: 4667ttcatttgaaagaataaa 7032 70511 4 SEQ ID NO: 33 3 9 aagttcaatgaatttattc 13190 13 20 9 SEQ ID NO:4668gaataccaatgctgaactt 10168 101871 4 SEQ ID NO: 3340 gaagaaaagatagtcag 13326 13345 SEQ ID NO: 4669ctgagagaagtgtcttcaa 12407 124261 4 SEQ ID NO: 33411acttccattctgaatatat 13377 13 39 6 SEQ ID NO:4670 atatctggaaccttgaagt 10737 107561 4 SEQ ID NO: 334 2 1cacagaaatattcaggaat 13451 134 7 0 SEQ ID NO: 4671 attccctgaagttgatgtg 11488 115071 4 SEQ ID NO: 334 3 1ccattgcgacgaagaaaat 13560 1 3 57 9 SEQ ID NO: 4672atttttattcctgccatgg 10103 101221 4 SEQ ID NO: 3344 ataaactgcaagattttt 13607 13626 SEQ ID NO: 4673aaaattcaaactgcctata 13873 138921 4 SEQIDNO: 334 ctgattactatgaaaaat 13637 1 3 65 6 SEQ ID NO:4674atttgtaagaaaatacaga 6436 64551 4 SEQ ID NO: 3346 gagttactgaaaaagctg 13726 13745 SEQ ID NO: 4675cagcatgcctagtttetcc 9952 99711 4 SEQ ID NO: 3347tgaagcttgctccaggaga 13773 1 3 79 2 SEQ ID NO:4676tctcctttcttcatcttca 10213 102321 4 SEQ ID NO: 3348 gaactggacctgcaccaa 13955 1 3 97 4 SEQ ID NO: 4677 ttggtagagcaagggttca 7856 78751 4 SEQ ID NO: 3349tgctaaacttgggggagg 14058 14 07 7 SEQ ID NO:4678cctcctacagtggtggcaa 4230 42491 4 SEQ ID NO: 3 3 5 0 1gattcgaatatcaaattca 4412 4431 SEQ ID NO: 4679 tgaaaacgacaaagcaatc 9603 96223 3 SEQ ID NO: 3351 atttgtttgtcaaagaagt 4551 4570 SEQ ID NO: 4680 acttttctaaacttgaaat 9063 90823 3 SEQ ID NO: 3352 ctcggttgctgccgctga 33 5 2 SEQ ID NO: 4681 tcagcccagccatttgaga 9236 92552 3 SEQ ID NO: 3353 gctgaggagcccgcccagc 47 6 6 SEQ ID NO: 4682gctggatgtaaccaccagc 11185 112042 3 SEQ ID NO: 3 3 54 ctggtctgtccaaaagatg 227 2 4 6 SEQ ID NO:4683catcagaaccattgaccag 8134 81532 3 SEQ ID NO: 3 3 55ctgagagttccagtggagt 291 3 1 0 SEQ ID NO:4684actcaatggtgaaattcag 7465 74842 3 SEQ ID NO: 3 35 6 cagtgcaccctgaaagagg 404 4 2 3 SEQ ID NO: 4685cctcacttcctttggactg 8977 89962 3 SEQIDNO: 3357ctctgaggagtttgctgca 472 4 9 1 SEQID NO: 686 tgcaaacttgacttcagag 11399 114182 3 SEQ ID NO: 3 35 8 acatcaagaggggcatcat 582 6 0 1 SEQ ID NO: 4687 atgacgttcttgagcatgt 7050 70692 3 SEQ ID NO: 3 35 9 ctgatcagcagcagccagt 830 8 4 9 SEQ ID NO:4688actggacttctctagtcag 8809 88282 3 SEQ ID NO: 3360ggacgctaagaggaagcat 865 8 84 SEQ ID NO:4689atgcctacgttccatgtcc 11354 113732 3 SEQ ID NO: 3361 agctgttttgaagactctc 1087 1 10 6 SEQ ID NO:4690gagaagtgtcttcaaagct 12411 124302 3 SEQ ID NO: 3362tgaaaaaactaaccatctc 1113 1 132 SEQ ID NO: 4691 gagatcaacacaatcttca 13112 131312 3 SEQ ID NO: 3363 ctgagctgagaggcctcag 1176 1 19 5 SEQ ID NO: 4692 ctgaattactgcacctcag 3035 30542 3 SEQIDNO:3364tgaaacgtgtgcatgccaa 1311 13 30 SEQ ID NO: 4693ttggtagagcaagggttca 7856 78752 3 SEQ ID NO: 3365ccttgtatgcgctgagcca 1440 14 59 SEQ ID NO:4694tggcactgtttggagaagg 9138 91572 3 SEQ ID NO: 3 36 6 aggagctgctggacattgc 1500 15 19 SEQ ID NO:4695gcaagtcagcccagttcct 10928 109472 3 SEQ ID NO:,3367atttgattctgcgggtcat 1575 15 94 SEQ ID NO: 4696atgaaaccaatgacaaaat 7428 74472 3 SEQ ID NO: 3368 ccagaactcaagtcttca 1627 16 46 1SEQ ID NO: 469 gaaatacaatgctctgga 5520 5539 2 3 303 WO 2004/091515 PCT/US2004/011255 SEQ ID No: 3369ggttcttcttcagactttc 1744 1 7 63 SEQ ID NO:4698gaaataccaagtcaaaacc 10455 104742 3 SEQ ID NO: 3370gttgatgaggagtccttca 1810 1829SEQ ID NO:4699tgaaaaagctgcaatcaac 13734 137532 3 SEQ ID NO: 3371 tccaagatctgaaaaagtt 1941 19 6 0 SEQ ID NO:4700aactgcttctccaaatgga 3552 35712 3 SEQ ID NO: 3372agttagtgaaagaagttct 1956 19 7 5 SEQ ID NO: 4701lagaattcataatcccaact 8275 82942 3 SEQ ID NO: 3373gaagggaatcttatatttg 2084 2103 SEQ ID NO: 4702caaaacctactgtctcttc 10467 104862 3 SEQ ID NO: 337 4 ggaagctctttttgggaag 2221 2240SEQ ID NO:4703cttcacataccagaattcc 8324 83432 3 SEQ ID NO: 3375tggaataatgctcagtgtt 2374 2393SEQ ID NO:4704aacaaacacaggcattcca 9656 96752 3 SEQ ID NO: 3376gatttgaaatccaaagaag 2408 2 4 2 7 SEQ ID NO:4705cttcatgtccctagaaatc 10037 100562 3 SEQ ID NO: 3377 ccaaagaagtcccggaag 2417 2436 SEQ ID NO: 4706cttcagcctgctttctgga 4951 49702 3 SEQ ID NO: 33 7 8 aggaagggctcaaagaatg 2570 2589SEQ ID NO:4707cattagagctgccagtcct 10020 100392 3 SEQ ID NO: 3379agaatgacttttttcttca 2583 2 6 0 2 SEQ ID NO: 4708tgaagatgacgacttttct 12160 121792 3 SEQ ID NO: 3380tgtgacaaatatgggca 2765 2 7 84 SEQ ID NO:4709tgccagtttgaaaaacaaa 11815 118342 3 SEQ ID NO: 3381 ctgaggctaccatgacatt 3252 3271 SEQ ID NO: 4710aatgtcagctctgttcag 10903 109222 3 SEQ ID NO: 338 gtagataccaaaaaaatga 3668 3687 SEQ ID NO: 4711 tcatttgccctcaacctac 11450 114692 3 SEQ ID NO: 3 38 3 1aaalgacftccaatttccc 3681 3700 SEQ ID NO: 4712gggaactgttgaaagattt 12927 129462 3 SEQ ID NO. 3384atgacttccaatttccctg 3683 3702 SEQ ID NO: 4713caggagaacttactatcat 13785 138042 3 SEQ ID NO: 3385atctgccatctcgagagtt 4104 4 12 3 SEQ ID NO:4714aactcctccactgaaagat 9547 95662 5 SEQ ID NO: 3 38 6 atttgtttgtcaaagaagt 4551 4 5 7 0 SEQ ID NO:4715acttccgtttaccagaaat 8247 82662 3 SEQ ID NO: 338 gcagagcttggcctctctg 5135 5 15 4 SEQ ID NO: 4716cagagotttctgccactgc 13518 135372 3 SEQ ID NO: 3388atatgctgaaatgaaattt 5353 5372 SEQ ID NO: 4717 aaattcaaactgcctatat 13874 138932 3 SEQ ID NO: 3389 caaaacttgacaacattt 5420 5 4 3 9 SEQ ID NO: 4718aaatacttccacaaattga 8780 87992 3 SEQ ID NO. 3 3 9 0 cagtgacctgaaatacaat 5512 5531 SEQ ID NO: 4719 attgaacatccccaaactg 8794 88132 3 SEQ ID NO: 3391 acaaatggcaatgggaaa 5848 5 8 6 7 SEQ ID NO: 4720 ttcaactgcctttgtgta 11229 112482 3 SEQ ID NO: 33 9 21cttttgtaaagtatgataa 6285 6304 SEQ ID NO: 4721 ttattgctgaatccaaaag 13656 136752 .3 SEQ ID NO: 3393 ttgtaaagtatgataaaaa 6288 6307 SEQ ID NO: 4722 ttttcaagcaaatgcacaa 8539 85582 3 SEQ ID NO: 3394tccattaacctcccatttt 6320 6339SEQ ID NO:4723aaaagaaaattttgctgga 10756 107752 3 SEQ ID NO: 33951gattatctgaattcattca 6488 6507SEQ ID NO: 4724 tgaagtagaccaacaaatc 7162 71812 3 SEQ ID NO: 3396 aattgggagagacaagttt 6506 6525 SEQ ID NO: 4725 aaactaaatgatctaaatt 11324 113432 3 SEQ ID NO: 339 atttgaaaatagctattgc 6696 6715 SEQ ID NO: 4726 gcaatttctgcacagaaat 13441 134602 3 SEQ ID NO: 3398 gagcatgtcaaacacttt 7060 7079 SEQ ID NO: 4727 aaagccattcagtctctca 12971 129902 3 SEQ ID NO: 3399 gaagatgttaacaaatt 7356 7 3 75 SEQ ID NO: 4728aattccatatgaaagtcaa 12660 126792 3 SEQ ID NO: 3400jacttgtcacctacatttct 7753 7 7 72 SEQ ID NO: 4729agaatattttgatccaagt 13276 132952 3 SEQ ID NO: 3401 gttttccacaccagaattt 8050 8069 SEQ ID NO: 4730 aaatctggatttcttaaac 9481 95002 3 SEQ ID NO: 3 4 0 2 ataagtacaaccaaaattt 9405 9424 SEQ ID NO: 4731 aaataaatggagtctttat 14083 14102 3 SEQ ID NO: 3403cgggactgcggggctgag 8 2 7 SEQ ID NO:4732ctcagttaactgtgtcccg 11571 115901 3 SEQ ID NO: 3 404 agtgccttctcggttgct 25 4 4 SEQ ID NO: 4733agcatctgattgactcact 12678 126971 3 SEQ ID NO: 3405 gctgaggagcccgcccagc 47 6 6 SEQ ID NO: 4734gctgattgaggtgtccagc 1225 12441 3 SEQ ID NO: 34061gaggagcccgcccagccag 50 6 9 1SEQ ID NO: 4735 ctggatcacagagtccctc 3752 37711 3 SEQ ID NO: 3407 gggCcgcgaggccgaggcc 72 9 1 SEQ ID NO: 4736ggccctgatccccgagccc 1363 13821 3 SEQ ID NO: 34081ccaggccgcagcccaggag 89 10 8 SEQ ID NO: 4737 ctcccggagccaaggctgg 2682 27011 3 SEQ ID NO: 340gggagccgccccaccgcagc 104 12 3 SEQ ID NO:4738gctgttttgaagactctcc 1088 11071 3 SEQ ID NO: 3410 ga2gaggaaatgctggaaa 200 2 19 SEQ ID NO: 4739ttcaagttcctgaccttc 8309 83281 5 SEQ ID NO: 3411 caaaagatgcgacccgatt 237 2 5 6 SEQ ID NO: 4740 aatcttattggggattttg 7085 71041 3 SEQ ID NO: 3412 attcaagcacctccggaag 253 272SEQ ID NO: 4741 cttccacatttcaaggaat 10067 100861 3 SEQ ID NO: 3413gttccagtggagtccctgg 297 3 1 6 SEQ ID NO:4742ccagcaagtacctgagaac 8610 86291 3 SEQIDNO:3414gactgctgattcaagaagt 316 3 3 5 SEQID NO:4743acttgaagaaaagatagtc 13324 133431 3 SEQ ID NO: 341 5 gtgccaccaggatcaactg 333 3 5 2 SEQ ID NO: 4744cagtgaagctgcagggcac 10704 107231 3 304 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3 4 1 6 gatcaactgcaaggttgag 3 43 362SEQ ID NO:4745ctcacctccacctctgatc 4748 47671 3 SEQ ID NO: 34 1 7actgcaaggttgagctgga 348 3 67 SEQ ID NO:4746tccactcacatcctccagt 1289 13081 3 SEQ ID NO: 3418 ccagctctgcagcttcatc 373 392SEQ ID NO:4747gatgtggtcacctacctgg 1343 13621 3 SEQ ID NO: 3 4 1 gagcttcatcctgaagacca 383 4 02 SEQ ID NO:4748tggtgctggagaatgagct 5112 51311 3 SEQ ID NO: 3 42 0 cttcatcctgaagaccagc 385 4 04 SEQ ID NO:4749gctggagtaaaactggaag 2696 27151 3 SEQ ID NO: 3421 ccagccagtgcaccctgaa 399 4 18 SEQ ID NO:4750tcaagatgactgcactgg 1539 15581 3 SEQ ID NO: 3 42 2 cagtgcaccctgaaagagg 404 4 23 SEQ ID NO: 4751 cctcacagagctatcactg 5230 52491 3 SEQ ID NO: 3423 ggcttcaaccctgagggc 427 4 46 SEQ ID NO: 4752gcccactggtcgcctgcca 3533 35521 3 SEQ ID NO: 3 42 4 cttcaaccctgagggcaaa 430 4 49 SEQ ID NO: 4753tttgagccaacattggaag 2207 22261 3 SEQ ID NO: 3425 tcaaccctgagggcaaag 431 4 50 SEQ ID NO:4754ctttgacaggcattttgaa 9727 97461 3 SEQIDNo:3426cttgctgaagaaaaccaag 451 4 70 SEQ ID NO:4755cttgaaattcaatcacaag 9074 90931 3 SEQ ID NO: 3427tgctgaagaaaaccaagaa 453 4 72 SEQ ID NO:4756ttctgctgccttatcagca 5647 56661 3 SEQ ID NO: 3428ptgctgcagccatgtccag 483 5 02 SEQ ID NO:4757ctggtcagtttgcaagcaa 3004 30231 3 SEQ ID NO: 3429tgctgcagccatgtccagg 484 5 03 SEQ ID NO:4758cctggtcagtttgcaagca 3003 30221 3 SEQ ID NO: 3 4 3 0 agccatgtccaggtatgag 490 5 09 SEQ ID NO: 4759ctcacatcctccagtggct 1293 13121 3 SEQ ID NO: 34311agctcaagctggccattcc 507 5 26 SEQ ID NO:4760ggaactaccacaaaaagct 7489 75081 3 SEQ ID NO: 3 4 3 2 agaagggaagcaggttttc 526 5 45 SEQ ID NO: 4761 gaaatcttcaattattct 13821 138401 3 SEQ ID NO: 3 4 3 3 aagggaagcaggttttcct 528 5 47 SEQ ID NO:4762aggacaccaaaataactt 7572 75911 3 SEQ ID NO: 3 4 3 4 agaaagatgaactactta 555 5 74 SEQ ID NO: 4763 taagaactttgccactct 4852 48711 3 SEQ ID NO: 3 4 3 5 atcctgaacatcaagaggg 575 5 94 SEQ ID NO:4764ccctaacagatttgaggat 7977 79961 3 SEQ ID NO: 3436tcctgaacatcaagagggg 576 5 95 1SEQ ID NO:4765cccctaacagatttgagga 7976 79951 3 SEQ ID NO: 3437ctgaacatcaagaggggca 578 5 97 SEQ ID NO:4766tgcctgcctttgaagtcag 7908 79271 3 SEQID NO: 3 4 3 8 aacatcaagaggggcatca 581 6 00 SEQ ID NO:4767tgataaaaaccaagatgtt 6298 63171 3 SEQ ID NO: 3 4 3 9 acatcaagaggggcatcat 582 6 0 1 SEQ ID NO: 4768atgataaaaaccaagatgt 6297 63161 3 SEQ ID NO: 3440 catttctgccctcctggt 597 6 16 SEQ ID NO:4769accaccagtttgtagatga 7413 74321 3 SEQ ID NO: 3441tcccccagagacagaaga 615 6 34 SEQ ID NO:4770tcttccacatttcaaggaa 10066 100851 3 SEQIDNo:34429aagaagccaagcaagtgt 629 64 8 SEQ ID NO: 4771lacaccttccacattccttc 8079 80981 3 SEQ ID NO: 3443tgtttctggataccgtgt 647 6 6 6 SEQ ID NO: 4772acactaaatacttccacaa 8775 87941 3 SEQ'ID NO: 3444tgtatggaaactgctccac 663 6 82 SEQ ID NO:4773gtggaggcaacacattaca 2928 29471 3 SEQ ID NO: 3 44 5 aaactgctccactcacttt 670 6 89 SEQ ID NO:4774aaagaaacagcatttgttt 4540 45591 3 SEQ ID NO: 3 44 6 actcactttaccgtcaaga 680 6 99 SEQ ID NO:4775tcttacttttccattgagt 10580 105991 3 SEQ ID NO: 3447ctttaccgtcaagacgagg 685 7 04 SEQ ID NO:4776 cctccagctcctgggaaag 2491 25101 3 SEQ ID NO: 344gtaccgtcaagacgaggaa 687 7 06 SEQ D NO:4777tcctaaagctggatgtaa 11177 111961 3 SEQ ID NO: 3 44 gacgaggaagggcaatgtgg 698 7 17 SEQ ID NO: 4778ccacaagtcatcatctcgt 5964 59831 3 SEQ ID NO: 3 4 5 0 cgaggaagggcaatgtggc 699 7 18 SEQ ID NO:4779gccagaagtgagatcctcg 3515 35341 3 FQD NO:3451gaggaagggcaatgtggca 700 7 19 SEQ ID NO:4780tgccagtctccatgacctc 2476 24951 3 SEQID NO: 3452 gaagggcaatgtggcaac 702 721 SEQ ID NO: 4781 gttgctcttaaggacttcc 13364 133831 3 SEQ ID NO: 3 4 5 3 gaagggcaatgtggcaaca 703 7 22 SEQ ID NO:4782tgttgatgaggagtccttc 1809 18281 3 SEQ ID NO: 3 4 5 4 caggcatcagcccacttgc 777 7 96 SEQ ID NO:4783gcaagtctttcctggcctg 3019 30381 3

SEQIDNO:

34 5 5 aggcatcagcccacttgct 778 7 97 SEQ ID NO:4784agcaagtctttcctggcct 3018 30371 3 SEQ ID NO: 3456tcagcccacttgctctcat 783 8 02 SEQ ID NO: 4785atgaaagtcaagcatctga 12668 126871 3 SEQ ID NO: 3457tcaactctgatcagcagc 823 8 42 SEQ ID NO:4786gctgactttaaaatctgac 4819 48381 3 SEQ ID NO: 3458gacgctaagaggaagcat 865 8 84 SEQ ID NO: 4787atgcactgtttctgagtcc 9339 93581 3 SEQ ID NO: 3459 aaggagcaacacctttcc 902 921 SEQ ID NO: 4788ggaatatcttagcatcctt 13465 134841 3 SEQ ID NO: 3460 aggagcaacacctcttcct 903 9 22 SEQ ID NO: 4789aggaatatcttagcatcct 13464 134831 3 SEQ ID NO: 3461 caacacctcttcctgcctt 908 9 27 SEQ ID NO: 4790aaggctgactctgtggttg 4292 43111 3 SEQ ID NO: 3462aacacctcttcctgccttt 909 9 28 1SEQ ID NO: 4791 aaagcaggccgaagctgtt 1075 10941 3 305 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3463acaagaataagtatgggat 933 9 52 SEQ ID NO:4792atccatgatctacatttgt 6794 68131 3 SEQ ID NO: 34641caagaataagtatgggatg 934 95 3 SEQ ID NO:4793catcactttacaagccttg 1246 12651 3 SEQ ID NO:3465 agcacaagtgacacagac 954 97 3 SEQ ID NO:4794gtctcttcgttctatgcta 4592 46111 3 SEQ ID NO: 3466 agcacaagtgacacagact 955 97 4 SEQ ID NO:4795agtctcttcgttctatgct 4591 46101 3 SEQ ID NO: 3467gcacaagtgacacagactt 956 97 5 SEQ ID NO: 4796aagtgtagtctcctggtgc 5099 51181 3 SEQ ID NO :3468aacttgaagacacaccaaa 978 99 7 SEQ ID NO:4797tttgaggattccatcagtt 7987 80061 3 SEQ ID NO: 3469gcttctttggtgaaggtac 1008 1 02 7 SEQ ID NO: 4798gtacctacttttggcaagc 8372 83911 3 SEQ ID NO: 3 4701ctttggtgaaggtactaag 1012 1031 SEQ ID NO: 4799 cttatgggatttcctaaag 11167 111861 3 SEQ ID NO: 3471 tactaagaagatgggcctc 1024 1043 SEQ ID NO:4800gagggtagtcataacagta 10337 103561 3 SEQ ID NO: 3472 tttgagagcaccaaatcca 1046 1065SEQ ID NO: 4801 tggaagtgtcagtggcaaa 10380 103991 3 SEQ ID NO: 34 7 3 agagcaccaaatccacatc 1050 1069 SEQ ID NO:4802gatggatatgaccttctct 4876 48951 3 SEQ ID NO: 3 47 4 agctgttttgaagactctc 1087 1 10 6 SEQ ID NO:4803gagaacatactgggcagct 5880 58991 3 SEQIDNO: 3475 tgaaaaaactaaccatctc 1113 1 13 2 SEQ ID NO: 4804 gagaaaatcaatgccttca 7112 71311 3 SEQ ID NO: 34 7 6gaaaaaactaaccatctct 1114 1133SEQ ID NO:4805agagccaggtcgagctttc 11052 110711 3 SEQ ID NO: 3477tctgagcaaaatatccaga 1130 1149SEQ ID NO:4806tctgatgaggaaactcaga 12260 122791 3 SEQ ID NO: 3478tctcttcaataagctggtt 1156 1175SEQ ID NO:4807aacctcccattttttgaga 6326 63451 3 SEQ ID NO: 34 7 9 ctgagctgagaggcctcag 1176 1 19 5 SEQ ID NO: 4808ctgatccccgagccctcag 1367 13861 3 SEQ ID NO: 3480 tgaagcagcacatctctc 1198 12 1 7 SEQ ID NO:4809gagaaaatcaatgccttca 7112 71311 3 SEQ ID NO: 3481 aagcagtcacattctct 1200 12 1 9 SEQ ID NO:4810aagaggcagcttctggctt 12297 123161 3 SEQ ID NO: 34 8 2 ctctcttgccacagctgat 1212 1231 SEQ ID NO: 4811atcaaaagaagcccaagag 12946 129651 3 SEQ ID NO: 3483 tcttgccacagctgattga 1215 1234 SEQ ID NO: 4812tcaaagttaattgggaaga 12279 122981 3 SEQ ID NO: 34 8 4 cttgccacagctgattgag 1216 12 3 5 SEQ ID NO:4813ctcaattttgattttcaag 8528 85471 3 SEQ ID NO: 3485tgaggtgtccagccccatc 1231 12 5 0 SEQ ID NO:4814gatggaaccctctccctca 4733 47521 3 SEQ ID NO: 3486tcagtgtggacagcctcag 1267 12 8 6 SEQ ID NO:4815ctgacatcttaggcactga 5001 50201 3 SEQ ID NO: 3 487acatcctccagtggctgaa 1296 13 1 5 SEQ ID NO:4816tcagaagctaagcaatgt 7239 72581 3 SEQ ID NO: 34 8 8 gcacagcagctgcgagaga 1385 14 04 SEQ ID NO: 4817 ctctgaaagacaacgtgc 12323 123421 3 SEQ ID NO: 34 8 gcagcagctgcgagagatct 1388 14 07 SEQ ID NO: 4818agataacattaaacagctg 13051 130701 3 SEQ ID NO: 34 gg 0 gcgagggatcagcgcagcc 1415 14 34 SEQ ID NO: 4819ggctcaacacagacatcgc 5718 57371 3 SEQ ID NO: 3491 aagacaaaccctacaggga 1478 1497 SEQ ID NO: 4820 tcccagaaaacctcttctt 3936 39551 3 SEQ ID NO: 3492caggagctgctggacattg 1499 15 18 SEQ ID NO:.4821 caatggagagtccaacctg 4660 46791 3 SEQ ID NO: 34 93aggagctgctggacattgc 1500 15 19 SEQ ID NO:4822gcaagggttcactgttcct 7864 78831 3 SEQ ID No: 3494tgctggacattgctaatt 1505 15 24 SEQ ID NO: 4823aattgggaagaagaggcag 12287 123061 3 SEQ ID NO: 34 95gattacacctatttgattc 1565 15 84 SEQ ID NO: 4824gaatattttgagaggaatc 6353 63721 3 SEQ ID NO: 34 9 6 atttgattctgcgggtcat 1575 15 94 SEQ ID NO: 4825atgaagtagaccaacaaat 7161 71801 3 SEQ ID NO: 3497 ctgcgggtcattggaaat 1582 1601 SEQ ID NO: 4826 atttgtaagaaaatacaga 6436 64551 3 SEQ ID NO: 3498 aaccatggagcagttaact 1609 16 28 SEQ ID NO: 4827agtttctccatcctaggtt 9962 99811 3 SEQ ID NO: 3499gggagcagttaactccagaa 1615 16 34 SEQ ID NO: 4828 ttctgaaaatccaatctcc 8400 84191 3 SEQ ID NO: 3500 actccagaactcaagtdtt 1625 1 64 4 SEQ ID NO: 4829 aagatcgcagactttgagt 11654 116731 3 SEQ ID NO: 3501 tccagaactcaagtcttca 1627 164 6 SEQ ID NO: 4830 tgaactcagaagaattgga 1920 19391 3 SEQ ID NO: 35 0 2aagtacaaagccatcactg 1663 1 6 82 SEQ ID NO: 4831 cagtcatgtagaaaaactt 4429 44481 3 SEQ ID NO: 35 0 3 gccatcactgatgatccag 1672 1691 SEQ ID NO:4832ctggaactctctccatggc 10883 109021 3 SEQ ID NO: 35 0 4 1ccatcactgatgatccaga 1673 1 6 92 SEQ ID NO: 4833 tctgaactcagaaggatgg 13999 140181 3 SEQDNO: 3505atccagaaagctgccatcc 1685 1 70 4 SEQ ID NO:4834ggatttcctaaagctggat 11173 111921 3 SEQ ID NO: 3506cagaaagctgccatccagg 1688 1 70 7 SEQ ID NO:4835cctgaaatacaatgctctg 5518 55371 3 SEQ ID NO: 3507 acaaggaccaggaggttct 1731 1 75 0 SEQ ID NO: 4836 agaaacagcatttgtttgt 4542 45611 3 SEQIDNO:3508aggaccaggaggttcttct 1734 1 75 3 SEQ ID NO:4837agaagctaagcaatgtcct 7242 72611 3 SEQ ID NO: 3509 accaggaggttcttcttca 1737 1 75 6 1SEQ ID NO: 4838tgaaggctgactctgtggt 4290 43091 3 306 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3510 tcttcagactttccttgat 1750 17 6 9 SEQ ID NO:4839atcaggaagggctcaaaga 2567 25861 3 SEQ ID NO: 3511 ttcagactttccttgatga 1752 1771 SEQ ID NO: 4840 tcattactcctgggctgaa 11307 113261 3 SEQ ID NO: 3512gttgatgaggagtccttca 1810 1 8 2 9 SEQ ID NO: 4841 tgaatctggctccctcaac 9046 90651 3 SEQ ID NO: 3 5 1 3 cttcacaggcagatattaa 1824 1843SEQ ID NO:4842ttaatcgagaggtatgaag 7148 71671 3 SEQIDNO: 3514ttcacaggcagatattaac 1825 1 8 44 SEQID NO:4843gftaatcgagaggtatgaa 7147 71661 3 SEQIDNO: 351 ggcagatattaacaaaatt 1831 1 8 5 0 SEQID NO:4844aattgcattagatgatgcc 6589 66081 3 SEQ ID NO: 3516atattaacaaaattgtcca 1836 1 8 5 5 SEQ ID NO:4845tggagtttgtgacaaatat 2760 27791 3 SEQ ID NO: 351 acaaaattgtccaaattct 1842 1861 SEQ ID NO: 4846 agaaacagcatttgtttgt 4542 45611 3 SEQ ID NO: 3 5 18gagcaagtgaagaactttg 1877 1 8 9 6 SEQ ID NO: 4847 caaatgacatgatgggctc 5334 53531 3 SEQ ID No: 3519 gtgaagaactttgtggct 1883 1 9 02 SEQ ID NO: 4848aagcatctgattgactcac 12677 126961 3 SEQ ID NO: 3 5 201agaactttgtggcttccca 1887 1 9 06 SEQ ID NO: 4849 tgggcctgccccagattct 8909 89281 3 SEQ ID NO: 3521 tttgtggcttcccatattg 1892 1 9 1 1 SEQ ID NO: 4850caataagatcaatagcaaa 8998 90171 3 SEQ ID NO: 35221tggcttcccatattgccaa 1896 1 9 15 1SEQ ID NO: 4851ttggctcacatgaaggcca 7631 76501 3 SEQ ID NO: 3523 ttcccatattgccaatatc 1900 1 9 19 SEQ ID NO: 4852gatatacactagggaggaa 12745 127641 3 SEQ ID NO: 3524 tcccatattgccaatatct 1901 1 92 0 SEQ ID NO: 4853agatcaaagttaattggga 12276 122951 3 SEQ ID NO: 3525 ttgccaatatcttgaactc 1908 1 92 7 SEQ ID NO: 4854gagtcccagtgcccagcaa 9352 93711 3 SEQ ID NO: 3526 ttggatatccaagatctga 1934 1 95 3 SEQ ID NO:4855tcagtataagtacaaccaa 9400 94191 3 SEQ ID NO: 3527tccaagatctgaaaaagtt 1941 1 96 0 SEQ ID NO:4856aacttccaactgtcatgga 1986 20051 3 SEQ ID NO: 3 52 8 1ctgaaaaagttagtgaaag 1949 19 6 8 SEQ ID NO:4857,ctttgaagtcagtcttcag 7915 79341 3 SEQ ID No: 3529agttagtgaaagaagttct 1956 19 7 5 SEQ ID NO:48581agaatctcaacttccaact 1978 19971 3 SEQ ID NO: 3530 aatctcaacttccaactgt 1980 19 9 9 SEQ ID NO: 4859 acaggggtcctttatgatt 12350 123691 3 SEQ ID NO: 35311gtcatggacttcagaaaat 1997 20 16 1SEQ ID NO: 4860atttgaaagaataaatgac 7036 70551 3 SEQ ID NO: 3532 tcaactctacaaatctgtt 2029 20 4 8 SEQ ID NO: 4861aacacattgaggetattga 6978 69971 3 SEQ ID NO: 3 5 33aactctacaaatctgtttc 2031 2 0 5 0 SEQ ID NO: 4862gaaaaaggggattgaagtt 10284 103031 3 SEQ ID NO: 3534aaatagaagggaatcttat 2079 2098SEQ ID NO:4863 ataagcaaactgttaattt 5457 54761 3 SEQ ID NO: 3 53 5 agaagggaatcttatattt 2083 2 10 2 SEQ ID NO: 4864aaatgcactgctgcgttct 4900 49191 3 SEQ ID NO: 3 53 6 gaagggaatcttatatttg 2084 2103 SEQ ID NO:4865caaaaacattttcaacttc 5287 53061 3 SEQ ID NO: 3537tgatccaaataactacctt 2101 2 12 0 SEQ ID NO:4866aaggaagaaagaaaaatca 3461 34801 3 SEQ ID NO: 3538 ggatttgcttcagctgac 2158 2 17 7 SEQ ID NO:4867gtcagcccagttccttcca 10932 109511 3 SEQIDNO:3539tgcttcagctgacctca 2162 2 18 1 SEQ ID NO:4868 tgaggaaactcagatcaaa 12265 122841 3 SEQ ID NO: 3 5 4 0 cttggaaggaaaaggcttt 2191 2 2 1 0 SEQ ID NO:4869aaagcattggtagagcaag 7850 78691 3 SEQ ID NO: 3541 ggaaggaaaaggctttga 2193 2212 SEQ ID NO: 4870 tcaagtctgtgggattcca 4086 41051 3 SEQ ID NO: 3542 gctttgagccaacattgg 2204 2 2 2 3 SEQ ID NO: 4871 ccaagaggtatttaaagcc 12958 129771 3 SEQ ID NO: 3543 gagccaacattggaagct 2209 2 2 2 8 SEQ ID NO: 4872agcttctgccactgctca 13521 13540 1 3 SEQ ID NO: 3 5 4 4 1gagccaacattggaagctc 2210 2 2 2 9 SEQ ID NO: 4873,gagcttctgccactgctc 13520 135391 3 SEO ID NO: 3545aacattggaagctcttttt 2215 2 2 34 SEQ ID NO: 4874aaaagaaacagcatttgtt 4539 45581 3 SEQ ID NO: 3546tggaagctctttttgggaa 2220 2239SEQ ID NO:4875ttccggcacgtgggttcca 3785 38041 3 SEQ ID NO: 3547ctctttttgggaagcaagg 2226 2245SEQ ID NO:4876ccttactgactttgcagag 7798 78171 3 SEQ ID NO: 3548 tgggaagcaaggatt 2229 2248 SEQ ID NO: 4877aatcattgaaaaattaaaa 6730 67491 3 SEQ ID NO: 3549 tcccagacagtgtcaa 2247 2266 SEQ ID NO:4878 tgatgaaatcattgaaaa 6723 67421 3 SEQ ID NO: 3550 ggctataccaaagatga 2331 2 3 5 0 SEQ ID NO: 4879 tcattgctcccggagccaa 2676 26951 3 SEQ ID NO: 3551 ataccaaagatgataaaca 2337 2356 SEQ ID NO: 4880 gttgcttttgtaaagtat 6280 62991 3 SEQ ID NO: 3552 agcaggatatggtaaatg 2357 2376 SEQ ID NO: 4881 catttcagccttcgggctc 4262 42811 3 SEQ ID NO: 3 553atggtaaatggaataatgc 2366 2 3 8 5 SEQ ID NO: 4882gcatgcctagtttctccat 9954 99731 3 SEQ ID NO: 3554 tggtaaatggaataatgct 2367 2 3 8 6 SEQ ID NO: 4883agcacagtacgaaaaacca 10809 108281 3 SEQ ID NO: 3555taaatggaataatgctcag 2370 2 3 89 SEQ ID NO:4884ctgaaagagatgaaattta 13067 130861 3 SEQ IDNO:3556tggaataatgctcagtgtt 2374 2393SEQ ID NO:4885 aacagatttgaggattcca 7981 80001 3 307 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3557 tcgtgttgagaagctgat 2385 2404 SEQ ID NO: 4886 atcacaactcctccactga 9542 95611 3 SEQ ID NO: 3 5 58 cagtgftgagaagctgaft 2386 24 0 5 SEQ ID NO:4887 aatcacaactcctccactg 9541 95601 3 SEQ ID NO: 3 5 5 9agtgttgagaagctgatta 2387 24 0 6 SEQ ID NO:4888taatcacaactcctccact 9540 95591 3 SEQ ID NO: 3 5 60 gattaaagatttgaaatcc 2401 24 2 0 SEQ ID NO:4889ggatactaagtaccaaatc 6874 68931 3 SEQ ID NO: 3561,gatttgaaatccaaagaag 2408 24271SEQ ID NO:4890 cttccgtttaccagaaatc 8248 82671 3 SEQ ID NO: 3562atttgaaatccaaagaagt 2409 2428 SEQ ID NO:4891 acttccgtttaccagaaat 8247 82661 3 SEQ ID NO: 3563 atccaaagaagtcccggaa 2416 2435 SEQ ID NO:4892 ttccaatttccctgtggat 3688 37071 3 SEQ ID NO: 3564 tccaaagaagtcccggaag 2417 2436 SEQ ID NO: 4893cttccaatttccctgtgga 3687 37061 3 SEQ ID NO: 3 5 65 agagcctacctccgcatct 2438 24 5 7 SEQ ID NO:4894agattaatccgctggctct 8571 85901 3 SEQ ID NO: 3 5 6 6gagcctacctccgcatctt 2439 2458SEQ ID NO:4895aagattaatccgctggctc 8570 85891 3 SEQIDNo:3567cttgggagaggagcttggt 2455 2 4 7 4 SEQID NO:4896accactgggacctaccaag 12527 125461 3 SEQ ID NO: 3 5 68ggagcttggttttgccagt 2464 2483SEQ ID NO:4897actggtggcaaaaccctcc 2734 27531 3 SEQ ID NO: 3569ttggttttgccagtctcca 2469 2488SEQ ID NO:4898tggagaagccacactccaa 10771 107901 3 SEQ ID NO: 3 57 0 cagtctccatgacctccag 2479 2498 SEQ ID NO: 4899ctggtcgcctgccaaactg 3538 35571 3 SEQ ID NO: 3571 ctccatgacctccagctcc 2483 2502SEQ ID NO:4900ggagtcattgctcccggag 2672 26911 3 SEQ ID NO: 3 57 2 ctgggaaagctgcttctga 2501 2 5 2 0 SEQ ID NO: 4901 tcagaaagctacctccag 7939 79581 3 SEQ ID NO: 3 57 3 gaggtcatcaggaagggct 2561 2 5 8 0 SEQ ID NO:4902agccagaagtgagatcctc 3514 35331 3 SEQ ID NO: 3574aagaatgacttttttcttc 2582 2601_SEQ ID NO:4903gaaggcatctgggagtctt 3835 38541 3 SEQ ID NO: 3575 cttttttcttcactacatc 2590 2609 SEQ ID NO:4904gatgcttacaacactaaag 6107 61261 3 SEQ ID NO: 3 57 6 catcttcatggagaatgcc 2605 2 6 24 SEQ ID NO:4905ggcacttccaaaattgatg 10718 107371 3 SEQIDNO: 3577 cttcatggagaatgccttt 2608 2 6 2 7 SEQID NO:4906aaagttaattgggaagaag 12281 123001 3 SEQ ID NO: 3 57 8 aatgcctttgaactcccca 2618 2 6 3 7 SEQ ID NO:4907tgggctggcttcagccatt 5737 57561 3 SEQ ID NO: 3 57 9gcctttgaactccccactg 2621 2640 SEQ ID NO:4908cagtctgaacattgcaggc 5383 54021 3 SEQ ID NO: 3 580caaggctggagtaaaactg 2692 2711 SEQ ID NO:4909cagtgcaacgaccaacttg 5080 50991 3 SEQ ID NO: 3581tggagtaaaactggaagta 2698 2717SEQ ID NO:4910tactcaacgccagctcca 3059 30781 3 SEQ ID NO: 3582ggaagtagccaacatgcag 2710 2729 SEQ ID NO:4911 ctgccatctcgagagttcc 4106 41251 3 SEQ ID NO: 3583tttgtgacaaatatgggca 2765 2 7 84 SEQ ID NO:4912tgcctttgtgtacaccaaa 11236 112551 3 SEQ ID NO: 3584tgtgacaaatatgggcatc 2767 2786SEQ ID NO:4913gatgggtctctacgccaca 4385 44041 3 SEQ ID NO: 35 85ggacttcgctaggagtggg 2794 2 8 13 SEQ ID NO:4914cccaaggccacaggggtcc 12341 123601 3 SEQ ID NO: 3586gtggggtccagatgaacac 2808 2 82 7 SEQ ID NO:4915gtgttctagacctctccac 4179 41981 3 SEQ ID NO: 3587tccacgagtcgggtctgg 2834 2853SEQ ID NO:4916ccagaatctgtaccaggaa 12562 125811 3 SEQ ID NO: 35 88agtcgggtctggaggctca 2841 2860 SEQ ID NO:4917tgagaactacgagctgact 4807 48261 3 SEQ ID NO: 3589 cgggtctggaggctcatg 2843 2862 SEQ ID NO:4918catgaaggccaaattccga 7639 76581 3 SEQ ID NO: 35 90aaaagctgggaagctgaag 2869 2888SEQ ID NO:4919cttccagacacctgatttt 7951 79701 3 SEQ ID NO: 3591 aagctgaagtttatcattc 2879 2898SEQ ID NO:4920gaatttacaattgttgctt 6269 62881 3 SEQ ID NO: 3592gagaccagtcaagctgctc 2908 2927 SEQ ID NO: 4921 gagcttcaggaagcttctc 13214 132331 3 SEQ ID NO: 3593gcaacacattacatttggt 2934 2953SEQ ID NO: 4922accagtcagatattgttgc 10191 102101 3 SEQ ID NO: 35 94 acattacatttggtctcta 2939 2958SEQ ID NO:4923tagaatatgaactaaatgt 11889 119081 3 SEQ ID NO: 3595cattacatttggtctctac 2940 2959SEQ ID NO:49241gtagctgagaaaatcaatg 7106 71251 3 SEQ ID NO: 3596aaacggaggtgatcccacc 2964 2983SEQ ID NO:4925ggtggataccctgaagttt 3205 32241 3 SEQ ID NO: 3 5 9 7 attgagaacaggcagtcct 2987 3006 SEQ ID NO:4926aggaaaagcgcacctcaat 12031 120501 3 SEQ ID NO: 3598 tgagaacaggcagtcctgg 2989 3008SEQ ID NO:4927ccagcttccccacatctca 8341 83601 3 SEQ ID NO: 3599 ctgcacctcaggcgcttac 3043 3062 SEQ ID NO: 4928gtaagaaaatacagagcag 6440 64591 3 SEQ ID NO: 3600 tccacagactccgcctcct 3074 3 09 3 SEQ ID NO: 4929aggacagagccttggtgga 3192 32111 3 SEQ ID NO: 3601 ctgaccggggacaccagat 3101 3120SEQ ID NO:4930atctgatgaggaaactcag 12259 122781 3 SEQ ID NO: 3602tagagctggaactgaggcC 3120 3139 SEQ ID NO: 4931ggcctctctggggcatcta 5144 51631 3 SEQ ID NO: 3603ctatgagctccagagagag 3175 3194 SEQ ID NO: 4932ctctcacaaaaaagtatag 6549 65681 3 308 WO 2004/091515 PCT/US2004/011255 SEQ ID No: 3604 cttggtggataccctgaag 3202 3221 SEQ ID NO: 4933cttcaggaagcttctcaag 13217 132361 3 SEQ ID NO: 3605 ttgtaactcaagcagaagg 3222 3241 SEQ ID NO: 4934ccttacacaataatcacaa 9530 95491 3 SEQ ID NO: 3606 taactcaagcagaaggtgc 3225 3244SEQ ID NO:4935gcacctagctggaaagtta 6955 69741 3 SEQ ID NO: 3607 gcagaaggtgcgaagcaga 3233 32 5 2 SEQ ID NO:4936tctgtgggattccatctgc 4091 41101 3 SEQ ID NO: 3608cagaaggtgcgaagcagac 3234 3253 SEQ ID NO:4937gtctgtgggattccatctg 4090 41091 3 SEQ ID NO: 3609 gtatgaccttgtccagtga 3288 3307 SEQ ID NO: 4938 tcaccaacggagaacatac 10851 108701 3 SEQ ID NO: 3610 atgaccttgtccagtgaa 3289 33 0 8 SEQ ID NO:4939tcaccaacggagaacata 10850 108691 3 SEQ ID NO: 3611 gaagtccaaattccggatt 3305 33 2 4 SEQ ID NO:4940aatctcaagctttctcttc 10052 100711 3 SEQ ID NO: 3612gagggcaaaacgtcttaca 3371 3390SEQ ID NO: 4941tgtacaactggtccgcctc 4215 42341 3 SEQ ID NO: 3613agggcaaaacgtcttacag 3372 3391 SEQ ID NO:4942ctgttaggacaccagccct 4062 40811 3 SEQ ID NO: 3614gactcaccctggacattca 3390 3 4 0 9 SEQ ID NO: 4943tgaaattcaatcacaagtc 9076 90951 3 SEQ ID NO: 36151ctggacattcagaacaaga 3398 3 4 17SEQ ID NO: 4944tcttttcttttcagcccag 9226 92451 3 EQ D NO: 3616 tcatggggacctaagttg 3435 3 4 54 SEQ ID NO: 4945caactgcagacatatatga 6635 66541 3 SEQ ID NO: 3617 tgggcgacctaagttgtga 3438 3 4 5 7 SEQ ID NO:4946tcactccattaacctccca 6316 63351 3 SEQ ID NO: 3618agttgtgacacaaaggaag 3449 3468SEQ ID NO:4947cttcttttccaattgaact 13838 138571 3 SEQ ID NO: 3619 tgacacaaaggaagaaaga 3454 3473 SEQ ID NO: 4948 tcttcatcttcatctgtca 10220 10239 3 EQID NO:362gacacaaaggaagaaagaa 3455 3474SEQ ID NO: 4949tcttcatcttcatctgtc 10219 102381 3 SEQ ID NO: 3621 ggaagaaagaaaaatcaag 3463 3482 SEQ ID NO: 4950 cttgtcatgcctacgttcc 11348 113671 3 SEQ ID NO: 3622 aaaatcaagggtgttattt 3473 3492 SEQ ID NO: 4951 aaatcttattggggatttt 7084 71031 3 SEQ ID NO: 3623tccataccccgtttgcaag 3491 3510 SEQ ID NO:4952cttggattcaaaatgtgga 6858 68771 3 SEQ ID NO: 3624tgcaagcagaagccagaag 3504 35 2 3 SEQ ID NO:4953cttcagggaacacaatgca 5185 52041 3 SEQ ID NO: 36 2 5 cagaagccagaagtgagat 3510 35 2 9 SEQ ID NO:4954atctatgccatctcttctg 5633 56521 3 SEQ ID NO: 3626tgagatcctcgcccactgg 3523 3542SEQ ID NO:4955,ccagcttccccacatctca 8341 83601 3 SEQ ID NO: 3627ggtcgcctgccaaactgct 3540 3559SEQ ID NO:4956agcacatatgaactggacc 13947 139661 3 SEQ ID NO: 3628tgcttctccaaatggactc 3555 3574SEQ ID NO:4957gagtttatcagtcagagca 9701 97201 3 SEQID NO: 3629tggactcatctgctacagc 3567 3 5 8 6 SEQ ID NO:4958gctgcagtggcccgttcca 8167 81861 3 SEQ ID NO: 3630gctacagcttatggctcca 3578 3597SEQ ID NO:4959tggaggacattcctctagc 8211 82301 3 SEQ ID NO: 3631 ggtggcatggcattatgat 3610 3629SEQ ID NO:4960 atcacaaattagtttcacc 8947 89661 3 SEQ ID NO: 3632agagaagattgaatttgaa 3631 3650 SEQ ID NO: 4961 ttcaacgatacctgtctct 7713 77321 3 SEQ ID NO: 3 6 33 ,caggcaccaatgtagatac 3657 3 6 7 6 SEQ ID NO: 4962gtatgctaatagactcctg 3736 37551 3 SEQ ID NO: 3634gacttccaatttccctgtg 3685 3 7 04 SEQ ID NO: 4963cacaatgcaaaattcagtc 5195 52141 3 SEQ ID NO: 3635gtccctcaaacagacatga 3764 3 78 3 SEQ ID NO:4964tcataagggaggtagggac 12777 127961 3 SEQ ID NO: 36361caaacagacatgactttcc 3770 3789SEQ ID NO:4965ggaactacaatttcatttg 7022 70411 3 SEQ ID NO: 363 atagttgcaatgagctcat 3809 3 82 8 SEQ ID NO: 4966atgatttgaaaatagctat 6693 67121 3 SEQ ID NO: 33819cttcagaaggcatctggg 3829 3 84 8 SEQ ID NO:4967 ccaagaggtatttaaagc 12957 129761 3 SEQ 1D NO: 363g ggagttcaacctccagaac 3895 39 14 SEQ ID NO: 4968gttcactccattaacctcc 6314 63331 3 SEQ ID NO: 3640agaaaacctcttcttaaaa 3940 39 5 9 SEQ ID NO: 4969tttctaaatggaacttct 12173 121921 3 3EQ ID NO: 3641 aaaacctcttcttaaaaag 3942 3961 SEQ ID NO: 4970 ctttgaaaaattetetttt 9213 92321 3 EQ ID NO: 3 6 4 2 aaaaagcgatggccgggtc 3955 3974 SEQ ID NO: 4971 gaccttgcaagaatatttt 6343 63621 3 SEQ ID NO: 36431gtcaaatataccttgaaca 3971 3990SEQ ID NO:4972tgttaacaaattccttgac 7363 73821 3 3EQ ID NO: 3644vgaacaagaacagtttgaa 3984 4003SEQ ID NO:4973:tcaagttcctgaccttca 8310 83291 3 3EQID NO: 3645agtttgaaaattgagattc 3995 4 0 1 4 SEQ ID NO:4974gaatctggctccctcaact 9047 90661 3 3EQ ID NO: 3646 tttgaaaattgagattcc 3996 4 0 1 5 SEQ ID NO: 4975ggaaataccaagtcaaaac 10454 104731 3 SEQ ID NO: 3647 gaaaattgagatcct 3998 4 0 1 7 SEQ ID NO:4976,aaggaaaagcgcacctcaa 12030 120491 3 SEQ ID NO: 3648 ctaaagatgttagagactg 4046 4065 SEQ ID NO: 4977 agttgaccacaagcttag 10545 105641 3 3EQ ID NO: 364g atgttagagactgttagga 4052 4071 SEQ ID NO:4978 ccttaacaccttccacat 8073 80921 3 3EQ ID NO: 3650 cagccctccacttcaagtc 4074 4093|SEQ ID NO: 4979gacttctctagtcaggctg 8813 8832|1 3 309 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3651 agccctccacttcaagtct 4075 4094SEQ ID NO: 980 agacatcgctgggctggct 5728 57471 3 SEQIDNo:3652ccatctgccatctcgagag 4102 4121 SEQ ID NO:4981ctctcaaatgacatgatgg 5330 53491 3 SEQ ID NO: 36 5 3 attcccaagttgtatcaac 4142 4161 SEQ ID NO:4982gttgagaagccccaagaat 6254 62731 3 SEQ ID NO: 3654 tcaactgcaagtgcctctc 4156 4 1 75 SEQ ID NO:4983gagatcaagacactgttga 8843 88621 3 SEQ ID NO: 365 5 1ggtgttctagacctctcca 4178 4 1 97 1SEQ ID NO: 4984 tggaaccctctccctcacc 4735 47541 3 SEQ ID NO: 365 6 ctccacgaatgtctacagc 4192 4211 SEQ ID NO:4985gctggtaacctaaaaggag 5588 56071 3 SEQ ID NO: 3657cacgaatgtctacagcaac 4195 4 2 14 SEQ ID NO:4986gttgcccaccatcatcgtg 11671 116901 3 SEQ ID NO: 36 5 8 acgaatgtctacagcaact 4196 4 2 15 SEQ ID NO:4987agttgcccaccatcatcgt 11670 116891 3 SEQ ID NO: 3659tcctacagtggtggcaaca 4232 4251 SEQ ID NO:4988tgttagttgctcttaagga 13359 133781 3 SEQ ID NO: 36601cgttaccacatgaaggctg 4280 4 29 9 SEQ ID NO:4989cagcaagtacctgagaacg 8611 86301 3 SEQID No: 3661gaaggctgactctgtggtt 4291 4 3 10 SEQ ID NO:4990aacctatgccttaatcttc 13169 131881 3 SEQ ID NO: 3662 gtggttgacctgctttcc 4303 4322 SEQ ID NO:4991ggaaagttaaaacaacaca 6965 69841 3 SEQIDNo:3663cctgcttcctacaatgtg 4312 4331 SEQ ID NO:4992cacaccttgacattgcagg 11088 111071 3 SEQID No: 3664ctgcittcctacaatgtgc 4313 4 33 2 SEQ ID NO:4993gcacaccttgacattgcag 11087 111061 3 SEQ ID NO: 3665 tcctacaatgtgcaaggat 4319 4338 SEQ ID NO:4994atccgctggctctgaagga 8577 85961 3 SEQ ID NO: 3666 atgaccacaagaatacgt 4352 4371 SEQ ID NO:4995 acgtccgtgtgccttcata 9984 100031 3 SEQ ID NO: 3667 atgaccacaagaatacgtc 4353 4 37 2 SEQ ID NO:4996gacgtccgtgtgccttcat 9983 100021 3 SEQ ID NO: 3 66 8 gaatacgtctacactatca 4363 4382SEQ ID NO:4997tgattatctgaattcattc 6487 65061 3 SEQ ID NO: 3669 tctagattcgaatatca 4406 4425 SEQ ID NO:4998tgatttacatgatttgaaa 6685 67041 3 SEQ ID NO: 3 67 0 gattcgaatatcaaattca 4412 4431 SEQ ID NO: 4999 tgaagtagctgagaaaatc 7102 71211 3 SEQ ID NO: 36 7 1 gaaacaacccagtctcaaa 4449 4 4 6 8 SEQ ID NO: 50 0 0 tttgaaaaattctcttttc 9214 92331 3 SEQ ID NO: 3 67 2 cccagtctcaaaaggttta 4456 4475 SEQ ID NO: 50 0 1 taaattcattactcctggg 11302 113211 3 SEQ ID NO: 36 7 3 ctcaaaaggtttactaata 4462 4481 SEQ ID NO: 5 0 0 2 tattcaaaactgagttgag 12231 122501 3 SEQ ID NO: 3674 tcaaaaggtttactaatat 4463 4 4 8 2 SEQ ID NO:5003atattcaaaactgagttga 12230 122491 3 SEQ ID NO: 3 67 5 aaaaggtttactaatattc 4465 4484SEQ ID NO:5004gaatttgaaagttcgtttt 9280 92991 3 SEQ ID NO: 36 7 6 gaaacagcatttgtttgtc 4543 4 5 6 2 SEQ ID NO: 5 0 0 5 gacagcatcttcgtgtttc 11214 112331 3 SEQ ID NO: 3677atttgtttgtcaaagaagt 4551 4570SEQ ID NO:5006acttaaaaaatataaaaat 8022 80411 3 SEQ ID NO: 3678tcaagattgatgggcagtt 4569 4 5 8 8 SEQ ID NO: 5 0 0 7aactctcaagtcaagttga 13422 134411 3 SEQ ID NO: 3679 cagagtctcttcgttct 4586 4 6 0 5 SEQ ID NO:5008agaagatggcaaatttgaa 11995 120141 3 SEQ ID NO: 36 8 0 cagagtctcttcgttctat 4588 4607SEQ ID NO:5009atagcatggacttcttctg 8873 88921 3 SEQ ID NO: 36 8 1 atgctaaaggcacatatgg 4605 4 6 2 4 SEQ ID NO: 501 ccatttgagatcacggcat 9245 92641 3 SEQlDNo:3682gcacatatggcctgtcttg 4614 4 6 3 3 SEQID NO: 011caagtggcaagtaagtgc 9372 93911 3 SEQ ID NO: 36 8 3 gagtccaacctgaggttta 4667 4686SEQ ID NO: 50 12 taaagtgccacttttactc 6190 62091 3 SEQ ID NO: 36 8 4 agtccaacctgaggtttaa 4668 4687SEQ ID NO: 5013ttaacagggaagatagact 9308 93271 3 SEQ ID NO: 36 8 5 cctacctccaaggcaccaa 4692 4711 SEQ ID NO: 50 14 ttggcaagtaagtgctagg 9376 93951 3 SEQ ID NO: 36 8 6 gaagatggaaccctctccc 4730 4 7 4 9 SEQ ID NO:5015gggaagaagaggcagcttc 12291 123101 3 SEQ ID NO: 3687gatctgcaaagtggcatc 4762 4781 SEQ ID NO: 5 0 16 gatgaggaaactcagatca 12263 122821 3 SEQ ID NO: 36 8 8 gatctgcaaagtggcatca 4763 4782SEQ ID NO: 5 0 1 7tgatgaggaaactcagatc 12262 122811 3 SEQ ID NO: 36 8 9gcttccctaaagtatgaga 4793 4 8 12 SEQ ID NO: 5 0 18 tctcgtgtctaggaaaagc 5977 59961 3 SEQ ID NO: 36 9 0 gtatgagaactacgagctg 4804 4823SEQ ID NO:5019:cagcttaagagacacatac 6920 69391 3 SEQ ID NO: 3691tctaacaagatggatatga 4868 4 8 8 7 SEQ ID NO: 5 02 0 tcattttccaactaataga 13032 130511 3 SEQ ID NO: 36 9 2 ctgctgcgttctgaatatc 4907 4926 SEQ ID NO: 5 02 1 gatacaagaaaaactgcag 6901 69201 3 SEQ ID NO: 3693tcattgaggttcttcagcc 4940 4959 SEQ ID NO:5022 gctcatatgctgaaatga 5348 53671 3 SEQ ID NO: 3694 ttctggatcactaaattcc 4963 4982 SEQ ID NO:5023 gaaggacaaggcccagaa 12549 125681 3 SEQ ID NO: 3695 ccatggtcttgagttaaat 4981 5 0 0 0 SEQ ID NO:5024atttttattcctgccatgg 10103 101221 3 SEQID NO: 3696 cttaggcactgacaaaat 5007 5 0 2 6 SEQ ID NO:5025attttttgcaagttaaaga 14019 140381 3 SEQ ID NO: 3 6 9 7 acaaggcgacactaaggat 5040 5 0 59 SEQ ID NO:5026atccatgatctacatttgt 6794 68131 3 310 WO 2004/091515 PCT/US2004/011255 SEQIDNo:3698gcaacgaccaacttgaag 5083 5 10 2 SEQ ID NO: 50 2 7cttcagggaacacaatgca 5185 52041 3 SEQIlDNo:3699caacttgaagtgtagtctc 5092 5111SEQIDNO:5028gagatgagagatgccgttg 6239 62581 3 SEQ ID NO: 3 7 0 0 gctggagaatgagctgaat 5116 5 13 5 SEQ ID NO:5029atctcttttcttttcagc 9222 92411 3 SEQ ID NO: 3701 gcagagctggcctctctg 5135 5 15 4 SEQ ID NO: 50 3 0 cagatacaagaaaaactgc 6899 69181 3 SEQ ID No: 3702tctctggggcatctatgaa 5148 5 16 7 ,SEQ ID NO: 50 3 1 ttcattcaattgggagaga 6499 65181 3 SEQ ID NO: 3703tctggggcatctatgaaat 5150 5169SEQ ID NO: 50 3 2atttgtaagaaaatacaga 6436 64551 3 SEQ ID NO: 3 70 4 aacacaatgcaaaaftcag 5193 5 2 1 2 SEQ ID NO:5033ctgaagcattaaaactgtt 7506 75251 3 SEQ ID NO: 370 5 ctcacagagctatcactgg 5231 5250 SEQ ID NO: 50 3 4 ccagatgctgaacagtgag 8149 81681 3 SEQ ID NO: 3706 tgggaagtgcttatcaggc 5247 5 2 6 6 SEQ ID NO:5035gcctacgttccatgtccca 11356 113751 3 SEQ ID NO: 3707 tcaaggtcagtcaagaag 5303 1 5322SEQ ID NO:5036cttcagtgcagaatatgaa 11977 119961 3 SEQ ID NO: 3708 aatgacatgatgggctcat 5336 5355SEQ ID NO:5037,atgattatctgaattcatt 6486 65051 3 SEQIDNO: 37 0 9gtcatatgctgaaatgaa 5349 5368SEQ ID NO:5038tcagccattgacatgagc 5746 57651 3 SEQ ID NO: 37 10 atatgctgaaatgaaattt 5353 5 3 72 SEQ ID NO:5039aaatagctattgctaatat 6702 67211 3 SEQ ID NO: 3711 tctgaacattgcaggctta 5386 5 4 05 SEQ ID NO: 5 0 4 0 taagaaccagaagatcaga 10996 110151 3 SEQ ID NO: 37 12 gaacattgcaggcttatca 5389 5408SEQ ID NO: 5 0 4 1 tgatatcgacgtgaggttc 12490 125091 3 SEQ ID NO: 3 7 1 3tgcaggcttatcactggac 5395 5 4 14 SEQ ID NO:5042gtcctggattccacatgca 11852 118711 3 SEQ ID NO: 3714 caaaacttgacaacattt 5420 5439SEQ ID NO:5043aaattccttgacatgttga 7370 73891 3 SEQDNO: 37 1 5 atttacagctctgacaagt 5435 5 45 4 SEQ ID NO:5044acttaaaaaatataaaaat 8022 80411 3 SEQIDNO: 37 16 ctctgacaagftttataag 5443 5 46 2 SEQ ID NO: 5045cttacttgaattccaagag 10674 106931 3 SEQ ID NO: 371 7ttaatttacagctacagc 5468 5 48 7 SEQ ID NO:5046gctgcatgtggctggtaac 5578 55971 3 SEQ ID NO: 3718 ctctggtaactacttta 5491 5 5 10 SEQ ID NO: 5 04 7 taaaagattactttgagaa 7275 72941 3 SEQ ID NO: 37 19cctaaaaggagcctaccaa 5596 5 6 15 SEQ ID NO: 5 04 8 ttggcaagtaagtgctagg 9376 93951 3 SEQ ID NO: 3 7 20 aaaaggagcctaccaaaat 5599 5 6 18 SEQ ID NO5049atttacaattgttgctttt 6271 62901 3 SEQ ID NO: 37 2 1 aggagcctaccaaaataat 5602 5621 SEQ ID NO:5050attacctatgatttctcct 10127 101461 3 SEQ ID NO: 37 2 2 ataatgaaataaaacacat 5616 1 5 63 5 SEQ ID NO:5051atgtcaaacactttgttat 7065 70841 3 SEQ ID NO: 37 2 3 aaaacacatctatgccatc 5626 5645 SEQ ID NO:5052gatgaagatgacgactttt 12158 121771 3 SEQ ID NO: 3724tgctaaggttcagggtgtg 5686 5705 SEQ ID NO:5053cacaagtcgattcccagca 9087 91061 3 SEQ ID NO: 3725gagtttagccatcggctca 5705 5724 SEQ ID NO: 5 05 4 tgaggtgactcagagactc 7450 74691 3 SEQ ID NO: 37 2 6gctggcttcagccattgac 5740 5759 SEQ ID NO:5055gtcagtgaagttctccagc 8596 86151 3 SEQ ID NO: 3727atttcagcaatgtcttccg 5790 5809 SEQ ID NO:5056cggagcatgggagtgaaat 8628 86471 3 SEQ ID NO: 3728 tcagcaatgtcttccgt 5791 5 8 10 SEQ ID NO: 5 05 7acggagcatgggagtgaaa 8627 86461 3 SEQ ID NO: 3729cagcaatgtcttccgtt 5792 5811 SEQ ID NO: 5058 aacggagcatgggagtgaa 8626 86451 3 SEQID NO: 37 3 0 cagcaatgtcttccgttct 5794 5 8 13 SEQ ID NO:5059agaagtgtttCa2agctg 12412 124311 3 SEQ ID NO: 3731 tgtcttccgttctgtaatg 5800 58191SEQ ID NO:5060 cattcaattgggagagaca 6501 65201 3 SEQ ID NO: 37 321gtcttccgttctgtaatgg 5801 5820 SEQ ID NO: 5 06 1 ccattcagtctctcaagac 12975 129941 3 SEQ ID NO: 37 3 3 atgggaaactcgctctctg 5859 5 87 8 SEQ ID NO:5062cagataaaaaactcaccat 12213 122321 3 SEQ ID NO: 3734ggagaacatactgggcagc 5879 5898 SEQ ID NO: 5 06 3 gctgttttgaagactctcc 1088 11071 3 SEQ ID NO: 37 3 5 gttgaaagcagaacctctg 5914 5 93 3 SEQ ID NO:5064cagaattcataatcccaac 8274 82931 3 SEQ ID NO: 3736 tctaggaaaagcatcagt 5983 6002 SEQ ID NO:5065actgcaagatttttcagac 13612 136311 3 SEQ ID NO: 37 3 7 agcatcagtgcagctcttg 5993 6 0 12 SEQ ID NO:5066caagaacctgtagttgct 13351 133701 3 SEQ ID NO: 3738 tgaacacaaagtcagtgc 6009 6028 SEQ ID NO: 5 06 7gcacatcaatattgatcaa 6418 64371 3 SEQ ID No: 3739gcagacaggcacctggaaa 6046 60 6 5 SEQ ID NO: 50 6 8 tttcagatggcattgctgc 11610 116291 3 SEQ ID NO: 37 4 0 gaaactcaagacccaattt 6061 60 8 0 SEQ ID NO:5069aaatcccatccaggttttc 8037 80561 3 SEQ ID NO: 3741 acaatgaatacagccagga 6084 6 10 3 SEQ ID NO: 50 7 0 tcctttggctgtgctttgt 9682 97011 3 SEQ ID NO: 37 4 2 cttggatgcttacaacact 6103 6 12 2 SEQ ID NO: 50 7 1 agtgaagttctccagcaag 8599 86181 3 SEQ ID NO: 3743 ggcgtggagcttactgg 6132 6151 SEQ ID NO:5072,ccagaattcataatcccaa 8273 82921 3 SEQ ID NO: 3 74 4 cacttttactcagtgagcc 6198 6 2 1 7 1SEQ ID NO:5073ggctattgatgttagagtg 6988 70071 3 311 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3745 tttagagatgagagatgcc 6235 6 2 54 SEQ ID NO:5074ggcatgatgctcatttaaa 9177 91961 3 SEQ ID NO: 3746 gagaagccccaagaattta 6257 6 2 76 SEQ ID NO: 50 7 5 taaagccattcagtctctc 12970 129891 3 SEQ ID NO: 3 74 7 caattgttgcttttgtaaa 6276 6 2 95 SEQ ID NO:5076 tttaaccagtcagataftg 10187 102061 3 SEQ ID NO: 3748 ttttgtaaagtatgataaa 6286 6 3 05 SEQ ID NO:5077 ttattgctgaatccaaaa 13655 136741 3 SEQ ID NO: 3749 ttgtaaagtatgataaaaa 6288 6307 SEQ ID NO:5078 ttttgagaggaatcgacaa 6358 63771 3 SEQ ID NO: 37501ttcactccattaacctccc 6315 6 33 4 SEQ ID NO:5079gggaaaaaacaggcttgaa 9576 95951 3 SEQ ID NO: 3751 gagaccttgcaagaa 6337 6356 SEQ ID NO:5080 ttctctctatgggaaaaaa 9566 95851 3 SEQ ID NO: 3 75 2 accttgcaagaatattttg 6344 6363 SEQ ID NO: 5081 caaaagaagcccaagaggt 12948 129671 3 SEQ ID NO: 3753 caatattgatcaatttgt 6423 64 4 2 SEQ ID NO:5082acaaagcagattatgttga 11829 118481 3 SEQ ID NO: 3 7 54 cagagcagccctgggaaaa 6451 6470SEQ ID NO:5083ttttcagaccaactctctg 13622 136411 3 SEQ ID NO: 3 7 55 cctgggaaaactcccacag 6460 6479 SEQ ID NO:5O84ctgtctctggtcagccagg 7724 77431 3 SEQ ID NO: 3 7 56 actcccacagcaagctaat 6469 64 8 8 SEQ ID NO:5085attacactcctttcgagt 12869 128881 3 SEQ ID NO: 3757 aattcattcaattgggaga 6497 6516SEQ ID NO:5086tctcttcctccatggaatt 10479 104981 3 SEQIDNO: 3758 ttcaattgggagagacaag 6503 6522SEQ ID NO: 5 0 8 7cttggagtgccagtttgaa 11808 118271 3 SEQ ID NO: 3 7 5 9aggagaaactgactgctct 6534 6553SEQ ID NO:5088agagttatgggatttcct 11163 111821 3 SEQ ID NO: 3 7 60 actgactgctctcacaaaa 6541 6560SEQ ID NO: 5 0 8 9 ttttggcaagctatacagt 8380 83991 3 SEQ ID NO: 3 7 6 1 gactgctctcacaaaaaag 6544 6563SEQ ID NO:5090ctttgtgagtttatcagtc 9695 97141 3 SEQ ID NO: 7 62 cagacatatatgatacaat 6641 6660 SEQ ID NO: 5 0 9 1 attggatatccaagatctg 1933 19521 3 SEQ ID NO: 3 7 63 aatttgatcagtatattaa 6657 6676 SEQ ID NO: 5 0 92 ttaaaagaaatctcaatt 13815 138341 3 SEQ ID NO: 3764tatgatttacatgatttga 6683 6 70 2 SEQ ID NO: 5 0 9 3 tcaatgaftatatcccata 13128 131471 3 SEQ ID NO: 3765tttgaaaatagctattgct 6697 6716SEQ ID NO:5094agcacagaaaaaattcaaa 13864 138831 3 SEQ ID NO: 3766ttgaaaatagctaftgcta 6698 6 7 17 SEQ ID NO: 5 0 9 5 tagcacagaaaaaattcaa 13863 138821 3 SEQ ID NO: 3 7 67 aatagtattgctaatatt 6703 6 72 2 SEQ ID NO:5096aataaatggagttttatt 14084 141031 3 SEQ ID NO: 3 7 68 attattgatgaaatcattg 6719 6 73 8 SEQ ID NO: 5 0 9 7caataccagaattcataat 8268 82871 3 SEQ ID NO: 3 7 6 gaaagtcttgatgagcacta 6747 6766SEQ ID NO: 5 0 9 8 tagtgattacactccttt 12864 128831 3 SEQ ID NO: 3 7 70 aagtcttgatgagcactat 6748 6767SEQ ID NO:5099atagcaacactaaatactt 8769 87881 3 SEQ ID NO: 3771 tgatgagcactatcatat 6753 6 77 2 SEQ ID NO:5100atatccaagatgagatcaa 13101 131201 3 SEQ ID NO: 3772taattttagtaaaaacaat 6777 6 79 6 SEQ ID NO:5101attgagattccctccatta 11702 117211 3 SEQIDNO:3773tagtaaaaacaatcca 6780 6799SEQIDNO:5102tggagtgccagtttgaaaa 11810 118291 3 SEQ ID NO: 3 7 74 acatttgtttattgaaaat 6805 6824 SEQ ID NO:5103latttcctaaagctggatgt 11175 111941 3 SEQ ID NO: 3 7 75 attgattttaacaaaagtg 6824 6843SEQ ID NO:5104cactgttccagttgtcaat 9871 98901 3 SEQ ID NO: 3 7 76 atttaacaaaagtggaag 6828 6 84 7 SEQ ID NO:5105cttcaaagacttaaaaaat 8014 80331 3 SEQ ID NO: 3 7 77 aaatcagaatccagataca 6888 6907SEQ ID NO: 5 1 0 6 tgtaccataagccatatt 10088 101071 3 SEQIDNo:3778gaatccagatacaagaaaa 6894 6 9 13

SEQIDNO:

5 1 0 7ttttctaaacttgaaattc 9065 90841 3

SEQIDNO:

3 7 7 9taagagacacatacagaa 6924 6 94 3 SEQ ID NO: 5 1 0 8 ttcttaaacattcctttaa 9491 95101 3 SEQ ID NO: 3 7 80 atccagcacctagctggaa 6950 6969SEQ ID NO: 5 1 0 9 ttccaatttacctgtggat 3688 37071 3 SEQIDNO: 3781gagcatgtcaaacacttt 7060 7 079SEQIDNO:5110aaagtgccacttttactca 6191 62101 3 SEQ ID NO: 3782gagcatgtcaaacactttg 7061 7080 SEQ ID NO: 5 1 1 1 caaatgacatgatgggctc 5334 53531 3 SEQ ID NO: 3 7 83 aaacactigttataaatc 7070 7 08 9 SEQ ID NO:5112gattatatcccatatgttt 13133 131521 3 SEQ ID NO: 3784tgagaaaatcaatgccttc 7111 7 13 0 SEQ ID NO: 5 1 13gaaggaaaagcgcacctca 12029 120481 3 SEQ ID NO: 3785tatgaagtagaccaacaaa 7160 7 17 9 SEQ ID NO: 5 1 14 tttgtggagggtagtcata 10331 103501 3 SEQ ID NO: 37 8 6aagtagaccaacaaatcca 7164 7 18 3 SEQ ID NO: 5 1 1 5 tggatgaagatgacgactt 12156 121751 3 SEQ ID NO: 3787aagttgaaggagactattc 7223 7 24 2 SEQ ID NO: 5 1 16gaataccaatgctgaactt 10168 101871 3 SEQIDNO:3788acaagtaagataaaagat 7264 7 28 3 SEQ ID NO:5117attaaattcagttcttgt 11334 113531 3 SEQ ID No: 3789aagataaaagattactttg 7271 7290SEQ ID NO:5118caaaatagaagggaatctt 2077 20961 3 SEQ ID NO: 3 7 90 gattacttgagaaaftag 7280 7299 SEQ ID NO: 5 1 1 9 ctaaacttgaaattcaatc 9069 90881 3 SEQIDNO: 3791 tgagaaattagttggattt 7288 7307SEQIDNO:5120aaatccgtgaggtgactca 7443 74621 3 312 WO 2004/091515 PCT/US2004/011255 SEQ DNO: 37 92aaattagttggatttattg 7292 7311 SEQ ID NO: 5 12 1 1caattttgagaatgaattt 10419 104381 3 SEQlD NO: 3793 tggatttattgatgatgct 7300 7 3 19 SEQ ID NO:5122agcatgcctagtttctcca 9953 99721 3 6EQ ID NO: 3794 tcattgaagatgttaacaa 7353 7372 SEQ ID NO: 5 12 3 ttgtagatgaaaccaatga 7422 74411 3 SEQ ID NO: 379 5 cattgaagatgttaacaaa 7354 7373 SEQ ID NO: 5 124 tttgtagatgaaaccaatg 7421 74401 3 SEQ ID NO: 379 6 attgaagatgttaacaaat 7355 73 74 SEQ ID NO:5125atttaagtatgatttcaat 10495 105141 3 SEQ ID NO: 3797tgaagatgttaacaaatt 7356 7 37 5 SEQ ID NO:5126aatttaagtatgatttcaa 10494 105131 3 SEQ ID NO: 3798tgaagatgttaacaaattc 7357 7 37 6 SEQ ID NO: 5 12 7gaatttaagtatgatttca 10493 105121 3 SEQ ID NO: 3 7 g 9 acatgttgataaagaaatt 7380 7399SEQ ID NO:5128aattccctga2gttgatgt 11487 115061 3 SEQID NO: 3800tgattaccaccagtttg 7406 74 2 5 SEQ ID NO:5129caaattgaacatccccaaa 8791 88101 3 SEQ ID NO: 3801 caaaatccgtgaggtgact 7441 7460 SEQ ID NO: 5130 agtccccctaacagatttg 7972 79911 3 SEQ ID NO: 3 8 0 2 1aaaatccgtgaggtgactc 7442 7461 SEQ ID NO: 5 13 1 gagtgaaatgctgttttt 8638 86571 3 SEQ ID NO: 3 80 3 aggtgactcagagactcaa 7452 7471 SEQ ID NO: 5 132 ttgatgatatctggaacct 10731 107501 3 SEQID NO:3 80 4 gtgaaattcaggctctgga 7473 74 9 2 SEQ ID NO: 5 13 3 tccaatctcctcttttcac 8409 84281 3 SEQl DNO: 3 80 5 gttgcagtgtatctggaaa 7547 7 56 6 SEQ ID NO: 5 134 tttcaagcaaatgcacaac 8540 85591 3 SEQIDNO: 3806taagttcagcatctttgg 7616 7 63 5 SEQ ID NO:5135ccaatgctgaactttttaa 10173 101921 3 SEQ ID NO: 38071tgaaggccaaattccgaga 7641 7650 SEQ ID NO: 5 1 36 tctcctttcttcatcttca 10213 102321 3 SEQ ID NO: 3808 aatgtatcaaatggacatt 7684 7703 SEQ ID NO: 5 1 3 7 aatgaagtccggattcatt 11021 110401 3 SEQ ID No: 3809atcagcaggaacticaac 7700 7719 SEQ ID NO:5138 gttgagaagccccaagaat 6254 62731 3 SEQ ID NO: 3 8 10 1acctgtctctggtcagcca 7722 7741 SEQ ID NO: 5 1 39 tggcaagtaagtgctaggt 9377 93961 3 SEQID NO: 3811 cctgtctctggtcagccag 7723 77 4 2 SEQ ID NO:5140ctggacttctagtcagg 8810 88291 3 SEQ ID NO: 3 8 12 ggtcagccaggtttatagc 7732 7751 SEQ ID NO: 5 14 1 gctaaaggagcagttgacc 10535 105541 3 S$Q ID NO: 3 8 131ccaggtttatagcacactt 7738 77 5 7 SEQ ID NO:5142 aagtccggattcattctgg 11025 110441 3 SEQ ID NO: 3 8 14 gtttatagcacacttgtca 7742 7761 SEQ ID NO: 5 14 3 tgacctgtccattcaaaac 13681 137001 3 SEQ ID NO: 3 8 15 1acttgtcacctacatttct 7753 77 7 2 SEQ ID NO:5144agaaaaaggggattgaagt 10283 103021 3 SEQ ID NO: 3 8 16 1ctgattggtggactcttgc 7770 7789 SEQ ID NO:5145gcaagttaaagaaaatcag 14026 140451 3 SEQ ID NO: 3 8 1 7 atgaaagcattggtagagc 7847 7866 SEQ ID NO:51461gctcatctcctttcttcat 10208 102271 3 SEQIDNo: 3818tgaaagcattggtagagca 7848 78 6 7

SEQIDNO:

5 14 7tgctcatctcctttcttca 10207 102261 3 SEQ ID NO: 3 8 1 ggggttcactgttcctgaaa 7868 78 8 7 SEQ ID NO: 5 14 8 tttcaccatagaaggaccc 8959 89781 3 SEQ [D NO: 3820 caagaccatccttgggac 7887 7906 SEQ ID NO:5149gtccccctaacagatttga 7973 79921 3 SEQ ID NO: 3821 ccttgggaccatgcctgcc 7897 79 1 6 ,SEQ ID NO: 5150ggcaccagggctcggaagg 13978 139971 3 SEQ ID NO: 3822 caggctcttcagaaagc 7929 7948SEQ ID NO:5151,gottgaaggaattcttgaa 9588 96071 3 SEQ ID NO: 3823 cagataaacttcaaaga 8004 8 0 23 SEQ ID NO: 5 15 2 cttcataagttcaatgaa 13183 132021 3 SEQIDNO:3824acttcaaagacttaaaaaa 8013 8 0 32

SEQIDNO:

5 15 3 ttaacaaaagtggaagt 6829 68481 3 SEQ ID NO: 3 82 5 atcccatccaggttttcca 8039 8 0 5 8 SEQ ID NO: 5 15 4 ggagaagcaaatctggat 9472 94911 3 SEQ ID NO: 3826gaatttaccatccttaaca 8063 8082SEQ ID NO: 5 15 5 tgttgaagtgtctccattc 9889 99081 3 SEQ IDNO: 3827 cattcctcctttacaatt 8089 8108 SEQ ID NO: 5156 aattccaattttgagaatg 10414 104331 3 SEQ ID NO: 3828 ttgaccagatgctgaacag 8145 8 164 SEQ ID NO: 5 15 7 ctgttgaaagatttatcaa 12932 129511 3 SEQ D NO: 3 82 gaatcaccctgccagacttc 8233 8252SEQ ID NO:5158gaagttctcaattttgatt 8522 85411 3 SEQ ID No: 3830 gacctcacataccagaa 8320 8 3 39 1SEQ ID NO: 5 15 9 ttcttctggaaaagggtca 8884 89031 3 SEQ ID NO: 3831 ccagcttccccacatct 8339 8358 SEQ ID NO:5160agattctcagatgagggaa 8921 89401 3 SEQ ID NO: 3 8 3 2 1aagtatacagtattctga 8387 8 4 06 SEQ ID NO: 5 16 1 tcagatggcattgctgctt 11612 116311 3 SEQ ID NO: 3 83 3 attctgaaaatccaatctc 8399 8 4 18 SEQ ID NO:5162gagataaccgtgcctgaat 11552 115711 3 SEQ ID NO: 3834 ticacattagatgcaaat 8422 8441 SEQ ID NO: 5 16 3 attttgaaaaaaacagaaa 9738 97571 3 SEQ ID NO: 3835 caaatgctgacatagggaa 8436 8455SEQ ID NO: 5 16 4 ttccatcacaaatcctttg 9670 96891 3 SEQDNO: 3836 gagagtccaaattagaagt 8508 8 52 7 SEQ ID NO:5165actttacttcccaactctc 13410 134291 3 SEQ ID NO: 3837 agagtccaaattagaagtt 8509 8528 SEQ ID NO: 5 16 6 aactttacttcccaactct 13409 134281 3 EQ ID NO: 3838 tctcaattttgattttcaa 8527 8546 SEQ ID NO: 5 16 7 tgattcccttttttgaga 11537 115561 3 313 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 383gcaattttgattttcaagca 8530 8 5 4 9 SEQ ID NO: 5 16 8 tgctgaatccaaaagattg 13660 136791 3 SEQ ID NO: 3840 aatgcacaactctcaaacc 8549 8 5 6 8 SEQ ID NO:5169ggtttatcaaggggccatt 12460 124791 3 SEQ ID NO: 3841agttotccagcaagtacct 8604 8 6 2 3 SEQ ID NO:517Oaggttccatcgtgcaaact 11388 114071 3 SEQ ID NO: 3842 agtacctgagaacggagca 8616 8635SEQ ID NO: 5 17 1 tgctccaggagaacttact 13780 137991 3 SEQ ID NO: 3843 tcaaacacagtggcaagtt 8678 8 6 9 7 SEQ ID NO:5172aactctcaagtcaagttga 13422 134411 3 SEQ ID NO: 3844acaatcagcttaccctgga 8751 8 7 7 0 SEQ ID NO: 5 17 3 tccattctgaatatattgt 13380 133991 3 SEQ ID NO: 3845 ctggatagcaacactaaat 8765 8 7 84 SEQ ID NO:5174attttctgaacttccccag 12702 127211 3 SEO ID NO: 384 6 ctgacctgcgcaacgagat 8829 8 84 8 SEQ ID NO:5175atctgatgaggaaactcag 12259 122781 3 SEQ ID NO: 3847 agatgagggaacacatgaa 8929 8 94 8 SEQ ID NO: 5 17 6 ttcatgtccctagaaatct 10038 100571 3 SEQ ID NO: 3848 tcaacttttctaaacttga 9060 9079 SEQ ID NO: 5 17 7 tcaaggataacgtgtttga 12618 126371 3 SEQ ID NO: 3 8 4 9ttctaaacttgaaattcaa 9067 9086SEQ ID NO:5178ttgatgatgctgtcaagaa 7308 73271 3 SEQ ID NO: 3 8 5 0 gaaattcaatcacaagtcg 9077 9 0 9 6 SEQ ID NO:5179cgacgaagaaaataatttc 13566 135851 3 SEQ ID No: 38511cactgtttggagaagggaa 9141 9 16 0 SEQ ID NO:5180 ttccagaaagcagccagtg 12506 125251 3 SEQIDNO: 3852actgtttggagaagggaag 9142 9161SEQIDNO:5181cttccccaaagagaccagt 2898 29171 3 SEQ ID NO: 3853aatctcttttcttttcag 9221 9 2 4 0 SEQ ID NO:5182 ctgattactatgaaaaatt 13638 136571 3 SEQ ID NO: 3854tcttttcagcccagccat 9230 9249SEQ ID NO:5183atggaaaagggaaagagaa 13494 135131 3 SEQ ID NO: 3855tgaaagttcgttttcca 9283 9 3 0 2 SEQ ID NO: 5 1 84 tggaagtgtcagtggcaaa 10380 103991 3 SEQ ID NO: 38 5 6 cagggaagatagacttcct 9312 9331 SEQ ID NO:5185aggaccttcaaattcctg 9848 98671 3 SEQ ID NO: 38 5 7 ataagtacaaccaaaattt 9405 9 4 2 4 SEQ ID NO:5186aaatcaggatctgagttat 14038 140571 3 SEQID NO: 38 5 8 acaacgagaacattatgga 9435 9 4 5 4 SEQ ID NO:5187tccattctgaatatattgt 13380 133991 3 SEQ ID NO: 38 5 9aggaataaatggagaagca 9463 9482 SEQ ID NO: 5 18 8 tgctggaattgtcattcct 11734 117531 3 SEQ ID NO: 3860 agcaaatctggatttctta 9478 9 4 9 7 SEQ ID NO: 5 18 9 taagttctctgtacctgct 11719 117381 3 SEQ ID NO: 3861 tcctttaacaattcctgaa 9502 9521 SEQ ID NO: 5 19 0 ttcaaaacgagcttcagga 13206 132251 3 SEQ ID NO: 3862tttaacaattcctgaaatg 9505 9524 SEQ ID NO: 5 19 1 catttgatttaagtgtaaa 9621 96401 3 SEQ ID NO: 38 6 3 acacaataatcacaactcc 9534 9 5 5 3 SEQ ID NO:5192ggagacagcatcttcgtgt 11211 112301 3 SEQ ID NO: 3864aagatttctctctatggga 9561 9 5 8 0 SEQ ID NO: 5 19 3 tcccagaaaacctcttctt 3936 39551 3 SEQ ID NO: 3865gaaaaaacaggcttgaagg 9578 9597 SEQ ID NO:5194ccttttacaattcattttc 13021 130401 3 SEQ ID NO: 3866ttgaaggaattcttgaaaa 9590 9 6 09 SEQ ID NO: 5 19 5 gagaatgaatttcaa 10422 104411 3 SEQIDNO:3867tgaaggaattcttgaaaac 9591 9610SEQIDNO:5196gttttggtgataaattca 11291 113101 3 SEQ ID NO: 3868agctcagtataagaaaaac 9640 9 6 59 SEQ ID NO: 5 19 7 gtttgataagtacaaagct 9805 98241 3 SEQ ID NO: 3869tcaaatcctttgacaggca 9720 9 73 9 SEQ ID NO: 5 19 8 tgcctgagcagaccattga 11688 117071 3 SEQ ID NO: 3870latgaaacaaaaattaagtt 9789 9808 SEQ ID NO:5199aactttgcactatgttcat 12762 127811 3 SEQ ID NO: 3871 aattcctggatacactgtt 9859 9878 SEQ ID NO: 52 0 0 aacacatgaatcacaaatt 8938 89571 3 SEQ ID NO: 3872tccagttgtcaatgttga 9876 9 89 5 SEQ ID NO: 52 0 1 tcaaaacgagcttcaggaa 13207 132261 3 SEQ ID NO: 3 873aagtgtctccattcaccat 9894 9 9 13 SEQ ID NO:5202,atgggaagtataagaactt 4842 48611 3 SEQ ID NO: 3874gtcagcatgcctagtttct 9950 9 96 9 SEQ ID NO:5203agaaaaggcacaccttgac 11080 110991 3 SEQ ID NO: 3875ctgccatgggcaatattac 10113 10 13 2 SEQ ID NO:5204gtaagaaaatacagagcag 6440 64591 3 SEQ ID NO: 3876tgaataccaatgctgaact 10167 10 18 6 SEQ ID NO:5205agttgaaggagactattca 7224 72431 3 SEQ ID NO: 3877 tattgttgctcatctcctt 10201 10 2 2 0 SEQ ID NO:5206aaggaaacataaactaata 12889 129081 3 SEQ ID NO: 3878 tgttgctcatctcctttct 10204 10 2 2 3 SEQ ID NO: 5 2 0 7 agaagaaatctgcagaaca 12431 124501 3 SEQ ID NO: 3879 tctgtcattgatgcactgc 10232 10251 SEQ ID NO:5208,gcagtagactataagcaga 13928 139471 3 SEQIDNO: 3880ccacagotctgtctCtgag 10305 10 3 2 4 SEQ ID NO:5209ctcagggatctgaaggtgg 8195 82141 3 SEQ ID NO: 3881atttgtggagggtagtcat 10330 10 3 4 9 SEQ ID NO:5210atgaagtagaccaacaaat 7161 71801 3 SEQ ID NO: 3882 atatggaagtgtcagtggc 10377 10396 SEQ ID NO: 5 2 1 1 gccacactccaacgcatat 10778 107971 3 SEQ ID NO: 3883 tggaaataccaagtcaaaa 10453 10 4 7 2 SEQ ID NO: 5 2 12 ttttacaattcattttcca 13023 130421 3 SEQ ID NO: 3884aagtcaaaacctactgtct 10463 10 4 8 2 SEQ ID NO:5213agacctagtgattacactt 12859 128781 3 SEQ ID NO: 3885actgtctcttcctccatgg 10475 1 0 4 94 SEQ ID NO:5214,ccatgcaagtcagcccagt 10924 109431 3 314 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 38 8 6 ottcctccatggaatttaa 10482 10501 SEQ ID NO: 52 15 ttaatcgagaggtatgaag 7148 71671 3 SEQ ID NO: 3887 attcttcaatgctgtactc 10512 10531 SEQ ID NO:5216gagttgagggtccgggaat 12242 122611 3 SEQ ID NO: 3888 ttgaccacaagcttagctt 10548 10 56 7 SEQ ID NO: 52 1 7aagcgcacctcaatatcaa 12036 120551 3 SEQ ID NO: 38 8 gcctcacctcttacttttcc 10573 10 59 2 SEQ ID NO:5218ggaactattgctagtgagg 10649 106681 3 SEQ ID NO: 3 89 0 agctgcagggcacttccaa 10710 10729SEQ ID NO: 52 19 ttgggaagaagaggcagct 12289 123081 3 SEQ ID NO: 3891 ccaaaattgatgatatc 10723 10 74 2 SEQ ID NO:5220gatatacactagggaggaa 12745 127641 3 SEQ ID NO: 38921gagaacatacaagcaaagc 10860 10 87 9 SEQ ID NO: 52 2 1 gcttggttttgccagtctc 2467 24861 3 SEQ ID NO: 3 8 93 atggcaaatgtcagctctt 10897 10 9 16 SEQ ID NO:5222aagaggtatttaaagccat 12960 129791 3 SEQ ID NO: 3894ggcaaatgtcagctcttg 10898 10 9 17 SEQ ID NO:5223caagaggtatttaaagcca 12959 129781 3 SEQ ID NO: 3895tgttcaggtccatgcaag 10914 10933SEQ ID NO:5224cttgggggaggaggaacaa 14066 140851 3 SEQ ID NO: 3896 gttcaggtccatgcaagt 10915 10 9 34 SEQ ID NO:5225acttgggggaggaggaaca 14065 140841 3 SEQ ID NO: 3897agttccttccatgatttcc 10940 10 9 59 SEQ ID NO:5226ggaatctgatgaggaaact 12256 122751 3 SEQ ID NO: 3898tgctaacactaagaaccag 10987 1 10 06 SEQ ID NO: 52 2 7ctggatgtaaccaccagca 11186 112051 3 SEQ ID NO: 3 8 9 9 actaagaaccagaagatca 10994 1 10 13 SEQ ID NO: 52 2 8 gatcaagaacctgttagt 13347 133661 3 SEQ ID NO: 3 9 0 0 ctaagaaccagaagatcag 10995 1 10 14 SEQ ID NO:5229ctgatcaagaacctgtag 13346 133651 3 SEQ ID NO: 3901 cagaagatcagatggaaaa 11003 1 102 2 SEQ ID NO: 52 3 0 ttcagaccaactctctg 13622 136411 3 SEQ ID NO: 3 9 02 1aaaaatgaagtccggattc 11018 1 10 37 SEQ ID NO:5231 gaatttgaaagttcgtt 9280 92991 3 SEQ ID NO: 3903 gattcattctgggtetttc 11032 1 10 5 1 SEQ ID NO: 5232 gaaaacctatgccttaatc 13166 131851 3 SEQ ID NO: 39 04 aagaaaaggcacaccttga 11079 1 10 98 SEQ ID NO: 52 3 3 tcaaaacctactgtctctt 10466 104851 3 SEQ ID NO: 39 0 5 aaggacacctaaggttcct 11115 11134 SEQ ID NO:5234aggacaccaaaataacctt 7572 75911 3 SEQ ID NO: 3906 ccagcattggtaggagaca 11199 1 12 18 SEQ ID NO: 52 3 5 tgtcaacaagtaccactgg 12370 123891 3 SEQ ID NO: 3907ctttgtgtacaccaaaaac 11239 1 12 5 8 SEQ ID NO:5236gtttttaaattgttgaaag 13148 131671 3 SEQ ID NO: 3908 ccatccctgtaaaagtttt 11277 1 12 9 6 SEQ ID NO: 52 3 7 aaaagggtcatggaaatgg 8893 89121 3 SEQ ID NO: 3909 tgatctaaattcagttctt 11332 11351 SEQ ID NO:5238aagatagtcagtctgatca 13334 133531 3 SEQ ID NO: 3 9 1 0 aagaagctgagaactcat 11432 11451 SEQ ID NO:5239atgagatcaacacaatctt 13110 131291 3 SEQ ID NO: 3911 tttgccctcaacctaccaa 11453 1 14 72 SEQ ID NO: 52 4 0 tggtacgagttactcaaa 12641 126601 3 SEQ ID NO: 39 1 2 cttgattccttttttgag 11536 1 15 5 5 SEQ ID NO: 52 4 1 ctcaattttgattttcaag 8528 85471 3 SEQ ID NO: 3913tcacgcttccaaaaagtg 11591 1 16 1 0 SEQ ID NO:5242cactcattgattttctgaa 12693 127121 3 SEQ ID NO: 3914 gtttcagatggcattgct 11608 1 16 2 7 SEQ ID NO:5243agcagattatgttgaaaca 11833 118521 3 SEQ ID NO: 39 1 5 aatgcagtagccaacaaga 11639 11658 SEQ ID NO: 52 4 4 tcttttcagcccagccatt 9231 92501 3 SEQ ID NO: 39 1 6ctgagcagaccattgagat 11691 1 17 1 0 SEQ ID NO:5245atctgatgaggaaactcag 12259 122781 3 SEQ ID NO: 3917tgagcagaccattgagatt 11692 11711 SEQ ID NO:5246aatctgatgaggaaactca 12258 122771 3 SEQ ID NO: 3918 gagattccctccattaa 11703 1 17 2 2 SEQ ID NO: 52 4 7 aatcttcataagttcaa 13179 131981 3 SEQ ID NO: 39 1 9acttggagtgccagtttga 11807 11826 SEQ ID NO: 52 4 8 tcaattgggagagacaagt 6504 65231 3 SEQ ID NO: 3 9 2 0 1caaatttgaaggacttcag 12004 1 20 2 3 SEQ ID NO:5249ctgagaacttcatcatttg 11438 114571 3 SEQ ID NO: 3921 agcccagcgttcaccgatc 12056 1 20 7 5 SEQ ID NO: 52 50 gatccaagtatagttggct 13286 133051 3 SEQ ID NO: 3 92 2 cagcgttcaccgatctcca 12060 1 20 7 9 SEQ ID NO: 5 25 1 tggacctgcaccaaagctg 13960 139791 3 SEQ ID NO: 3923ictccatctgcgctaccaga 12074 12093SEQ ID NO:5252tctgatatacatcacggag 13711 137301 3 SEQ ID NO: 3 92 4 atgaggaaactcagatcaa 12264 1 22 8 3 SEQ ID NO: 5 2 53 gagttgcccaccatcat 11667 116861 3 SEQ ID NO: 3 92 5 aggcagcttctggcttgct 12300 1 23 1 9 SEQ ID NO:5254agcaagtctttcctggcct 3018 30371 3 SEQ ID NO: 3926 tgaaagacaacgtgcccaa 12327 12346SEQ ID NO:5255ttgggagagacaagtttca 6508 65271 3 SEQ ID NO: 3927 atgattatgtcaacaagt 12362 12381 SEQ ID NO:5256actttgcactatgftcata 12763 127821 3 SEQ ID NO: 3 9 2 8 1cattaggcaaattgatgat 12475 12494 SEQ ID NO: 5 2 5 7 atcaacacaatcttcaatg 13115 131341 3 SEQ ID NO: 3929 gactcaggaaggccaag 12584 12603 SEQ ID NO:5258cttggtacgagttactcaa 12640 126591 3 SEQ ID NO: 39 3 0 gaaacctgggatatacact 12736 12755SEQ ID NO:5259agtgattacacttcctttc 12865 128841 3 SEQ ID NO: 3931 tccttcgagtaaggaaa 12877 12896 SEQ ID NO: 5 2 60 tttctgccactgctcagga 13524 135431 3 SEQ ID NO: 3 9 3 2 gccattcagtctctcaaga 12974 12993 SEQ ID NO:5261tcttccgttctgtaatggc 5802 58211 3 315 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 3933 gtgctacgtaatcttcagg 13001 13020SEQIDNO:5262 cctgcaccaaagctggcac 13964 139831 3 SEQ ID NO: 3934 agctgaaagagatgaaatt 13065 13 0 84 SEQ ID NO: 52 6 3 aatttattcaaaacgagct 13200 132191 3 EQID NO: 3935aatttacttatctattaa 13080 13099SEQ ID NO:5264f taaaagaaatctcaatt 13815 138341 3 SEQID NO: 3936 ttttaaattgtgaaagaa 13150 13 16 9 SEQ ID NO:5265ttctctctatgggaaaaaa 9566 95851 3 SEQ ID NO: 3937 taatcttcataagttcaat 13180 1 3 19 9 'SEQ ID NO:5266 attgagattccctccafta 11702 117211 3 SEQ ID NO: 3938 atatttligatccaagtata 13279 13 2 9 8 SEQ ID NO: 52 6 7tataagcagaagcacatat 13937 139561 3 SEQ ID NO: 3939 tgaaatattatgaacttga 13311 13 3 3 0 SEQ ID NO: 52 6 8 tcaaccttaatgattttca 8295 83141 3 EQ ID NO: 3940caatittgcacagaaata 13442 13461 SEQ ID NO: 5 2 6 9 tattcttcttttccaattg 13834 138531 3 SEQ ID NO: 3941 agaagattgcagagctttc 13509 13 52 8 SEQIDNO:5270gaaatcttcaatttattet 13821 138401 3 SEQ ID NO: 3942gaagaaaataatttctgat 13570 13 58 9 SEQ ID NO:5271atcagttcagataaacttc 7999 80181 3 SEQIDNO: 3943ttgacctgtccattcaaaa 13680 1 36 9 9 SEQIDNO:5272tgagaatgaatttcaa 10422 104411 3 SEQ ID NO: 3944 tcaaaactaccacacattt 13693 13 7 1 2 SEQ ID NO:5273aaatccftgacatgtga 7370 73891 3 SEQ ID NO: 394 aaaagaaatcttc 13811 1 3 83 0 SEQ ID NO:5274,gaagtgtcagtggcaaaaa 10382 104011 3 SEQ ID NO: 3946aggatctgagttattttgc 14043 14062SEQ ID NO: 275gcaagggttcactgttcct 7864 78831 3 SEQ ID NO: 3947ttgctaaacttgggggag 14057 14076 SEQIDNO:5276ctccccaggacctttcaaa 9842 98611 3 316 WO 2004/091515 PCT/US2004/011255 Table 11. Selected palindromic sequences from human glucose-6-phosphatase Source Start End Match Start End B Index Index Index Index SEQ ID NO: 5291 tccatcttcaggaagctgt 222 241 SEQ ID NO: 5369acagactctttcagatgga 1340 13591 6 SEQ ID NO:5292ccatcttcaggaagctgtg 223 242SEQ ID NO:5370cacagactctttcagatgg 133 13581 6 SEQ ID NO: 5293cctctggccatgccatggg 417 4 36SEQ ID NO:5371cccattttgaggccagagg 1492 151116 SEQ ID NO:5294ctctggccatgccatgggc 418 4 37SEQ ID NO:5372gcccattttgaggccagag 1491 15101 6 SEQ ID NO: 5295 ttgaatgtcattttgtggt 521 540SEQ ID NO: 5373accatacattatcattcaa 2945 29641 6 SEQ ID NO:5296 tcagtaatgggggaccagc 1886 1905SEQ ID NO:5374gctggtctcgaactcctga 2731 27501 6 SEQ ID NO:5297ttttactgtgceatacatgt 1956 19 7 5SEQ ID NO:5375acatctttgaaaagaaaaa 2983 30021 6 SEQ ID NO: 5298tgaggtgccaaggaaatga 50 69 SEQ ID NO:5376tcatgtctcagcctcctca 262C 26391 5 SEQ ID NO: 5299 gaggtgccaaggaaatgag 51 70SEQ ID NO:5377ctcatgtctcagcctcctc 2619 26381 5 SEQ ID NO:5300gggaaagataaagccgacc 487 506SEQ ID NO:5378ggtcgcctggcttattccc 1295 1311 5 SEQ ID NO:5301 tttcctcatcaagttgtt 598 6 17SEQ ID NO: 5 3 7 9aacatctttgaaaagaaaa 2982 30011 5 SEQ ID NO:5302ctttcagccacatccacag 651 67 0SEQ ID NO:5 3 80ctgtggactctggagaaag 773 7921 5 SEQ ID NO:5303 ggactctggagaaagccc 776 79 5SEQ ID NO: 5381 gggctggctctcaactcca 884 9031 5 SEQ ID NO:5304agcctcctcaagaacctgg 848 867 SEQ ID NO:5382ccagattcttccactggct 2107 21261 5 SEQ ID NO: 5 3 0 5 ggcctggggctggctctca 878 8 97 SEQ ID NO: 53 83 gagccaccgcaccgggcc 2801 28201 5 SEQ ID NO: 5306gagctcactcccactggaa 1439 14 58 SEQ ID NO:5384 ccaggtagg gctc 1676 16951 5 SEQ ID NO:|5307agctaatgaagctattgag |1572 1591 SEQ ID NO:5385tcagcctcctcagtagct 2626 26451 5 SEQ ID NO:5308gctaatgaagctattgaga 1573 1592 |SEQ ID NO: 5386 ctcagcctcctcagtagc 2625 26441 5 SEQ ID NO:5309 ctaaatggctttaattata 1854 1 87 3SEQ ID NO:5387 tatatttttagaattttag 2683 27021 5 SEQ ID NO:5310ctgcttttctttttttttc 2509 2 52 8 SEQ ID NO:5388gaaaaatatatatgtgcag 2996 30151 5 SEQ ID NO: 5311 caatcaccaccaagcctgg 0 19SEQ ID NO:5 3 89ccagaatgggtccacattg 812 8311 4 SEQ ID NO:5312 agcctggaataactgcaag 12 31 SEQ ID NO:539Ccttggatttctgaatggct 1987 20061 4 SEQ ID NO: 5313gttccatcttcaggaagct 220 23 9SEQ ID NO: 5391 agctcactcccactggaac 1440 14591 4 SEQ ID NO: 5314 ggtgggttttggatactg 326 345SEQ ID NO:5392cagtcctcccaccctacca 2425 24441 4 SEQ ID NO: 53151acctgtgagactggaccag 392 411 SEQ ID NO:5 3 93ctggagaaagcccagaggt 782 8011 4 SEQ ID NO: 5316gctgttacagaaactttca 638 6 57SEQ ID NO:5394 gaatggtcttctgccagc 1474 14931 4 SEQ ID NO:5317acagcatctataatgccag 666 6 85sEQ ID NO:5395ctgggtgtagacctcctgt 758 7771 4 SEQ ID NO:5318gggtgtagacctcctgtgg 760 779SEQ ID NO:5396ccacattgacaccacaccc 823 8421 4 SEQ ID NO: 5319ggtgtagacctcctgtgga 761 7 80SEQ ID NO:5 397 tccacattgacaccacacc 822 84114 SEQ ID NO: 53201gtgtagacctcctgtggac 762 781 SEQ ID NO: 5398 gtccacattgacaccacac 821 8401 4 SEQ ID NO: 5321 gacctcctgtggactctgg 767 7 8 6 SEQ ID NO:5399 ccagatattgcactaggtc 2014 203314 SEQ ID NO: 5322cctgggcacgctctttggc 862 881 SEQ ID NO:5 4 00gccagctcacaagcccagg 1687 17061 4 SEQ ID NO:5323ctgggcacgctctttggcc 863 882 SEQ ID NO: 5401 ggccagctcacaagcccag 1686 17051 4 SEQ ID NO:5324ctggtcttctacgtcttgt 1028 104 7 SEQ ID NO:5 4 02acaaaagcaagacttccag 1663 16821 4 SEQ ID NO: 5325agagtgcggtagtgcccct 1056 1075SEQ ID NO:5 4 3agggccaggattcctctct 2229 22481 4 SEQ ID NO:5326tgggcactggtatttggag 1217 12 3 6EQ ID NO: 404 ct~ccactggaacagccca 1446 146514 SEQ ID NO:5327gaattaaatcacggatggc 1267 1 2 86 SEQ ID NO:5405 gccaaccaagagcacattc 2311 233014 SEQ ID NO: 5328 gttgctagaagttgggtt 1598 161 7 SEQ ID NO: 540 aaccatcctgctcataaca 2967 298614 SEQ ID NO: 53291aggagctctgaatctgata 1764 178 3 SEQ ID NO:5407 tatcacattacatcatcct 2063 20821 4 SEQ ID NO:5330 aaatggctttaattatat 1855 1 8 74SEQ ID NO:5 4 08 atatatgtgcagtatttta 3003 30221 4 SEQ ID NO:53311aaaatgacaaggggagggc 2215 2234SEQ ID NO: 5409 gccctccttgcctgttttt 2817 28361 4 SEQ ID NO:5332ttaaaggaaaagtcaacat 2330 234 9 SEQ ID NO:5410atgtgcagtattttattaa 3007 3021 4 SEQ ID NO:5333acatcttctctcttttttt 2345 2364 SEQ ID NO: 5411 aaaagaaaaatatatatgt 2992 301114 SEQ ID NO:5334ttctacgtcctcttcccca 197 2 16 SEQ ID NO:1541 2 tgggccagccgcacaagaa 1116 11351 3 317 WO 2004/091515 PCT/US2004/011255 SEQ ID NO:5335tgggtagctgtgattggag 257 276SEQ ID NO:5413ctcccactggaacagccca 1446 14651 3 SEQ ID NO:5336gctgtgattggagactggc 263 282SEQ ID NO: S 4 1 4 gccatgccatgggcacagc 423 44213 SEQ ID NO:5337cacttccgtgcccctgata 358 377SEQ ID NO:5415 atcacccaggctggagtg 2548 25671 3 SEQ ID NO:|5338acatctactctttccatct 464 483SEQ ID NO:5416agatgggatttcatcatgt 2705 27241 3 SEQ ID NO: 5339ctactctttccatctttca 468 487SEQ ID NO:5417 gaatactctcacaagtag 1419 14381 3 SEQ ID NO: 5340agataaagccgacctacag 492 511 SEQ ID NO: 5418ctgtttttcaatctcatct 2828 28471|3 SEQ ID NO: 5341 tgtgcagctgaatgtctgt 553 572SEQ ID NO:5419acagaaactttcagccaca 644 6631 3 SEQ ID NO: 5342atgtctgtctgtcacgaat 564 583SEQ ID NO:5420attcaggtatagctgacat 2038 20571 3 SEQ ID NO:5343ictgtcacgaatctaccttg 572 591 SEQ ID NO: 5421 caaggtgctaggattacag 2779 27981 3 SEQ ID NO: 5344[atcaagttgttgctggagt 606 6 25 SEQ ID NO:5 4 2 2 actcctgacctcaagtgat 2742 27611 3 SEQ ID NO: 5345cagaaactttcagccacat 645 6 6 4 SEQ ID NO:5423atgtttcaattaggctctg 2185 22041 3 SEQ ID NO: 5346 actttcagccacatccaca 650 669 SEQ ID NO: 5424 tgtggcgtatcatgcaagt 1818 18371 3 SEQ ID NO:5347 atgccagcctcaagaaata 678 6 9 7SEQ ID NO:5425 tatttttttactgtgcat 1950 19691 3 SEQ ID NO:5348agaaatattttctcattac 690 7 09SEQ ID NO:5426gtaaatatgactcctttct 2283 23021 3 SEQ ID NO:5349gaaatattttctcattacc 691 7 01SEQ ID NO:5427ggtaaatatgactcctttc 2282 23011 3 SEQ ID NO:5350 tgctgctcaagggactggg 744 763 SEQ ID NO:5 4 2 8 cccaagccaaccaagagca 2306 23251 3 SEQ ID NO:5351 cctgtggactctggagaaa 772 7911SEQ ID NO:5 4 2 9tttcatcatgttggccagg 2713 27321 3 SEQ ID NO:5352ggagaaagcccagaggtgg 784 8 0 3 SEQ ID NO:5 4 3 C ccaccgcaccgggccctcc 2805 28241 3 SEQ ID NO: 5353ttgaaacccccatcccaag 1004 1023SEQ ID NO: 5431 cttgaattcctgggctcaa 2405 24241 3 SEQ ID NO: 5354cagatggaggtgccatatc 1351 1 3 7 0SEQ ID NO: 5 4 3 2gatatgcagagtatttctg 2847 28661 3 SEQ ID NO:5355ggagctcactcccactgga 1438 1457SEQ ID NO:5433tccacctgccttggcctcc 2760 27791 3 SEQ ID NO: 5356 ttgggtaatgttttgaaa 1553 1572SEQ ID NO:!5434tttctctatcccaagccaa 2297 23161 3 SEQ ID NO:5357gaagttgggttgttctgga 1606 16 25SEQ ID NO:5435 ccaccccactggatcttc 2131 21501 3 SEQ ID NO: 5358 aaaagaaggctgcctaagg 1785 1804SEQ ID NO:5436ccttgcctgcttttctttt 2503 25221 3 SEQ ID NO:5359aaagaaggctgcctaagga 1786 1805SEQ ID NO:5^ 4 37tccttgcctgcttttcttt 2502 25211 3 SEQ ID NO:5360 aagaaggctgcctaaggag 1787 1 8 0 6SEQ ID NO:5438ctccttgcctgcttttctt 2501 25201 3 SEQ ID NO: 5361 agaaggctgcctaaggagg 1788 1 8 0 7SEQ ID NO:5439cctccttgcctgcttttct 2500 25191 3 SEQ ID NO: 5362 atttccttggatttctgaa 1982 2001 SEQ ID NO:5 4 4 0 ttcaattaggctctgaaat 2189 22081 3 SEQ ID NO: 5363tccttataagcccagctct 2081 2 100 SEQ ID NO:5441 agagcacattcttaaagga 2319 23381 3 SEQ ID NO:5364ataagcccagctctgcttt 2086 2 1 05 5 EQ ID NO: 4 4 2aaag tgaagcctatttat 2889 29081 3 SEQ ID NO:5365ggccaggattcctctctca 2231 2 2 5 0 SEQ ID NO: 54 4 3 gagccaccgcaccgggcc 2801 28201 3 SEQ ID NO:5366gccaactcctccttgcctg 2493 2 5 1 2 SEQ ID NO:5 4 44caggtggagtggagtggc 2555 25741 3 SEQ ID NO:5367 tttttttctttttttgag 2519 2 5 3 8SEQ ID NO:5 4 4 5ctcataacatctttgaaaa 2977 29961 3 SEQ ID NO:5368ccggcgtgcaccaccatgc 2652 2671 SEQ ID NO:5 4 4 6 gcatgagccaccgcaccgg 2798 28171 3 318 WO 2004/091515 PCT/US2004/011255 Table 12. Selected palindromic sequences from rat glucose-6-phosphatase Source Start End Match Start End B Index Index Index Index SEQ ID NO:5447ctgactattacagcaacag 301 3 20 SEQ ID NO:5471ctgtggctgaaactttcag 598 61716 SEQ ID NO:5448ctcttggggttggggctgg 831 8 501SEQ ID NO:5472ccagcatgtaccgcaagag 859 8781 6 SEQ ID NO:5449tgcaaaggagaactgcgca 879 8 98 SEQ ID NO:5473tgcgaccgtcccctttgca 1019 10381 6 SEQ ID NO: 5450cctcgggccatgccatggg 376 3 9 5SEQ ID NO: 5474cccagtgtggggccagagg 1171 11901 5 SEQ ID NO:5451 tgagcaaaccatatgcaa 1478 1497 SEQ ID NO:5475ttgcagagtgtgtcttcaa 2057 20761 5 SEQ ID NO:5452cagcttcctgaggtaccaa 2 21 SEQ ID NO:5476ttggtgtctgtgatcgctg 123 1421 4 SEQ ID NO:5453ggtaccaaggaggaaggat 13 3 2 1SEQ ID NO:5477atccagtcgactcgctacc 66 851 SEQ ID NO:5454ctccacgactttgggatcc 51 7 0 SEQ ID NO:5478ggatcgggaggagggggag 1448 14671 4 SEQ ID NO:5455caggactggtttgtcttgg 108 127SEQ ID NO:5479ccaagcccgactgtgcctg 2018 20371 4 SEQ ID NO:5456cttctatgtcctctttccc 155 17 4 SEQ ID NO:5480gggacagacaacaagaag 1076 109514 SEQ ID NO:545 7 ttctatgtcctctttccca 156 17 5 SEQ ID NO: 548 1 gggacagacacacaagaa 1075 109414 SEQ ID NO:5458 tggttccacattcaagaga 177 1961SEQ ID NO:5482tctcaataatgatagacca 1549 156814 SEQ ID NO:5459tgcctctgataaaacagtt 325 344 1SEQ ID NO:5483aactctgagatcttgggca 1868 188711 SEQ ID NO:5460agcccggctcctgggacag 1064 1083 SEQ ID NO:5484ctgtcctccagcctgggct 2034 20531 4 SEQ ID NO: 5461 agtctctgacacaagtcag 1111 1130 SEQ ID NO:5485ctgaatggtaatggtgact 1659 16781 4 SEQ ID NO:5462aaaaaggtgaatttttaaa 1237 1256 SEQ ID NO:5486tttattaaaacgacatttt 2201 22201 4 SEQ ID NO:5463acactctcaataatgatag 1545 1564SEQ ID NO:5487ctatgaatgatgcctgtgt 2121 214014 SEQ ID NO:5464aaagaatgaacgtgctcca 37 56,SEQ ID NO:5488tggacctcctgtggacttt 724 7431 3 SEQ ID NO:5465ctttgggatccagtcgact 59 78SEQ ID NO:5489agtcagcggccgtgcaaag 1124 11431 3 SEQ ID NO:5466,gtgatcgctgacctcagga 132 151 SEQ ID NO:5490tcctctctccaaaggtcac 1911 19301 3 SEQ ID NO:5467ggaacgccttctatgtcct 148 167SEQ ID NO:5491 aggactcatcactgcttcc 1748 17671 3 SEQ ID NO:5468gactgtgggcatcaatctc 194 213SEQ ID NO:5492gagactggaccagggagtc 357 3761 3 SEQ ID NO:5469ggacactgactattacagc 296 3151SEQ ID NO:5493gctgaacgtctgtctgtcc 518 5371 3 SEQ ID NO:5470aagcccccgtcccagattg 966 985 SEQ ID NO:5494caattgtttgctggtgctt 1833 18521 3 319 WO 2004/091515 PCT/US2004/011255 Table 13. Selected palindromic sequences from human B-catenin Source Start End Match Start End B Index Index Index Index SEQ ID NO: 5495agcagcttcagtccccgcc 70 8 9SEQ ID NO: 5542ggcgacatatgcagctgct 2152 21711 5 SEQ ID NO: 5496 ccattctggtgccactacc 304 3 2 3 SEQ ID NO:5543ggtatggaccccatgatgg 2387 240615 SEQ ID NO:5497tccttctctgagtggtaaa 328 3 4 7 SEQ ID NO:5544tttattacatcaagaagga 985 10041 5 SEQ ID NO:5498 tctgagtggtaaaggcaat 334 353 SEQ ID NO:5545attgtacgtaccatgcaga 791 8101 5 SEQ ID NO: 5499cagagggtacgagctgcta 473 492 SEQ ID NO:5546tagctgcaggggtcctctg 2037 20561 5 SEQ ID NO: 5500ctaaatgacgaggaccagg 677 6 9 6 SEQ ID NO:5547cctgtaaatcatcctttag 2539 25581 5 SEQ ID NO:5501 taaatgacgaggaccaggt 678 6 971SEQ ID NO: 5548acctgtaaatcatccttta 2538 25571 5 SEQ ID NO: 5502gtcctgtatgagtgggaac 383 4 02SEQ ID NO:5549gttccgaatgtctgaggac 2176 2195214 SEQ ID NO: 5503cccagcgccgtacgtccat 1839 1 858SEQ ID NO:5550atgggctgccagatctggg 2451 247024 SEQ ID NO: 5504tcccctgagggtatttgaa 143 162 SEQ ID NO:5551 ttcacatcctagctcggga 1929 194814 SEQ ID NO:5505gggtatttgaagtatacca 151 170SEQ ID NO:5552tggttaagtcttacaccc 1680 16991 4 SEQ ID NO:5506gctgttagtcactggcagc 260 2 7 9 SEQ ID NO:5553gctgcctccaggtgacagc 2494 25131 4 SEQ ID NO:5507gtcctgtatgagtgggaac 383 4 02SEQ ID NO:5554gttcgccttcactatggac 1652 1671114 SEQ ID NO: 5508tcctgtatgagtgggaaca 384 4031SEQ ID NO:5555tgttccgaatgtctgagga 2175 21941 4 SEQ ID NO:5509gtatgcaatgactcgagct 454 4731SEQ ID NO:5556agctggcctggtttgatac 2517 25361 4 SEQ ID NO:551Ogtccagcgtttggctgaac 563 582 SEQ ID NO:5557gttcgccttcactatggac 1652 16711 4 SEQ ID NO: 5511 tatcaagatgatgcagaac 623 642 SEQ ID NO:5558 gttcgtgcacatcaggata 1820 18391 4 SEQ ID NO: 5 5 1 2 tatggtccatcagctttct 718 7 3 7 SEQ ID NO:5559agaaagcaagctcatcata 1126 11451 4 SEQ ID NO:5513ccctggtgaaaatgcttgg 915 9 3 4 SEQ ID NO:5560ccaaagagtagctgcaggg 2029 20481 4 SEQ ID NO:5514agctttaggacttcacctg 1291 1310 SEQ ID NO: 5 5 6 1 caggtgacagcaatcagct 2502 252114 SEQ ID NO:5515ggaatcttcagatgctgc 1356 1375SEQ ID NO:5562 gcagctgctgttttgttcc 2162 21811 4 SEQ ID NO: 5 5 1 6 gtccttcgggctggtgac 1549 1 5 6 8 SEQ ID NO:5563gtcatctgaccagccgaca 1605 16241 4 SEQ ID NO:5517 cacagctcctctgacagag 2107 2126SEQ ID NO:5564ctctaggaatgaaggtgtg 2134 21531 4 SEQ ID NO:5518ccagacagaaaagcggctg 245 2 6 4 SEQ ID NO:5565cagctcgttgtaccgctgg 828 84723 SEQ ID NO:5519cagcagcgttggcccggcc 4 2 3 SEQ ID NO:5566ggccaccaccctggtgctg 2420 243913 SEQ ID NO:5520aggtCtgaggagcagcttc 60 79SEQ ID NO:55671gaagaggatgtggatacct 359 3781 3 SEQ ID NO:5521 actgttttgaaaatccagc 174 193SEQ ID NO:5568gctgatattgatggacagt 437 4561 3 SEQ ID NO:5522ctgatttgatggagttgga 213 2 3 2 SEQ ID NO:5569tccaggtgacagcaatcag 2500 25191 3 SEQ ID NO:5523ccagacagaaaagcggctg 245 2 6 4 SEQ ID NO:5570cagcaacagtcttacctgg 275 2941 3 SEQ ID NO:5524acagctccttctctgagtg 323 342SEQ ID NO:5571 cactgagcctgccatctgt 1579 15981 3 SEQ ID NO:5525 ggatacctcccaagtcct 369 3 8 8 SEQ ID NO:55721aggactaaataccattcca 1972 19911 3 SEQ ID NO:5526 tcaagaacaagtagctgat 424 443SEQ ID NO:5573 atcagctggcctggtttga 2514 253313 SEQ ID NO:5527agctcagagggtacgagct 469 488SEQ ID NO:5574agctggtggaatgcaagct 1276 12951 3 SEQ ID NO:5528gcatgcagatcccatctac 516 535SEQ ID NO:5575gtagaagctggtggaatgc 1271 12901 3 SEQ ID NO: 5529 ccacacgtgcaatccctga 645 66 4 SEQ ID NO:5576 tcagatgatataaatgtgg 1430 14491 3 SEQ ID NO:5530cacacgtgcaatccctgaa 646 6 6 5SEQ ID NO:5577 tcagatgatataaatgtg 1429 14481 3 SEQ ID NO:5531 ggaccttgcataacctttc 846 865SEQ ID NO:5578 gaaatcttgccctttgtcc 1743 17621 3 SEQ ID NO:5532c tccacaaccttttattac 974 993SEQ ID NO:5579gtaaatcatcctttaggag 2542 25611 3 SEQ ID NO:5533cagagtgctgaaggtgcta 1222 1241 SEQ ID NO: 5580tagctgcaggggtcctctg 2037 20561 3 SEQ ID NO:5534ggactctcaggaatctttc 1347 1 3 6 6 1SEQ ID NO:5581 gaaatcttgccctttgtcc 1743 17621 3 SEQ ID NO: 5 5 3 5 gatataaatgtggtcacc 1435 1 4 5 4 SEQ ID NO:5582,ggtgacagggaagacatca 1562 15811 3 SEQ ID NO:5536,cccagcgccgtacgtccat 1839 1858 SEQ ID NO:5583 atggccaggatgccttggg 2370 23891 3 SEQ ID NO:5537 gtccatgggtgggacacag 1852 1871 SEQ ID NO: 5584 ctgtgaacttgctcaggac 2053 20721 3 SEQ ID NO:5538ttgtaccggagcccttcac 1915 1934SEQ ID NO:5585gtgaacttgctcaggacaa 2055 207413 SEQ ID NO:|5539 tgttatcagaggactaaa 1962 1981 SEQ ID NO: 5586 ttaggagtaacaatacaa 2553 25721 3 SEQ ID NO:5540gaagctattgaagctgagg 2084 2 103SEQ ID NO:,5587 cctctgacagagttacttc 2114 21331 3 SEQ ID NO: 5 5 4 1 cagaacagagccaatggc 2247 2 2 6 6 SEQ ID NO:5588jgccaccaccctggtgctga 2421 24401 3 320 WO 2004/091515 PCT/US2004/011255 Table 14. Selected palindromic sequences from human hepatitis C virus (HCV) Source Start End Match Start End#B Index Index Indexindex SEQ ID NO:5589cagcacctgggtgctggta 5314 5333SEQ ID NO:6135taccatcacccagctgctg 6196 62151 9 SEQ ID NO:5590aactcgtccggatgcccgg 1682 1701 SEQ ID NO:6136 ccgggcagcgggtcgagtt 8202 82211 8 SEQ ID NO:5591cgctgctgggtagcgctca 1049 1068SEQ ID NO:6137tgagagcgacgccgcagcg 6151 617017 SEQ ID NO:55921ctccggatcccacaagccg 1352 1371 SEQ ID NO:6138cggcatgtgggcccgggag 6053 60721 7 SEQ ID NO: 5593tgtaacatcgggggggtcg 2048 2067SEQ ID NO:6139cgacccctcccacattaca 6871 68901 7 SEQ ID NO:5594gtaacatcgggggggtcgg 2049 2068SEQ ID NO: 6140 ccgacccctcccacattac 6870 68891 7 SEQ ID NO: 5595cagccaccaagcaggcgga 5556 5575SEQ ID NO: 6141 tccggctggttcgttgctg 9254 92731 7 SEQ ID NO:5596 ctcaccacccagaacaccc 5744 5763SEQ ID NO: 6142 gggtgtgcacggtgttgag 6291 63101 7 SEQ ID NO: 5597ccagccttaccatcaccca 6189 6208SEQ ID NO: 6143 tgggcgctggtatcgctgg 5832 58511 7 SEQ ID NO:5598ctacgccgtgttccggctc 6249 626 8 SEQ ID NO: 6144gagcccgaaccggacgtag 6830 68491 7 SEQ ID NO: 55991tacgccgtgttccggctcg 6250 6269SEQ ID NO:6145cgagcccgaaccggacgta 6829 68481 7 SEQ ID NO: 5600 gagttcctggtaaaagcct 8216 8235SEQ ID NO: 6146aggctatgactaggtactc 8634 86531 7 SEQ ID NO: 5601 atggcggggaactgggcta 1430 1449SEQ ID NO: 6147tagcgcattttcactccat 9019 90382 6 SEQ ID NO:5602 aaccaaacgtaacaccaac 370 389SEQ ID NO:6148,gttgccgctaccttaggtt 4115 41341 6 SEQ ID NO:5603 ggtggtcagatcgttggtg 419 43 8 SEQ ID NO:6149caccagcccgctcaccacc 5734 57531 6 SEQ ID NO: 5604 ccttggcccctctatggca 584 603SEQ ID NO: 6150 tgccaacgtgggtacaagg 6374 63931 6 SEQ ID NO: 56051taccccggccacgcgtcag 1265 1284SEQ ID NO: 6151 ctgacgactagctgcggta 8465 84841 6 SEQ ID NO:5606gggcacgtgCCcgcctca 1508 1527SEQ ID NO:6152tgagacgacgaccgtgccc 4759 47781 6 SEQ ID NO: 5607ctgcaatgactccctccag 1624 16 4 3SEQ ID NO: 6153ctggtggccctcaatgcag 2594 26131 6 SEQ ID NO: 5608aaccgatcgtctcggcaac 1897 1916SEQ ID NO: 6154gttgccgctaccttaggtt 4115 41341 6 SEQ ID NO:5609gtgcggggcccccccgtgt 2032 2051 SEQ ID NO: 6155acaccacgggcccctgcac 6537 65561 6 SEQ ID NO:5610latgtggggggcgtggagca 2238 2257SEQ ID NO:6156tgctcaatgtcctacacat 7610 76291 6 SEQ ID NO: 5611 ggagagcgttgcaacttgg 2288 2307SEQ ID NO: 6157ccaagctcaaactcactcc 9207 92261 6 SEQ ID NO:5612cgtccgttgccggagcgca 2613 2632 SEQ ID NO:6158tgcgagcccgaaccggacg 6827 68461 6 SEQ ID NO:5613gtctggcattattgacctt 2817 2836SEQ ID NO:6159aaggtcacctttgacagac 7763 77821 6 SEQ ID NO:5614tctttgatatcaccaaact 2997 3016SEQ ID NO:6160agttcgatgaaatggaaga 5454 54731 6 SEQ ID NO:56151cttctgattgccatactcg 3014 3033 SEQ ID NO: 6161 cgagcaattcaagcagaag 5518 55371 6 SEQ ID NO:5616gcggcgtgtggggacatca 3314 3333SEQ ID NO:6162tgatcacgccatgcgccgc 7641 76601 6 SEQ ID NO:5617gggacatcatcctgggcct 3324 3343SEQ ID NO:6163aggcggtggattttgtccc 3915 39341 6 SEQ ID NO: 56181gggcgtcttccgggccgct 3874 3893SEQ ID NO: 6164agcggcacggcgaccgccc 7439 74581 6 SEQ ID NO:5619ggcgtcttccgggccgctg 3875 3894 SEQ ID NO: 6165cagcggcacggcgaccgcc 7438 74571 6 SEQ ID NO: 56201gcgtcttccgggccgctgt 3876 3895SEQ ID NO: 6166acaggtgccctgatcacgc 7631 76501 6 SEQ ID NO:5621 gtccccggtcttcacagac 3961 3980SEQ ID NO:6167gtcttggaagaacccggac 7252 72711 6 SEQ ID NO:5622catcaggactggggtaagg 4174 4193SEQ ID NO: 6168ccttcctcaagccgtgatg 8155 81741 6 SEQ ID NO:5623ccgacggtggttgctccgg 4245 4 264 SEQ ID NO: 6169ccgggggaacggccctcgg 4853 48721 6 SEQ ID NO:56241ggggggaaggcacctcatt 4501 4520SEQ ID NO: 6170aatgttgtgacttggcccc 8334 83531 6 SEQ ID NO: 5625 ccgagcaattcaagcagaa 5517 5536SEQ ID NO: 6171 ttctgattgccatactcgg 3015 30341 6 SEQ ID NO:5626 agatgaaggcaaaggcgtc 7821 7840SEQ ID NO: 6172gacgaccttgtcgttatct 8564 85831 6 SEQ ID NO:5627cccctagggggcgctgcca 767 786 SEQ ID NO: 6173 tggccggcgccccccgggg 3674 3693315 SEQ ID NO: 5628 ctcccggcctagttggggc 646 665SEQ ID NO:6174gcccccccttgagggggag 7519 753825 SEQ ID NO:5629ttccgctcgtcggcggccc 750 769 SEQ ID NO:6175gggcaaaggacgtccggaa 7923 794225 SEQ ID NO:5630cccctagggggcgctgcca 767 786SEQ ID NO:6176 tggcgggggcccactgggg 1383 140225 SEQ ID NO: 5631 gccccgccggcatgcgaca 1222 1241 SEQ ID NO: 6177tgtcccagggggggagggc 9147 916625 SEQ ID NO: 5632 aggacgaccgggtcctttc 178 197SEQ ID NO:6178gaaaaaggaggttgtcct 7341 73601 5 SEQ ID NO: 5633 ggacgaccgggtcctttct 179 198SEQ ID NO: 6179agaaaaaggacggttgtcc 7340 73591 5 321 WO 2004/091515 PCT/US2004/01 1255 6d acca 368 3 8 7SEQ ID NO: 6180 tggtttttttttttttttt 9443 94621 5 SEQ ID NO:5635caaccgccgcccacaggac 385 4 0 4 SEQ ID NO:6 18 1 gtcctgaacccgtctgttg 4100 41191 5 SEQ ID NO: 5636cggtggtcagatcgttggt 418 4 3 7SEQ ID NO:61821accattgagacgacgaccg 4754 47731 5 SEQ ID NO:5637acctgttgccgcgcagggg 444 4 6 3SEQ ID NO:6183ccccggccacgcgtcaggt 1267 12861 5 SEQ ID NO:5638tgccgcgcaggggccccag 450 4 6 9SEQ ID NO:6184ctgggcgcgctgacgggca 3164 31831 5 SEQ ID NO:5639 gggccccaggttgggtgtg 460 4 7 9 SEQ ID NO:6185cacagcctgtctcgtgccc 9296 93151 5 SEQ ID NO:564Ogttggggcccacggaccc 657 6 76SEQ ID NO:6186gggtgggtagccgcccaac 5783 58021 5 SEQ ID NO:5641ttggggccccacggacccc 658 677SEQ ID NO:6187,ggggtgggtagccgcccaa 5782 58011 5 SEQ ID No: 56421tggggccccacggaccccc 659 6 78SEQ ID NO:6188igggggtgggtagccgccca 5781 58001 5 SEQ ID NO:5643cctcacatgcggcctcgcc 715 7 3 4 SEQ ID NO:6189ggcggggcgacaatagagg 3774 37931 5 SEQ ID NO: 5644cacatgcggcctcgccgac 718 737SEQ ID NO:6190gtcgtcggagtcgtgtgtg 6020 60391 5 SEQ ID NO:5645tccgctcgtcggcggcccc 751 7 7 0 SEQ ID NO: 6 1 9 1 ggggcaaaggacgtccgga 7922 79411 5 SEQ ID NO:56461ggcgctgccagggccttgg 776 795SEQ ID NO:6192ccaagccacagtgtgcgcc 5110 51291 5 SEQ ID No:5647ccatgtcacgaacgactgc 943 9 62SEQ ID NO: 693gcagcaacacgtggatgg 6498 651715 SEQ ID NO:5648gtgccctgcgttcgggagg 1019 10 3 8 SEQ ID NO: 6194cctcacaacgggggggcac 1495 15141 5 SEQ ID NO: 5 6 4 9 gccctgcgttcgggaggg 1020 10 3 9 SEQ ID NO:6I95ccctcacaaegggggggca 1494 1513115 SEQ ID NO:56501gccctgcgttcgggagggt 1021 1 0 4 0 SEQ ID NO:6196accctcacaacgggggggC 1493 15121 5 SEQ ID NO: 5651 aggaatgctaccatcccca 1085 1104SEQ ID NO: 6197 tgggcatcggcacagtcct 4323 43421 5 SEQ ID NO: 5652tccccactacgacaatacg 1098 1117SEQ ID NO: 6198cgtattcccagatttggga 8092 81111 5 SEQ ID NO:5653atacgacaccacgtcgatt 1112 1131 SEQ ID NO: 6199 aatcaatgctgtagcgtat 4576 45951 5 SEQ ID NO:5654atttgctcgttggggcggC 1128 11 4 7SEQ ID NO:6200gccgccacttgcggcaaat 9164 91831 5 SEQ ID NO:5655ccttctcgccccgccggca 1215 1234SEQ ID NO: 6201 tgccaacgtgggtacaagg 6374 63931 5 SEQ ID NO:5656accccggccacgcgtcagg 1266 1285SEQ ID NO:6202cctgccgcggttaccgggt 6340 63591 5 SEQ ID NO:5657gccctcgtagtgtcgcagt 1331 1350SEQ ID NO:6203actgcgtcggcatgtgggc 6046 60651 5 SEQ ID NO:5658gccgtctcagagaatccag 1558 1 577SEQ ID NO:6204,ctggtatcgctggtgcggc 5838 58571 5 SEQ ID NO:56591ctgaactgcaatgactccc 1619 1638 SEQ ID NO: 6205 gggacagatcggagctcag 2313 23321 5 SEQ ID NO:5660agactgggtttcttgccgc 1641 1660 SEQ ID NO: 62061gcggcgagcctacgagtct 8609 86281 5 SEQ ID NO: 5661 cgtccggatgcccggagc 1685 1704SEQ ID NO: 62071gctccgggggcgcttacga 4257 42761 5 SEQ ID NO:5662ccagggatggggtcctatc 1738 1757SEQ ID NO: 6208gataacttcccctacctgg 5084 51031 5 SEQ ID NO: 5663gacaaccgatcgtctcggc 1894 1913SEQ ID NO: 6209gccgcggttaccgggtgtc 6343 63621 5 SEQ ID NO: 5664caagacgtgcggggccccc 2026 2045SEQ ID NO: 6210 ggggtctcccccctccttg 6919 69381 5 SEQ ID NO:5665acgtgcggggcccccccgt 2030 2049 SEQ ID NO:6211 acgggcgcccccattacgt 4202 42211 5 SEQ ID NO:5666ccggaagcaccccgaggcc 2101 2120SEQ ID NO: 6212,ggccgctgtatgcacccgg 3886 39051 5 SEQ ID NO:5667aggccacgtactcaaaatg 2115 213 4 SEQ ID NO:6213cattatgtccaaatggcct 3137 31561 5 SEQ ID NO:5668tgtatgtggggggcgtgga 2235 2254SEQ ID NO: 6214 tccaagtggcccatctaca 4011 40301 5 SEQ ID NO: 5669gagtggcaggttctgccct 2354 2373SEQ ID NO: 6215agggcaggggtggcgactc 3400 34191 5 SEQ ID NO: 5670 cctttgcaatcaaatggg 2474 2493SEQ ID NO: 6216cccaccttatgggcaagga 8861 88801 5 SEQ ID NO: 56711agcccaggccgaggccgcc 2566 2585SEQ ID NO: 6217,ggcgtccacagtcaaggct 7834 78531 5 SEQ ID NO:5672ggcggcatatgctttctat 2698 2717SEQ ID NO:6218latagaagaagcctgccgcc 7865 78841 5 SEQ ID NO:5673 gcggcatatgctttctatg 2699 2718SEQ ID NO:62191catagaagaagcctgccgc 7864 78831 5 SEQ ID NO:5674Gggcatatgctttctatgg 2700 2719SEQ ID NO:6220ccatagaagaagcctgccg 7863 78821 5 SEQ ID NO:5675tgcatgtgtgggttccccc 2913 2932 SEQ ID NO: 6221 ggggggacggcatcatgca 6402 64211 5 SEQ ID NO: 56761cccccctcaacgtccgggg 2928 2947 SEQ ID NO: 6222 ccccaatcgatgaacgggg 9376 93951 5 SEQ ID NO:5677gggcaggggtggcgactcc 3401 3420 SEQ ID NO:6223ggaggccgcaagccagccc 8066 80851 5 SEQ ID NO:5678latgttggactgtctaccat 3574 3593SEQ ID NO:6224atggtaccgaccctaacat 4158 41771 5 SEQ ID NO:5679 gttggactgtctaccatg 3575 3594 SEQ ID NO: 6225catggtaccgaccctaaca 4157 41761 5 SEQ ID NO: 56801cgttccctgacaccatgca 3695 37 1 4SEQ ID NO: 6226tgcacgatgctcgtgaacg 8543 85621 5 SEQ ID NO: 5681 acaccatgcacctgtggca 3704 3723SEQ ID NO:6227 gccgcggttaccgggtgt 6342 63611 5 SEQ ID NO: 5682caccatgcacctgtggcag 3705 3724,SEQ ID NO:6228ctgccgcggttaccgggtg 6341 63601 5 SEQ ID NO:5683ggcatcggcacagtcctgg 4325 43441SEQ ID NO:6229ccaggattgcccgtttgcc 4979 49981 5 322 WO 2004/091515 PCT/US2004/011255 s 'filfN:O8aagggagacggctggagc 4347 4366SEQ ID NO: 6230gctccccccagcgctgctt 5804 58231 5 SEQ ID NO:5685 ggagcgcggcttgtcgtgc 4361 4 3 8 0 SEQ ID NO: 6 2 3 1 gcacggcgaccgcccctcc 7443 74621 5 SEQ ID NO:5686cgaagccatcaagggggga 4489 4508SEQ ID NO: 6232tccccccagcgctgcttcg 5806 58251 5 SEQ ID NO:5687tggaagtgtctcatacggc 5165 5184SEQ ID NO:6233gccggattacaatcctcca 7225 72441 5 SEQ ID NO:5688gggtgctggtaggcggagt 5322 5341 SEQ ID NO: 6234actcgcgatcccaccaccc 8765 87841 5 SEQ ID NO:5689 gtgggtaggatcatcttgt 5390 5409SEQ ID NO: 6235acaacatggtctacgccac 7713 77321 5 SEQ ID NO:56901cgccgagcaattcaagcag 5515 5534SEQ ID NO: 6236ctgcacgccttccccggcg 6550 65691 5 SEQ ID NO:5691tggagtccaagtggcgagc 5592 5611 SEQ ID NO:6237gctcctcatacggattcca 8175 819415 SEQ ID NO: 5692 tggcgagctttggagacct 5603 5622SEQ ID NO: 6238 aggtgccctgatcacgcca 7633 76521 5 SEQ ID NO:5693gcccgctcaccacccagaa 5739 5758SEQ ID NO:6239ttctggcgggctatggggc 5895 59141 5 SEQ ID NO:5694 gagtgacttcaagacctg 6306 6325SEQ ID NO:6240caggctataaaatcgctca 8363 83821 5 SEQ ID NO:5695atgtcaaaaacggttccat 6456 6475SEQ ID NO:6241 atggtaccgaccctaacat 4158 41771 5 SEQ ID NO:5696ccgaaaacctgcagcaaca 6488 6507SEQ ID NO: 6242tgttcctccaatgtgtcgg 8708 87271 5 SEQ ID NO:5697ggcgccaaactattccaag 6565 6584SEQ ID NO: 6243cttgaaagcctctgccgcc 8500 85191 5 SEQ ID NO: 5698gccctccttgagggcgaca 6967 6986SEQ ID NO: 6244tgtctcctacttgaagggc 3814 38331 5 SEQ ID NO: 5699 cacccgcgtggagtcggag 7078 7097SEQ ID NO: 6245ctccggtggtacacgggtg 7278 72971 5 SEQ ID NO: 5700,ggagggggatgagaatgaa 7138 7157SEQ ID NO:6246ttcatgctgtgcctactcc 9326 93451 5 SEQ ID NO:57011gcggcgatacccatatggg 7202 7221 SEQ ID NO:6247cccagggggggagggccgc 9150 916915 SEQ ID NO: 5702ttgccacctgtcaaggccc 7301 7320SEQ ID NO:6248gggccgccacttgcggcaa 9162 91811 5 SEQ ID NO:5703ccccccttgagggggagc 7520 7539SEQ ID NO:6249gctcccggcctagttgggg 645 6641 5 SEQ ID NO:57041ctgctgctcaatgtcctac 7606 7625SEQ ID NO: 6250gtaggactggcaggggcag 4809 48281 5 SEQ ID NO:5705catggacaggtgccctgat 7626 7 64 5SEQ ID NO: 6251 atcattgaacgactccatg 8996 90151 5 SEQ ID NO: 5706atggacaggtgccctgatc 7627 7646SEQ ID NO:6252gatcattgaacgactcCat 8995 90141 5 SEQ ID NO: 5707ggctatgactaggtactcc 8635 8654SEQ ID NO:6253ggagcaacttgaaaaagcc 8920 89391 5 SEQ ID NO:5708caccatagatcactcccct 27 46SEQ ID NO:6254agggccttggcacatggtg 785 80424 SEQ ID NO: 5709agctgttcaccttctcgcc 1206 1225SEQ ID NO:6255ggcgtgctgacgactagct 8459 847824 SEQ ID NO: 5710 ctgcaatgactccctccag 1624 1643SEQ ID NO:6256ctggtgcggctgttggcag 5847 586624 SEQ ID NO: 5711 atgtggggggcgtggagca 2238 2257SEQ ID NO:6257tgctgcgccatcacaacat 7701 77202,4 SEQ ID NO: 5712tggggacatcatcctgggc 3322 3341 SEQ ID NO:6258gcccaactcgctcccccca 5795 5814214 SEQ ID NO:5713gggacatcatcctgggcct 3324_3343SEQ ID NO:6259aggcaggagataacttccc 5076 509524 SEQ ID NO: 5714gggagatactcctggggcc 3366 3385SEQ ID NO:626Oggcccctgcacgccttccc 6545 656424 SEQ ID NO:5715atgttggactgtctaccat 3574 3593SEQ ID NO:6261 atggtctacgccacgacat 7718 773724 SEQ ID NO:5716ccagccttaccatcaccca 6189 6208SEQ ID NO:62621tgggtacaagggagtctgg 6382 64012 4 SEQ ID NO: 5717gccctccttgagggcgaca 6967 6986SEQ ID NO:6263tgtcccagggggggagggc 9147 91662,4 SEQ ID NO: 5718ccagcccccgattggggc 1 20SEID NO.6264gcccgagggcagggcctgg 550 56914 SEQ ID NO:5719accatagatcactcccctg 28 47SEQ ID NO:6265cagggccttggcacatggt 784 8031 4 SEQ ID NO:5720atgagtgtcgtgcagcctc 95 114SEQ ID NO:6266gaggccgcgatgccatcat 2946 29651 4 SEQ ID NO: 5721 gtgcagcctccaggacccc 104 123SEQ ID NO:6267gggggacggcatcatgcac 6403 64221 4 SEQ ID NO: 5722tgcagcctccaggaccccc 105 124SEQ ID NO:6268ggggggacggcatcatgca 6402 64211 4 SEQ ID NO: 5723ccaggaccccccctcccgg 113 132SEQ ID NO:6269cggctggttcgttgctgg 9255 92741 4 SEQ ID NO: 5724accccccctcccgggagag 118 137SEQ ID NO:6270 ctctcatgccaacgtgggt 6368 63871 4 SEQ ID NO:5725ccccCtcccgggagagcca 121 140 SEQ ID NO:6271 tggcaatgagggcatgggg 598 61714 SEQ ID NO:5726agactgctagccgagtagt 243 2 6 2 SEQ ID NO:6272 actatgcggtccccggtct 3953 39721 4 SEQ ID NO:5727agccgagtagtgttgggtc 251 2 70SEQ ID NO:62731gaccaggatctcgtcggct 3656 36751 4 SEQ ID NO:57281ggtgcttgcgagtgccccg 299 318 SEQ ID NO:6274cggggccttggttgacacc 2139 21581 4 SEQ ID NO:5729gcgagtgccccgggaggtc 306 325SEQ ID NO:6275 gaccccoggcgtaggtcgc 671 6901 4 SEQ ID NO: 5730accgtgcaccatgagcacg 331 350SEQ ID NO:62761cgtgcaatacctgtacggt 2437 24561 4 SEQ ID NO: 5731 cccgggcggtggtcagatc 412 431 SEQ ID NO:62771gatcatgcatactcccggg 997 10161 4 SEQ ID NO:5732gccgcgcaggggccccagg 451 470SEQ ID NO:6278 cctgcacgccttccccggc 6549 656814 SEQ ID NO:5733accccgtggaaggcgacag 511 530SEQ ID NO:6279 Ctgtatgcacccggggggt 3891 39101 4 323 WO 2004/091515 PCT/US2004/011255 N i >:3 ccdigeN &cgaagc 512 531 SEQ ID NO:6280gctgtatgcacccgggggg 3890 39091 4 SEQ ID NO:5735agcctatccccaaggctcg 528 547SEQ ID NO:6281 cgagggcagggcctgggct 553 5721 4 SEQ ID NO:5736ctatccccaaggctcgccg 531 550SEQ ID NO:6282cggctgtcgttcccgatag 5418 54371 4 SEQ ID NO:5737 tatccccaaggctcgccgg 532 551 SEQ ID NO:6283 ccggctgtcgttcccgata 5417543614 SEQ ID NO:5738 cgggtatcottggcccctc 577 596SEQ ID NO:6284 gaggccgcaagccagcccg 8067 80861 4 SEQ ID NO: 5739gcatggggtgggcaggatg 609 628SEQ ID NO:6285catcgataccctcacatgc 706 7251 4 SEQ ID NO:5740 tcctgtcaccccgcggctc 630 649SEQ ID NO:6286gagctgcaaagctccagga 8523 8542114 SEQ ID NO: 5741 gggccccacggacccccgg 661 680SEQ ID NO:6287ccggccgcatatgcggccc 4064 40831 4 SEQ ID NO: 5742ggccccacggacccccggc 662 681 SEQ ID NO:|6288gccggccgcatatgcggcc 4063 40821 4 SEQ ID NO: 5743cggcctcgccgacctcatg 724 743SEQ ID NO: 6289catgaggatcatcgggccg 6472 64911 4 SEQ ID NO: 5744 ggcctcgccgacctcatgg 725 744 SEQ ID NO: 6290 ccatgaggatcatcgggcc 6471,649014 SEQ ID NO:5745ggccccctagggggcgctg 764 783SEQ ID NO: 6291 cagctccgaattgtcggcc 7414 74331 4 SEQ ID NO:5746tggcacatggtgtccgggt 792 811 SEQ ID NO: 6292 acccacgctgcacgggcca 5188 52071 4 SEQ ID NO:5747cttcctcttggctctgctg 868. 887SEQ ID NO: 6293cagcataggtcttgggaag 5863 588214 SEQ ID NO: 5748catgtcacgaacgactgct 944 963SEQ ID NO:6294agcagtgctcacttccatg 6847 68661 4 SEQ ID NO: 5749gaggcggcggacttgatca 983 1002SEQ ID NO: 6295tgatggcattcacagcctc 5712 57311 4 SEQ ID NO: 5750 catccccactacgacaata 1096 1115SEQ ID NO: 6296tattaccggggtcttgatg 4592 46111 4 SEQ ID NO: 5751 gctgttcaccttctcgccc 1207 1226SEQ ID NO: 6297gggctgcgtgggaaacagc 8793 88121 4 SEQ ID NO: 5752gccccgccggcatgcgaca 1222 1241 SEQ ID NO: 6298tgtctcctacttgaagggc 3814 38331 4 SEQ ID NO: 5753tggcctgggacatgatgat 1293 1 3 12SEQ ID NO: 6299atcaatttgctccctgcca 5981,60001 4 SEQ ID NO:5754cacaagccgtcatcgacat 13621381 SEQ ID NO:6300atgtttgggactgggtgtg 6279 62981 4 SEQ ID NO:57551agccgtcatogacatggtg 1366 1 3 8 5 SEQ ID NO: 6 3 0 1 caccaagcaggcggaggct 5560 55791 4 SEQ ID NO:5756ggtggcgggggcccactgg 1381 14 0 0 SEQ ID NO: 6302ccagggtcaggccccacc 5127 51461 4 SEQ ID NO:5757gggggcccactggggagtc 1387 1406SEQ ID NO:6303gactaggtactccgccccc 8641 86601 4 SEQ ID NO:5758atggcggggaactgggcta 1430 1449SEQ ID NO: 6304tagcagtgctcacttccat 6846 68651 4 SEQ ID NO: 5759ttgattgtgatgctacttt 1454 14 7 3SEQ ID NO:6305aaagcaagctgcccatcaa 7665 768414 SEQ ID NO:5760caacgggggggcacgctgc 1500 1519sEQ ID NO:6306gcagaaggcgctcgggttg 5530 55491 4 SEQ ID NO: 5761 acgctgcccgcctcaccag 1512 1531 SEQ ID NO: 6307 ctggacccgaggagagcgt 2278 22971 4 SEQ ID NO:5762 tcagagaatccagcttata 1564 1 5 83SEQ ID NO:6308 tatatcgggggtcccctga 8393 84121 4 SEQ ID NO:5763accaatggcagttggcaca 1586 1605SEQ ID NO:6309tgtggctcggggccttggt 213221511 4 SEQ ID NO:5764ccaatggcagttggcacat 1587 1606SEQ ID NO:6310atgtggctcggggccttgg 2131 21501 4| SEQ ID NO: 5765 gtcctatcacttatgctga 1749 1768 SEQ ID NO: 6311 tcaggactggggtaaggac 4176 4195114 SEQ ID NO:5766ctgagcctacaaaagaccc 1764 1783 SEQ ID NO:6312gggtggcttcatgcctcag 9063 90821 4 SEQ ID NO:5767caggtgtgtggtccagtgt 1844 1863 SEQ ID NO:6313acactccagttaactcctg 8817 883614 SEQ ID NO: 5768 1gtggtccagtgtattgct 1850 1869SEQ ID NO:6314agcagggccatcaaccaca 7949 79681 4 SEQ ID NO:57691gcttcaccccaagtcctgt 1866 1885SEQ ID NO:6315acagcagaggcggctaagc 6887 69061 4 SEQ ID NO:5770iCtgttgtcgtggggacaac 1881 1900SEQ ID NO:6316igttgcaacttggacgacag 2295 23141 4 SEQ ID NO:5771 gccgccgcaaggcaactgg 1972 1991 SEQ ID NO:6317ccagttggacttatccggc 9241 92601 4 SEQ ID NO:5772 ggcaactggttcggctgta 1982 2001 SEQ ID NO:6318 tacacgggtgcccattgcc 728773061 4 SEQ ID NO:5773gcaactggttcggctgtac 1983 2002SEQ ID NO:6319gtacacgggtgcccattgc 7286 7305114 SEQ ID NO: 5774,cccgtgtaacatcggggg 2043 2062SEQ ID NO:6320ccccaatcgatgaacgggg 9376 93951 4 SEQ ID NO:5775 ggactgcttccggaagcac 2092 2111 SEQ ID NO:6321 gtgctggtaggcggagtcc 5324 534314 SEQ ID NO: 5776gactgcttccggaagcacc 2093 2112 SEQ ID NO:6322 ggtgctggtaggcggagtc 5323 53421 4 SEQ ID NO:5777 ccggaagcaccccgaggc 2100 2119 SEQ ID NO:6323 gcctacgagtcttcacgga 8616 86351 4 SEQ ID NO:5778actcaaaatgtggctcggg 2124 2143SEQ ID NO:6324Cccgggcagcgggtcgagt 8201 82201 4 SEQ ID NO:5779ggccttggttgacacctag 2142 2161 SEQ ID NO: 6325ctagccggcccaaaaggcc 3611 36301 4 SEQ ID NO:5780aggagagcgttgcaacttg 2287 2306SEQ ID NO:6326caagccgtgatgggctcct 8162 81811 4 SEQ ID NO:5781 ggacagatcggagctcagc 2314 23331SEQ ID NO:6327gctgggggtcattatgtcc 3128 31471 4 SEQ ID NO:5782agatcggagctcagcccg 2317 2336 SEQ ID NO:6328cgggtggcccactgctctg 3837 385614 SEQ ID NO:5783ggagctcagcccgctgctg 2323 2 3421SEQ ID NO:6329cagctgctgaagaggctcc 6206 62251 4 324 WO 2004/091515 PCT/US2004/011255 iSt&'dif&6184 6 bctaccggctctgtcc_ 2383 2402SEQ ID NO: 63 30ggactgggtgtgcacggtg 6286 63051 4 SEQ ID NO:5785cggctctgtccactggctt 2391 2410 SEQ ID NO: 6 3 3 1 aagcaggcggaggctgccg 5564 55831 4 SEQ ID NO:5786ccatcagaacatcgtggac 2419 2438 SEQ ID NO:6332gtccccgttgagtccatgg 3929 39481 4 SEQ ID NO:5787ggtcagcggttgtctcctt 2460 2479 SEQ ID NO:6 3 33aaggatgattctgatgacc 8875 88941 4 SEQ ID NO:5788 gccgccttagagaacctgg 2579 2598SEQ ID NO:6334ccagttggacttatccggc 9241 92601 4 SEQ ID NO:|5789gccttagagaacctggtgg 2582 2601 SEQ ID NO: 633 5ccaccaagcaggcggagge 5559 55781 4 SEQ ID NO:5790 gccggagcgcacggcatcc 2621 2640 SEQ ID NO:|6336ggattgggcccacgccggc 3214 32331 4 SEQ ID NO:5791 gctgcatcgtgcggaggcg 2786 2805 SEQ ID NO:6337 cgccacgacatcccgcagc 7726 77451 4 SEQ ID NO: 5792!attattgaccttgtcgcca 2824 2843 SEQ ID NO: 6338 ggcaacagacgctctaat 4647 46661 4 SEQ ID NO: 5793 cgccatattacaaggtgt 2837 2856SEQ ID NO: 6339 acacaatctttcctggcga 3539 35581 4 SEQ ID NO: 5794 cgccatattacaaggtgtt 2838 2 8 57SEQ ID NO: 6340 aacacaatctttcctggcg 3538 35571 4 SEQ ID NO: 5795 gtccggggaggccgcgatg 2939 2958 SEQ ID NO: 6341 catcggcacagtcctggac 4327 43461 4 SEQ ID NO: 5 7 96tcaccccactgcgggattg 3201 3220SEQ ID NO: 6342 caatttaccaatgttgtga 8325 83441 4 SEQ ID NO: 5797 ttgggcccacgccggccta 3217 3236 SEQ ID NO: 6343 aggctaggggccgtccaa '5221 52401 4 SEQ ID NO: 5798ctacgggaccttgcggtag 3233 3 25 2SEQ ID NO:6344ctactcctactttctgtag 9338 935714 SEQ ID NO:5799cctgtcgtcttctctgaca 3260 3 279 SEQ ID NO:6345 gtcctacacatggacagg 7617 76361 4 SEQ ID NO: 5800 ctgtcgtcttctctgacat 3261 3280 SEQ ID NO: 6346 atgtcctacacatggacag 7616 76351 4 SEQ ID NO: 58011cctggggggcagacaccgc 3297 3316 SEQ ID NO: 6 34 7gcggggtaggactggcagg 4804 48231 4 SEQ ID NO: 5802gggggcagacaccgcggcg 3301 332 0SEQ ID NO: 6348cgcccaactcgctcccccc 5794 58131 4 SEQ ID NO: 5803ggcgtgtggggacatcatc 3316 3 33 5SEQ ID NO:6349gatgttattccggtgcgcc 3755 37741 4 SEQ ID NO: 5804 ggggccggccgatagtct 3378 3397 SEQ ID NO:6350|agacgacgaccgtgcccca 4761 47801 4 SEQ ID NO:5805gaaccaggtcgagggggag 3499 3518SEQ ID NO:6351 ctccacctatggcaagttc 4222 42411 4 SEQ ID NO:5806gagggggaggttcaagtgg 3509 3528SEQ ID NO: 6 352ccacctgtcaaggcccctc 7304 73231 4 SEQ ID NO:5807aggcccaatcgcccagatg 3625 3644 SEQ ID NO:63531catcccgcagcgcgggcct 7734 77531 4 SEQ ID NO:'5808ggcccaatcgcccagatgt 3626 3 645 SEQ ID NO: 6 354acatcccgcagcgcgggcc 7733 77521 4 SEQ ID NO:5809caggatctcgtcggctggc 3659 3678 SEQ ID NO: 6355 gccaataggccatttcctg 9410 94291 4 SEQ ID NO:5810aggatctgtcggctggcc 3660 3679SEQ ID NO: 6 356 ggccaataggccatttcct 9409 94281 4 SEQ ID NO: 5811 gccccccggggcgcgttcc 3682 3701 SEQ ID NO:6357ggaacctatccagcagggc 7938 79571 4 SEQ ID NO: 5812gcacctgtggcagctcgga 3711 373 0SEQ ID NO:6358 ccggtggtacacgggtgc 7279 729814 SEQ ID NO:5813ctgtggcagctcggacctt 3715 3 734 SEQ ID NO: 63 59aaggcaaaggcgtccacag 7826 78451 4 SEQ ID NO:5814gcggggcgacaatagaggg 3775 37 9 4SEQ ID NO: 636 0ccctgcctgggaaccccgc 5682 57011 4 SEQ ID NO:58151ggagcttgctctcccccag 3792 3811 SEQ ID NO: 6361 ctggttgggtcacagctcc 6806 682514 SEQ ID NO:5816gagcttgctctcccccagg 3793 38 12 SEQ ID NO: 6362 cctggttgggtcacagctc 6805 68241 4 SEQ ID NO: 5817acttgaagggctcttcggg 3822 3841 SEQ ID NO: 6363 cccgtggtggagtccaagt 5585 5604ii SEQ ID NO: 818tgtcccgttgagtccatg 3928 394 7 SEQ ID NO: 6364catggtctacgccacgaca 7717 77361 4 SEQ ID NO: 5819gaaactactatgcggtccc 39 47 3 96 6 SEQ ID NO: 63 65gggaaggcacctcattttc 4504 45231 4 SEQ ID NO: 5820aaactactatgcggtcccc 3948 3 967 SEQ ID NO:6366ggggggcatatacaggttt 4828 48471 4 SEQ ID NO: 5821|ctcccactggcagcggcaa 4032 4051 SEQ ID NO: 6367 tgccaggaccatctggag 4993 50121 4 SEQ ID NO: 5822ggcgtatatgtctaaagca 4138 4 157SEQ ID NO: 6368 tgctcgccaccgctacgcc 4377 43961 4 SEQ ID NO: 5823gcgtatatgtctaaagcac 4139 4 15 8 SEQ ID NO: 6 369gtgctcgccaccgctacgc 4376 439514 SEQ ID NO: 5824tggggtaaggaccattacc 4183 4202 SEQ ID NO:6370 ggtaaccatgtctccccca 6119 61381 4 SEQ ID NO:5825|accattaccacgggcgccc 4193 4212 SEQ ID NO:6371 gggcgctggtatcgctggt 5833 58521 4 SEQ ID NO: 5826cgtactccacctatggcaa 4218 42 37SEQ ID NO: 6372 tgccccaaccagaatacg 8669 868814 SEQ ID NO:5827cagtcctggaccaagcgga 4335_ 43 54SEQ ID NO:6373tccgtgagccgcatgactg 9560 95791 4 SEQ ID NO:5828aggggggaaggcacctcat 4500 4 51 9 SEQ ID NO:6374atgagcggcgaggcgccct 5948 59671 4 SEQ ID NO:5829cactccaagaagaagtgcg 4526 4545 SEQ ID NO:6375cgcatgactgcagagagtg 9569 95881 4 SEQ ID NO: 5830atcaatgctgtagcgtatt 4577 4596 SEQ ID NO:6376aatacgacttggagttgat 8682 87011 4 SEQ ID NO: 5831 cataccgaccagcggagac 4618 4 637 SEQ ID NO:6377gtctcccccacgcactatg 6128 614714 SEQ ID NO: 5832 aggactggcaggggcaggg 4811 4830 SEQ ID NO: 6378 ccctgccatcctctctcct 5992 601114 SEQ ID NO:|5833gggaacggccctcgggcat 4857 487 6 5EQ ID NO:6379atgctcaccgacccctccc 6863 68821 4 325 WO 2004/091515 PCT/US2004/011255 SEQ ID NO:|5834cgggcatgttcgattcctc 4869 4888 SEQ ID NO: 6 3 80gaggccgcaagccagcccg 8067 80861 4 SEQ ID NO:5835tggtacgagctcacccccg 4922 4941 SEQ ID NO:6381cggggacttgccccaacca 8662 86811 4 SEQ ID NO:5836gggcttacctaaatacacc 4962 4981 SEQ ID NO:6382ggtggctccatcttagccc 9518 95371 4 SEQ ID NO:5837ggcttactaaatacacca 4963 4982 SEQ ID NO: 6383 tggtggctccatcttagcc 9517 95361 4 SEQ ID NO: 5838 gagataacttcccctacct 5082 5101 SEQ ID NO: 6384 ggttggccagggggtctc 6908 69271 4 SEQ ID NO:5839cccacctccatcgtgggat 5140 5159SEQ ID NO:6385atccaagttggctatggg 7906 79251 4 SEQ ID NO:5840catggcatgcatgtcggcc 5278 5297SEQ ID NO:6386ggcctctctgcagatcatg 9596 96151 4 SEQ ID NO: 5841 ggccgacctggaagtcgtc 5293 5312SEQ ID NO: 6 387gacgcccccacattcggcc 7885 7904114 SEQ ID NO:5842gccgacctggaagtcgtca 5294 5313SEQ ID NO:6388 gacgcccccacattcggc 7884 790314 SEQ ID NO:5843 tggaagtcgtcaccagcac 5301 5320SEQ ID NO:6389gtgcccatgtcaggttcca 6676 66951 4 SEQ ID NO: 5844 gcacctgggtgctggtagg 5316 5335SEQ ID NO:6390cctacacatggacaggtgc 7620 763914 SEQ ID NO:5845ggttatcgtgggtaggatc 5383 5402SEQ ID NO: 6391 gatcatcgggccgaaaacc 6478 64971 4 SEQ ID NO:5846cccgatagggaagtcctct 5429 5 4 48SEQ ID NO: 6392 agagcggctttatatcggg 8383 84021 4 SEQ ID NO: 5847 gaaatggaagaatgcgcc 5461 5480SEQ ID NO:6393ggcgcgctcgtggccttca 5924 59431 4 SEQ ID NO: 5848ccaagtggcgagctttgga 5598 561 7 SEQ ID NO: 6394 ccattgttagagtcttgg 7240 72591 4 SEQ ID NO:5849ttcatcagcgggatacagt 5645 566 4SEQ ID NO:6395actgcacgatgctcgtgaa 8541 85601 4 SEQ ID NO: 5850agcgggcttatccaccctg 5668 5 68 7SEQ ID NO: 6 396caggggtggctggcgcgCt 5913 59321 4 SEQ ID NO: 5851,ccagcccgctcaccaccca 5736 5 75 5SEQ ID NO: 6397 gggcgctggtatcgctgg 5832 58511 4 SEQ ID NO:5852gtgggcgctggtatcgctg 5831 58 50 SEQ ID NO: 6 3 98cagcagggccatcaaccac 7948 79671 4 SEQ ID NO: 5853ggaaggtgctagtggacat 5877 58 96 SEQ ID NO: 6 399atgtggtctccacccttcc 8142 81611 4 SEQ ID NO:S854ggtcatgagcggcgaggcg 5944 59 63SEQ ID NO: 640 0cgcccctcctgaccagacc 7453 74721 4 SEQ ID NO: 855catgtgggcccgggagagg 6056 6 0 7 5SEQ ID NO:6401 cctccttgagggcgacatg 6969 69881 4 SEQ ID NO:S856atgtgggcccgggagaggg 6057 6 0 7 6SEQ ID NO: 6 402ccctccttgagggcgacat 6968 69871 4 SEQ ID NO: 857ggggccgtgcagtggatga 6074 6 0 9 3 SEQ ID NO:6403 catgctcctctatgcccc 7505 75241 4 SEQ ID NO: 858gcgttcgcttcgcggggta 6104 6123 SEQ ID NO:6404 accaccacgagcttacgc 2751 27701 4 SEQ ID NO:'859ggggtaaccatgtctcccc 6117 613 6 SEQ ID NO: 64 05gggggagccgggggacccc 7531 75501 4 SEQ ID NO: 5860 catcacccagctgctgaag 6199 6218~SEQ ID NO: 6406cttcgagcggagggggatg 7130 71491 4 SEQ ID NO: 5861 aggactgttctacgccgtg 6240 62 59SEQ ID NO:6407cacggcgaccgcccctcct 7444 74631 4 SEQ ID NO:|5862 tcaagacctggctccagt 6314 63 33 SEQ ID NO: 64 0 8 actgcacgatgctcgtgaa 8541 85601 4 SEQ ID NO:5863'ctcctgccgcggttaccgg 6338 63 57 SEQ ID NO: 64 09ccgggacgtgcttaaggag 7804 78231 4 SEQ ID NO:5864caccacgggcccctgcacg 6538 655 7SEQ ID NO: 6410cgtggaggtcacgcgggtg 6613 66321 4 SEQ ID NO:5865ggaggtcacgcgggtgggg 6616 6 63 5SEQ ID NO: 6411 cccctccaataccacctcc 7317 733614 SEQ ID NO:5866gaggtcacgcgggtggggg 6617 6636SEQ ID NO: 64 12cccctcctgaccagacctc 7455|74741 4 SEQ ID NO: 5867atgtcaggttccagctcct 6682 6701 SEQ ID NO:6413aggagatgggcggaaacat 7059 70781 4 SEQ ID NO:5S868atgaaatatccattgcggc 7152 7171 SEQ ID NO: 64 14gccgtgatgggctcctcat 8165 818414 SEQ ID NO:5869ctccattgttagagtctg 7239 725 8SEQ ID NO:6415caagtggcgagctttggag 5599 56181 4 SEQ ID NO:5870 gcccattgccacctgtca 7295 73 14 SEQ ID NO:6416 gactaattcaaaagggca 8409 84281 4 SEQ ID NO: 5871 accacctccacggagaaaa 7327 7346 SEQ ID NO: 6417 tttttccctctttatggt 9502 95211 4 SEQ ID NO:5 8 72 ccacctcacggagaaaaa 7328 73 47 SEQ ID NO:6418'tttccctctttatggtgg 9504 95231 4 SEQ ID NO:5873acctccacggagaaaaagg 7330 7349 SEQ ID NO: 6 419cctttgacagactgcaggt 7770 77891 4 SEQ ID NO:5874ggttgtcctgacggactcc 7351 737 0 SEQ ID NO: 6 420 ggagctcgctaccaaaacc 7390 74091 4 SEQ ID NO:5875cctgaccagacctccgaca 7460 7479 SEQ ID NO:6421 tgtcctacacatggacagg 7617 76361 4 SEQ ID NO:5876agcaagctgcccatcaacg 7667 76 86SEQ ID NO:6422cgttgagcaactctttgct 7686 770514 SEQ ID NO:5877ggatgaccattaccgggac 7792 7811 SEQ ID NO:|6423 gtcccagttggacttatcc 9238 92571 4 SEQ ID NO:5878tggcaaagaatgaggtttt 8028 8047SEQ ID NO: 6 424aaaaagccctggattgcca 8931 89501|4 SEQ ID NO:5879 ggcaaagaatgaggttttc 8029 8048 SEQ ID NO:| 6 425gaaaaagccctggattgcc 8930 89491,4 SEQ ID NO:5880 gggcagcgggtcgagttcc 8204 8223SEQ ID NO:6426ggaagaaagcaagctgccc 7660 767914 SEQ ID NO: 5881 gactagctgcggtaatacc 8470 8489SEQ ID NO:6427ggtaccgcccttgcgagtc 9091 91101 4 SEQ ID NO: 5882ctcgcgatcccaccacccc 8766 8 785SEQ ID NO:6428 ggggtaccgcccttgcgag 9089 91081 4 SEQ ID NO:|5883aggatgattctgatgaccc 8876 889 5SEQ ID NO: 64 29gggtcagcggttgtctcct 2459 24781 4 326 WO 2004/091515 PCT/US2004/011255 SEID NO:5884agccacttgacctacctca 89768995SEQ ID NO:6430 tgagatcaatagggtggct 9052'90711 4 SEQ ID NO:5885gggtaccgcccttgcgagt 9090 9109 SEQ ID NO: 6431 actcgcgatcccaccaccc 8765 87841 4 SEQ ID NO:5886ctgcaatgactccctccag 1624 16 4 3SEQ ID NO:6432ctggcgggctatggggcag 5897 591633 SEQ ID NO:5887ccagcccccgattgggggc 1 20SEQ ID NO:6433gcccactggggagtcctgg 1391 141023 SEQ ID NO: 5888aaggcgacagcctatcccc 520 5 3 9SEQ ID NO:6434gggggtctcccccctcctt 6918 69372 3 SEQ ID NO:5889ggccccacggacccccggc 662 681 SEQ ID NO:6435gccgcaaagctgtcaggcc 4553 457223 SEQ ID NO:5890gaggcggcggacttgatca 983 1002SEQ ID NO:6436 tgataacatcatgttcctc 8697 871623 SEQ ID NO: 5891 ctgcaattgttcgatctac 1249 1268SEQ ID NO:6437gtaggcggagtcctcgcag 5330 53492 3 SEQ ID NO:5892,ctccagactgggtttcttg 1637 1656SEQ ID NO:6438 caagtggcgagctttggag 5599 561823 SEQ ID NO:5893tcgtacctgcgtcgcaggt 1830 1 8 4 9 SEQ ID NO:6439acctcagatcattgaacga 8989 9008213 SEQ ID NO:5894caagacgtgcggggccccc 2026 2045SEQ ID NO:6440gggggagggccgccacttg 9156 917523 SEQ ID NO:5895aatgctgcatgcaactgga 2264 2283SEQ ID NO:6441 tccaggccaataggccatt 9405 94242 3 SEQ ID NO: 5896caccctaccggctctgtcc 2383 2402SEQ ID NO:6442ggactacgtccctccggtg 7267 728623 SEQ ID NO:5897cgccatattacaaggtgtt 2838 2 8 5 7 SEQ ID NO:6443aacagccaccaagcaggcg 5554 557323 SEQ ID NO: 58981cgaagccatcaagggggga 4489 4508SEQ ID NO:6444 tcccagatttgggagttcg 8097 8116213 SEQ ID NO:58991ccagcccgctcaccaccca 5736 5755SEQ ID NO: 6445tgggtacaagggagtctgg 6382 640123 SEQ ID NO:5900 ggctatgactaggtactcc 8635 8654SEQ ID NO: 6446,ggagacatatatcacagCC 9284 930323 SEQ ID NO: 5 9 0 1 ctccaccatagatcactcc 24 4 3 SEQ ID NO:64471ggagacatcgggccaggag 9111 91301 3 SEQ ID NO: 5902 tccaccatagatcactccc 25 44SEQ ID NO: 6448gggagttcgatgaaatgga 5451 54701 3 SEQ ID NO:59031caccatagatcactcccct 27 46SEQ ID NO: 6449aggggccccaggttgggtg 458 4771 3 SEQ ID NO: 5904tcactcccctgtgaggaac 36 55SEQ ID NO:6450gttctggaggacggcgtga 809 8281 3 SEQ ID NO:5905cgttagtatgagtgtcgtg 88 10 7 SEQ ID NO: 6 4 5 1 cacgctgcacgggccaacg 5191 52101 3 SEQ ID NO: 5906tgtcgtgcagcctccagga 100 119SEQ ID NO:6452 tcctgttgtcgtggggaca 1879 18981 3 SEQ ID NO: 5907ccccccctcccgggagagc 119 138SEQ ID NO: 64531gctcccggcctagttgggg 645 6641 3 SEQ ID NO:59081ggagagccatagtggtctg 131 150SEQ ID NO:6454 cagatcattgaacgactcc 8993 90121 3 SEQ ID NO:5909gagccatagtggtctgcgg 134 153SEQ ID NO:6455ccgctgctgggtagcgCtc 1048 10671 3 SEQ ID NO:5910gtggtctgCggaaccggtg 142 161 SEQ ID NO: 6456cacccatatagatgcccac 5038 50571 3 SEQ.ID NO:5911lagtacaccggaattgccag 161 180SEQ ID NO:6457ctggCgggCCttgcCtact 1406 14251 3 SEQ ID NO: 5912ggtcctttcttggatcaac 188 207SEQ ID NO:6458gttgagtgacttcaagacc 6304 63231 3 SEQ ID NO: 5 9 1 3 ttcttggatcaacccgctc 194 2 1 3 SEQ ID NO: 6459gagcggagggggatgagaa 7134 71531 3 SEQ ID NO:5914ctcaatgcctggagatttg 210 229SEQ ID NO:6460caaagactccgacgctgag 7486 75051 3 SEQ ID NO: 5 9 1 5 tgcctggagatttgggcgt 215 2 3 4 SEQ ID NO: 6461acgcggccgccgcaaggca 1967 198613 SEQ ID NO:5916gcctggagatttgggcgtg 216 2 3 5 SEQ ID NO:6462cacgcggccgccgcaaggc 1966 19851 3 SEQ ID NO: 5917gagatttgggcgtgccccc 221 2401SEQ ID NO: 6463ggggacaaccgatcgtctc 1891 19101 3 SEQ ID NO:5918aaaggccttgtggtactgc 273 292SEQ ID NO:6464gcagaagaaggtcaccttt 7756 77751 3 SEQ ID NO: 5919 aaggccttgtggtactgcc 274 293 SEQ ID NO:6465ggcagaagaaggtcacctt 7755 77741 3 SEQ ID NO:5920 gtggtactgcctgataggg 282 301 SEQ ID NO:6466ccctaccggctctgtccac 2385 24041 3 SEQ ID NO:5921 cctgatagggtgcttgcga 291 3 1 0 SEQ ID NO:6467tcgccggcccgagggcagg 544 5631 3 SEQ ID NO: 59221cgagtgccccgggaggtct 307 326SEQ ID NO: 6468agacgcagtgtcgcgctcg 4780 47991 3 SEQ ID NO: 5923gccccgggaggtctcgtag 312 331 SEQ ID NO: 6469ctaccttaggttttggggc 4122 41411 3 SEQ ID NO: 5924 ttacctgttgccgcgcagg 442 461 SEQ ID NO: 6470cctgcgttcgggagggtaa 1023 10421 3 SEQ ID NO:5925tacctgttgccgcgcaggg 443 462SEQ ID NO: 6471 ccctgcgttcgggagggta 1022 10411 3 SEQ ID NO:5926cctgttgccgcgcaggggc 445 4 6 4 SEQ ID NO:6472gcccccgaagccagacagg 8348 83671 3 SEQ ID NO: 5927 ctgttgccgcgcaggggcc 446 4 6 5 SEQ ID NO: 6473ggcccccgaagccagacag 8347 83661 3 SEQ ID NO: 5928ccgagcggtcgcaacccc 497 5 16 SEQ ID NO: 6474ggggcaaaggacgtccgga 7922 79411 3 SEQ ID NO:59291ggtcgcaaccccgtggaag 504 523SEQ ID NO: 6475cttctctgacatggagacc 3268 32871 3 SEQ ID NO: 5930 gtcgcaaccccgtggaagg 505 524SEQ ID NO: 6476ccttcaccattgagacgac 4749 47681 3 SEQ ID NO: 5931 aaggcgacagcctatcccc 520 539 SEQ ID NO: 6477ggggcgctgccagggcctt 774 793|1 3 SEQ ID NO: 5932 cagcctatccccaaggctc 527 546 SEQ ID NO: 6478gagcacaggcttaatgctg 2252 22711 3 327 WO 2004/091515 PCT/US2004/01 1255 SEQ ID NO:j5933gagggcagggcctgggctc 554 573 SEQ ID NO: 6479gagcgtcttcacaggcctc 5020 50391 3 SEQ ID NO:15934cagggcctgggctcagccc 559 578SEQ ID NO:6480 gggcatcggcacagtcctg 4324 43431 3 SEQ ID NO: 5935gggcctgggtcagcccgg 561 580SEQ ID NO: 6 4 8 1 ccggccgcatatgcggccc 4064 40831 3 SEQ ID NO:5936cctgggtcagcccgggta 564 583SEQ ID NO: 6 4 8 2 taccgaccctaacatcagg 4162 41811 3 SEQ ID NO:5937ccctctatggcaatgagg 590 609SEQ ID NO:6483cctcgccgacctcatgggg 727 7461 3 SEQ ID NO: 5938gagggcatggggtgggcag 605 624SEQ ID NO: 6484ctgcggatctgttttcctc 1180 11991 3 SEQ ID NO: 5939agggcatggggtgggcagg 606 625SEQ ID NO:6485cctgctcttcaccaccCt 2370 23891 3 SEQ ID NO:5940aggatggctcctgtcaccc 622 641 SEQ ID NO: 6486gggtcagcggttgtctcct 2459 24781 3 SEQ ID NO: 5941 gatggctcctgtcaccccg 624 643SEQ ID NO: 6487,cgggggcgcttacgacatc 4261 42801 3 SEQ ID NO: 5942tgtcaccccgcggctcccg 633 652SEQ ID NO: 6488cggggcgcgttccctgaca 3688 37071 3 SEQ ID NO: 5943gtcaccccgcggctcccgg 634 653SEQ ID NO: 6489ccggggcgcgttccctgac 3687 37061 3 SEQ ID NO: 5944gcggctcccggcctagttg 642 661 SEQ ID NO: 6490caacgtccggggaggccgc 2935 29541 3 SEQ ID NO: 5945ctcccggcctagttggggc 646 665 SEQ ID NO: 6491 gccctgtcgaacactggag 4439 44581 3 SEQ ID NO: 5946lataccctcacatgcggcct 711 730 SEQ ID NO: 6492,aggcaacattatcatgtat 8839 88581 3 SEQ ID NO: 5947tccgctcgtcggcggccc 750 769SEQ ID NO:6493gggcaaagcacatgtggaa 5625 56441 3 SEQ ID NO: 5948cccctagggggcgctgcca 767 786SEQ ID NO:6494tggcaatgagggcatgggg 598 6171 3 SEQ ID NO: 5949tgcaacagggaacctgccc 832 851 SEQ ID NO:6495gggctcattcgtgcatgca 3092 31111 3 SEQ ID NO:5950gcgtaacgcgtccggggta 922 941 SEQ ID NO: 6496taccaccacgagcttacgc 2751 27701 3 SEQ ID NO:5951tcaagcattgtgtttgagg 968 987SEQ ID NO: 6497cctctatgcccccccttga 7512 75311 3 SEQ ID NO:5952cccacgctcgcggccagga 1070 1089SEQ ID NO:6498tcctgtttaacatcttggg 5763 57821 3 SEQ ID NO:5953cggccaggaatgCtaccat 1080 1099SEQ ID NO:6499atggcatgcatgtcggccg 5279 52981 3 SEQ ID NO:5954acgacaatacgacaccacg 1106 1125SEQ ID NO:6500cgtggggacaaccgatcgt 1888 190713 SEQ ID NO:5955gggcggctgctctctgctc 1140 1 159SEQ ID NO: 6501 gagcaacttgaaaaagccc 8921 89401 3 SEQ ID NO: 5956cgtgggggacctctgcgga 1168 1187SEQ ID NO: 6502tccgttgccggagcgcacg 2615 26341 3 SEQ ID NO: 5957agctgttcaccttctcgcc 1206 1225SEQ ID NO: 6503ggcgacaatagagggagct 3779 37981 3 SEQ ID NO:5958ctgttcaccttctcgcccc 1208 1227SEQ ID NO: 6504ggggagacatatatcacag 9282 93011 3 SEQ ID NO:5959ctgcaattgttcgatctac 1249 1268SEQ ID NO:6505gtaggaCtggcaggggcag 4809 48281 3 SEQ ID NO:5960attgttcgatctaccccgg 1254 12 7 3 SEQ ID NO:6506 ccggcccaaaaggcccaat 3615 36341 3 SEQ ID NO: 5961 atctaccccggccacgcgt 1262 1281 SEQ ID NO:6507acgccatggaccgggagat 2766 27851 3 SEQ ID NO:5962cggccacgcgtcaggtcac 1270 1289SEQ ID NO:6508gtgatgtactttttgccg 1460 14791 3 SEQ ID NO: 5963ccgcatggcctgggacatg 1288 1307SEQ ID NO:6509catggaaactactatgcgg 3943 39621 3 SEQ ID NO:5964cgcagttactccggatccc 1344 13 6 3 SEQ ID NO:6510gggaacccaggaggatgcg 8593 86121 3 SEQ ID NO: 5965cccacaagccgtcatcgac 1360 1379SEQ ID NO: 6511 gtcgtcaccagcacctggg 5306 53251 3 SEQ ID NO:5966ctggggagtcctggcgggc 1396 14 1 5 SEQ ID NO:6512gcccggagcgcatggccag 1695 17141 3 SEQ ID NO: 5967ggcgggccttgcctactat 1408 1427SEQ ID NO:6513atagaagaagcctgccgcc 7865 78841 3 SEQ ID NO: 5968tttgccggcgttgacgggc 1472 1491 SEQ ID NO: 6514gcccccacattcggccaaa 7888 79071 3 SEQ ID NO: 5969caccctcacaacggggggg 1492 1511 SEQ ID NO: 6515ccccaatatcgaggaggtg 4420 44391 3 SEQ ID NO: 5970gggggggcacgctgcccgc 1504 1 5 2 3 SEQ ID NO: 6516gcggcacggcgaccgcccc 7440 74591 3 SEQ ID NO: 5971 ggggcacgctgcccgcctc 1507 1526SEQ ID NO: 65171gagggagcttgctctcccc 3789 38081 3 SEQ ID NO:5972gcccgcctcaccagcgggt 1517 15 3 6 SEQ ID NO: 6518accctcacaacgggggggc 1493 15121 3 SEQ ID NO: 5973atccagcttataaacacca 1571 1590 SEQ ID NO: 6519 ggttatcgtgggtaggat 5382 54011 3 SEQ ID NO:5974ctccagactgggtttcttg 1637 1656 SEQ ID NO:6520caagcggagacggctggag 4346 43651 3 SEQ ID NO: 5975cccggagcgcatggccagc 1696 1715SEQ ID NO: 6521 gctgtgggcgtcttccggg 3869 38881 3 SEQ ID NO: 5976ctgccgctccattgacaag 1714 1733SEQ ID NO:6522cttggtacatcaagggcag 2667 26861 3 SEQ ID NO:5977aagttcgaccagggatggg 1730 1749SEQ ID NO:6523cccaaccagaatacgactt 8673 86921 3 SEQ ID NO:5978ggggtcctatcacttatgc 1746 1765SEQ ID NO:6524gcatgtgtgggttcccccc 2914 29331 3 SEQ ID NO: 5979ccagaggccttattgctgg 1786 1805SEQ ID NO:6525ccaggatctcgtcggctgg 3658 36771 3 SEQ ID NO:5980cccacctcaacaatgtggt 1810 1829 SEQ ID NO: 6526accaagatcatcacctggg 3284 33031 3 SEQ ID NO:5981 cgtacctgcgtcgcaggt 1830 1849SEQ ID NO: 6527accttcaccattgagacga 4748 47671 3 SEQ ID NO:5982tgcgtcgcaggtgtgtggt 1837 1856SEQ ID NO: 6528accatgtctcccccacgca 6123 61421 3 328 WO 200/09115 - -. PCT/US2004/011255 SEQ ID NO: 5 9 8 3 ggggacaaccgatcgtct 1890 19 0 9 SEQ ID NO:6529agacgacgaccgtgcccca 4761 47801 3 SEQ ID NO:5984cagctggggggagaacgat 1924 1943 SEQ ID NO:6530atcggagctcagcccgctg 2320 23391 3 SEQ ID NO:5985cgccgcaaggcaactggtt 1974 19 9 3 SEQ ID NO: 6 5 3 1 aacccaggaggatgcggcg 8596 86151 3 SEQ ID NO:59861gccgcaaggcaactggttc 1975 1994SEQ ID NO:6532gaacccaggaggatgcggc 8595 86141 3 SEQ ID NO:5987ctgtacatggatgaatagc 1996 2 0 1 5 SEQ ID NO: 6533gctataaaatcgctcacag 8366,83851 3 SEQ ID NO:5 9 8 8 tgtacatggatgaatagca 1997 2016SEQ ID NO:6534tgctgctcaatgtcctaca 7607 76261 3 SEQ ID NO:5989gttcaccaagacgtgcggg 2020 2 0 3 9 SEQ ID N 0 : 6535cccgctcaccacccagaac 5740 57591 3 SEQ ID NO:5990agacgtgcggggcccccc 2028 2047SEQ ID No: 6536ggggaggttcaagtggtct 3512 35311 3 SEQ ID NO: 5 9 9 1 1cccccgtgtaacatcgggg 2042 2061 SEQ ID NO: 6537ccccaatcgatgaacgggg 9376 93951 3 SEQ ID NO:5992taacaccttgacctgcccc 2071 2090SEQ ID NO:6538ggggacgaccttgtcgtta 8561 85801 3 SEQ ID NO:5993 ggctctggcactacccctg 2184 2203SEQ ID NO:6539caggaggatgcggcgagcc 8600 86191 3 SEQ ID NO:5994tgcactgtcaacttctcca 2201 2220SEQ ID NO:6540tggatggggtgcggttgca 6717 67361 3 SEQ ID NO:5995caggcttaatgctgcatgc 2257 2276SEQ ID NO: 6541 gcatcatgcacaccacctg 6411 64301 3 SEQ ID NO:5996aatgctgcatgcaactgga 2264 2283SEQ ID NO:6542tccatggtcttagcgcatt 9009 90281 3 SEQ ID NO:5997ctgcatgcaactggacccg 2268 2287SEQ ID NO:6543cgggaccttgcggtagcag 3236 32551 3 SEQ ID NO:5998caactggacccgaggagag 2275 2294SEQ ID NO: 6544ctcttacgggatgaggttg 6761 67801 3 SEQ ID NO:5999gacagggacagatcggagc 2309 2328SEQ ID NO:6545gctctcccccaggcctgtc 3799 38181 3 SEQ ID NO:6000gacagatcggagctcagcc 2315 2334SEQ ID NO: 6546ggctggagcgcggcttgtc 4357 43761 3 SEQ ID NO:6001,acagatcggagctcagccc 2316 2335SEQ ID NO: 6547gggccaacgcccctgctgt 5201 52201 3 SEQ ID NO:6002actggcttgatccacctcc 2402 2421 SEQ ID NO: 6548ggagagggggccgtgcagt 6068 60871 3 SEQ ID NO:6003ggcttgatccacctccatc 2405 2424SEQ ID NO: 6549gatgatgctgctgatagcc 2551 25701 3 SEQ ID NO:6004gtcagcggttgtctccttt 2461 2480SEQ ID NO:6550aaaggacggttgtcctgac 7344 73631 3 SEQ ID NO: 6005gagtatgtcgtgttgcttt 2492 2511 SEQ ID NO: 6551 aaagaccaagctcaaactc 9202 92211 3 SEQ ID NO: 6006tgtggatgatgctgctgat 2547 2566SEQ ID NO: 6552atcactgatggcattcaca 5707 57261 3 SEQ ID NO: 6007ccgaggccgccttagagaa 2574 2593SEQ ID NO: 6553ttctgattgccatactcgg 3015 30341 3 SEQ ID NO: 6008agaacctggtggccctcaa 2589_2608SEQ ID NO: 6554ttgatatcaccaaacttct 3000 30191 3 SEQ ID NO: 6009 acatcaagggcaggctgg 2672 2691 SEQ ID NO: 6555ccagatgtacactaatgta 3637 36561 3 SEQ ID NO:6010caagggcaggctggtccct 2677 2696SEQ ID NO:6556aggggtaggcatctacttg 9355 93741 3 SEQ ID NO:6011 Igcatggccgctgctcctgc 2720 2739SEQ ID NO:6557gcagtgctcacttccatgc 6848 68671 3 SEQ ID NO: 6012catggccgctgctcctgct 2721 2740SEQ ID NO: 6558agcagtgctcacttccatg 6847 68661 3 SEQ ID NO: 6013gccgctgctcctgctcctc 2725 2744SEQ ID NO: 6559gagggccgCcacttgcggc 9160 91791 3 SEQ ID NO: 6014ggagatggctgcatcgtgc 2779 2 7 9 8 SEQ ID NO:6560gcacggcgaccgcccctcc 7443 74621 3 SEQ ID NO: 6015atggctgcatcgtgcggag 2783 2802 SEQ ID NO: 6561 ctccaggccaataggccat 9404 94231 3 SEQ ID NO:60161ggcgcggtttttgtgggtc 2801 2820 SEQ ID NO:6562gaccattaccacgggcgcc 4192 42111 3 SEQ ID NO:6017tcttatcaccagagctgag 2887 2 9 0 6 SEQ ID NO: 6563ctcacaggccgggacaaga 3482 35011 3 SEQ ID NO: 6018gtgtgggttcccccctca 2918 2937SEQ ID NO: 6564tgaggtcaccctcacacac 5242 52611 3 SEQ ID NO: 6019tccccccctcaacgtccgg 2926 2945SEQ ID NO: 6565ccggctcgtggctgaggga 6261 62801 3 SEQ ID NO: 6020ctcaacgtccggggaggcc 2933 2952SEQ ID NO:6566ggcctgttactccattgag 8959 89781 3 SEQ ID NO: 6021 accaaacttctgattgcca 3008 3027SEQ ID NO: 6567tggctctctacgatgtggt 8130 81491 3 SEQ ID NO:6022caaacttctgattgccata 3010 3029SEQ ID NO: 6568tatgacacccgctgttttg 8267 82861 3 SEQ ID NO:6023ggaccgctcatggtgctcc 3032 3051 SEQ ID NO: 6569|ggagatcctgcggaagtcc 7171 71901 3 SEQ ID NO: 6024gaccgctcatggtgctcca 3033 3052SEQ ID NO: 6570tggaaactactatgcggtc 3945 39641 3 SEQ ID NO:6025,atgcatgttagtgcggaaa 3106 3125SEQ ID NO: 6 5 7 1|ttctgtaggggtaggcat 9348 93671 3 SEQ ID NO: 6026ttatgtccaaatggccttc 3139 3158SEQ ID NO: 6572|gaagccagacaggctataa 8354 83731 3 SEQ ID NO: 6027ccaaatggccttcatgaga 3145 3164SEQ ID NO: 6573tctcagcgacgggtcttgg 7552 75711 3 SEQ ID NO:6028ccttcatgagactgggcgc 3153 3172SEQ ID NO: 6574gcgctcgtggccttcaagg 5927 59461 3 SEQ ID NO: 6029ccttgcggtagcagtggag 3241 3 2 6 0 SEQ ID NO:6575ctccgcccgaaggggaagg 3349 33681 3 SEQ ID NO: 6030 tgtcgtcttctctgacatg 3262 3281 SEQ ID NO: 6576catggtctacgccacgaca 7717 77361 3 SEQ ID NO: 6031 tggggggcagacaccgcgg 3299 3318SEQ ID NO: 6577|ccgccttatcgtattccca 8083 81021 3 SEQ ID NO: 6032ggggggcagacaccgcggc 3300 3319SEQ ID NO: 6578|gccgcccaactcgctcccc 5792 58111 3 329 WO 2004/091515 ____PCT/US2004/01 1255 SEQ ID NO: 6033gtggggacatcatcctggg 3321 3340SEQ ID NO:6579cccatctacacgCtcccac 4020|40391 3 SEQ ID NO: 6034 tggggacatcatcctgggc 3322 3341 SEQ ID NO: 6580 gcccatctacacgctccca 4019 40381 3 SEQ ID NO:6035ggggacatcatcctgggcc 3323 3342SEQ ID NO:6581ggccagggggtctcccccc 6913693213 SEQ ID NO:6036acctgtctccgoccgaagg 3343 3362SEQ ID NO:6582cctttgacagactgcaggt 7770|77891 3 SEQ ID NO:|6037tgtctccgcccgaagggga 3346 3365SEQ ID NO:6583tccccggtcttcacagaca 3962 39811 3 SEQ ID NO:|6038gggagatactcctggggcc 3366 3385SEQ ID NO:6584ggcccatctacacgctccc 4018 40371 3 SEQ ID NO: 6039ctcccaacagacccggggc 3439 3458SEQ ID NO:6585gcccccccttgagggggag 7519 75381 3 SEQ ID NO: 6040 ccaccgcaacacaatctt 3530 3549SEQ ID NO:6586aagaggctccaccagtgga 6215 62341 3 SEQ ID NO: 6041 cacaatctttcctggcgac 3540 3559SEQ ID NO:6587gtcgtcggagtcgtgtgtg 6020 60391 3 SEQ ID NO:6042ggctggccggcgcccccg 3671 3690SEQ ID NO:6588cgggttgttgcaaacagcc 5542 55611 3 SEQ ID NO: 6043ccccggggcgcgttccctg 3685 3704SEQ ID NO:6589caggtttgtaactccgggg 4840 48591 3 SEQ ID NO: 6044tccctgacaccatgcacct 3698 3717SEQ ID NO:6590aggtcacgcgggtggggga 6618 66371 3 SEQ ID NO: 6045 tccggtgcgccggcgggg 3762 3781 SEQ ID NO: 6591 ccccgttgagtccatggaa 3931 39501 3 SEQ ID NO: 6046 ctcccccaggcctgtctcc 3802 3821 SEQ ID NO:6592ggagacatcgggccaggag 9111 91301 3 SEQ ID NO: 6047gggggttgcaaaggcggtg 3904 3923SEQ ID NO:6593caccctgcctgggaacccc 5680 56991 3 SEQ ID NO: 6048 ttgtccccgttgagtcca 3926 3945SEQ ID NO: 6594 tggagaccttctgggcaaa 5613 56321 3 SEQ ID NO: 6049ccgtaccgcaaacattcca 3996 4015SEQ ID NO:6595 ggattgccaaatctacgg 8940 89591 3 SEQ ID NO: 6050 caagtggcccatctacacg 4013 4032SEQ ID NO:6596cgtgggtaggatcatcttg 5389|54081 3 SEQ ID NO: 6051 cacgctcccactggcagcg 4028 4047SEQ ID NO:6597cgctgcttcggcttcgtg 5815 58341 3 SEQ ID NO: 6052ccgcatatgcggcccaagg 4068 4087SEQ ID NO:6598ccttcaaggtcatgagcgg 5937 59561 3 SEQ ID NO:6053cgtatatgtctaaagcaca 4140 4159SEQ ID NO:6599 tgtggaagtgtctcatacg 5163 51821 3 SEQ ID NO:6054gtatatgtCtaaagcacat 4141 4160SEQ ID NO:6600atgtggaagtgtctcatac 5162|51811 3 SEQ ID NO: 6055ggaccattaccacgggcgc 4191 4 21OSEQ ID NO: 6601 gcgcgtgtcactcaggtcc 6167 61861 3 SEQ ID NO: 6056cccccattacgtactccac 4209 4 2 2 8 SEQ ID NO:6602gtgggcccgggagaggggg 6059 60781 3 SEQ ID NO:6057agttccttgccgacggtgg 4236 4255SEQ ID N:6603ccacagtcaaggctaaact 7839 78581 3 SEQ ID NO: 6058 gagacggctggagcgcggc 4352 4371 SEQ ID NO:6604gccgggggaccccgatctc 7537 75561 3 SEQ ID NO: 6059 caccgctacgcctccagga 4384 4403SEQ ID NO:6605tcctacacatggacaggtg 7619 76381 3 SEQ ID NO: 6060 ggagagatccccttctac 4453 4472SEQ ID NO:6606gtagcagtgctcacttcca 6845 68641 3 SEQ ID NO: 606 1 1agccatccccatcgaagcc 4477 4496SEQ ID NO:6607ggctggttcgttgctggct 9257 92761 3 SEQ ID NO: 6062tcCccatcgaagccatcaa 4482 4501 SEQ ID NO:6608ttgagggggagccggggga 7527 75461 3 SEQ ID NO: 60631ccccatcgaagccatcaag 4483 4502SEQ ID NO:6609cttgagggggagccggggg 752675451 3 SEQ ID NO: 6064ggcctcggaatcaatgctg 4568 4587SEQ ID NO:6610,cagctccgaattgtcggcc 7414 74331 3 SEQ ID NO: 6065 gtccgtcataccgaccagc 4612 4631 SEQ ID NO: 6611 gctgagggatgtttgggac 6271 62901 3 SEQ ID NO: 6066gtcataccgaccagcggag 4616 4635SEQ ID NO:6612ctccattgagccacttgac 8968 89871 3 SEQ ID NO:6067cgggctataccggtgactt 4668 4687SEQ ID NO:6613aagtccaagaagttccccg 7184 72031 3 SEQ ID NO:6068rctttgattcagtgatcgac 4684 4703SEQ ID NO:6614gtcgagttcctggtaaaag 8213 82321 3 SEQ ID NO: 6069acagtcgacttcagcttgg 4724 4743SEQ ID NO: 6615ccaaatctacggggcctgt 8947 89661 3 SEQ ID NO:6070cttggaccccaccttcacc 4738 4757SEQ ID NO:6616ggtgttgagtgacttcaag 6301 63201 3 SEQ ID NO: 6071 gagacgacgaccgtgcccc 4760 4779SEQ ID NO:6617ggggacaaccgatcgtctc 1891 19101 3 SEQ ID NO: 6072 ggggtaggactggcagggg 4806 4825SEQ ID N:6618ccccccggggacttgcccc 8657 86761 3 SEQ ID NO: 6073 gggcatatacaggtttgta 4831 4 850SEQ ID NO:6619tacacatggacaggtgccc 7622 76411 3 SEQ ID NO: 6074gggggaacggccctcgggC 4855 4874SEQ ID NO:6620gcccctgcacgccttcccc 6546 65651 3 SEQ ID NO: 6075tgacgcgggctgtgcttgg 4906 4925SEQ ID NO: 6621 ccaattgacaccaccgtca 8009 80281 3 SEQ ID NO:6076gacgcgggctgtgcttggt 4907 4926SEQ ID NO:6622,accaattgacaccaccgtc 8008 80271 3 SEQ ID NO:6077 gcttggtacgagctcacc 4918 4937SEQ ID NO:6623ggtgcggctgttggcagca 5849 58681 3 SEQ ID NO:6078tgcccacttcctgtcccag 5050 5069SEQ ID NO: 6624ctgggcgcgctgacgggca 3164 31831 3 SEQ ID NO:6079ggtggcataccaagccaca 5101 5120SEQ ID NO:6625tgtgacaccaattgacacc 8002 80211 3 SEQ ID NO:6080gggctcaggccccacctcc 5130 5 14 9 SEQ ID NO:6626ggaggccgcaagccagccc 8066 80851 3 SEQ ID NO: 6081 ccatcgtgggatcaaatgt 5147 5166SEQ ID NO: 6627acattctggcgggctatgg 5892 59111 3 SEQ ID NO:60 8 2 tcatacggctaaaacccac 5175 5194SEQ ID NO:6628 gtggccttCaaggtcatga 5933 59521 3 330 WO 2004/091515 PCT/US2004/011255 SEQ ID NO: 083tgctgtataggctaggggc 5214 5 2 33 SEQ ID NO: 6629gcccgaaccggacgtagca 6832 68511 3 SEQ ID NO: 60840caaatacatcatggcatg 5268 5287SEQ ID NO: 6630catgcctcaggaaacttgg 9072 90911 3 SEQ ID No: 6085ggagtcctcgcagctctgg 5336 5355SEQ ID NO: 6631 ccagctgtctgcgccctcc 6955 69741 3 SEQ ID NO: 6086gcctgacaacaggcagtgt 5364 5383SEQ ID NO: 6632acactccaggccaataggc 9401 94201 3 SEQ ID NO: 6087agccaccaagcaggcggag 5557 5576SEQ ID NO: 6633ctccagttaactcctggct 8820 88391 3 SEQ ID NO:6088catgtggaatttcatcagc 5635 5654SEQ ID NO:6634gctgcgccatcacaacatg 7702 77211 3 SEQ ID NO:6089ctctatcaccagcccgctc 5728 5747SEQ ID NO:6635gagccgcatgactgcagag 9565 95841 3 SEQ ID NO: 6090cccagaacaccctcctgtt 5751 5770SEQ ID NO:6636aacatcttgggggggtggg 5771 57901 3 SEQ ID NO: 6091 ctcctgtttaacatcttgg 5762 5781 SEQ ID NO:16637ccaatcgatgaacggggag 9378 93971 3 SEQ ID NO: 6092ftgggggggtgggtagccg 5777 5796SEQ ID NO:6638cggcgccaaactattccaa 6564 65831 3 SEQ ID NO: 6 0 9 3 tgcttcggctttcgtgggc 5818 5 8 3 7 SEQ ID NO:6639gcccgaaccggacgtagca 6832 68511 3 SEQ ID NO: 6094cgtgggcgctggtatcgc 5829 5848SEQ ID NO:6640gcgagcggcgtgctgacga 8453 84721 3 SEQ ID NO: 6095cgctggtgcggctgttggc 5845 5864SEQ ID NO:6 6 4 11gccacgacatcccgcagcg 7727 77461 3 SEQ ID NO: 60961cggctgttggcagcatagg 5853 5872SEQ ID NO: 6642cctagactctttcgagccg 7111 71301 3 SEQ ID NO: 6097ggggcaggggtggctggcg 5909 5928SEQ ID NO: 6643cgcccaactcgctcccccc 5794 58131 3 SEQ ID NO: 6098ctggcgcgctcgtggcctt 5922 5941 SEQ ID NO: 6644aagggaggccgcaagccag 8063 80821 3 SEQ ID NO: 6099tggcgcgctcgtggccttc 5923 5942SEQ ID NO: 6645gaagggaggccgcaagcca 8062 80811 3 SEQ ID NO: 6100gagcggcgaggcgccctct 5950 5969SEQ ID NO: 6646agagcgtcgtctgctgctc 7596 76151 3 SEQ ID NO: 6101 gggcccgggagagggggc 6060 6079SEQ ID NO: 6647gcccatctacacgctccca 4019 40381 3 SEQ ID NO: 6102cggctgatagcgttcgctt 6095 6114SEQ ID NO: 6648aagcaggcggaggctgccg 5564 55831 3 SEQ ID NO: 6103gtgcctgagagcgacgccg 6146 6 16 5 SEQ ID NO: 6649cggccgccgacagcggcac 7428 74471 3 SEQ ID NO:6104atgaggactgttctacgcc 6237 6256SEQ ID NO:6650ggcggggggacggcatcat 6399 64181 3 SEQ ID NO: 6105gtccaagctcctgccgcgg 6331 6350SEQ ID NO: 6651 ccgctccgtgtgggaggac 7969 79881 3 SEQ ID NO: 6106acagatcgccggacatgtc 6442 6461 SEQ ID NO: 6652gacatatatcacagcctgt 9287 93061 3 SEQ ID NO: 6107acgtggcatggaacattcC 6506 6525SEQ ID NO:6653ggaagaacccggactacgt 7257 72761 3 SEQ ID NO: 6108gggcccctgcacgccttcc 6544 6 5 6 3 SEQ ID NO:6654ggaagaaagcaagctgccc 7660 76791 3 SEQ ID NO:6109agtgcccatgtcaggttcc 6675 6694SEQ ID NO:6655ggaaacagctagacacact 8803 88221 3 SEQ ID NO: 6110 gcccatgtcaggttccag 6677 6696SEQ ID NO:6656ctgggcgcgctgacgggca 3164 31831 3 SEQ ID NO: 6111 cagctcctgagtttttcac 6693 6712SEQ ID NO: 6657gtgagagcgtcgtctgctg 7593 76121 3 SEQ ID NO: 6112tcacggaggtggatggggt 6708 6727SEQ ID NO: 6658acccttcctcaagccgtga 8153 81721 3 SEQ ID NO: 6113cacggaggtggatggggtg 6709 6728SEQ ID NO: 6659cacccttcctcaagccgtg 8152 8171,1 3 SEQ ID NO: 61141gacccctcccacattacag 6872 6891 SEQ ID NO: 6660 ctgttttgactcaacggtc 8278 82971 3 SEQ ID NO:611 5 ttggccagggggtctcccc 6911 6930SEQ ID NO:6661ggggtgggtagccgcccaa 5782 580113 SEQ ID NO:61161ccttgagggcgacatgcac 6972 6991 SEQ ID NO: 6662gtgcttaaggagatgaagg 7811 78301 3 SEQ ID NO: 6117ggagatgggcggaaacatc 7060 7079SEQ ID NO:6663gatgaccCattcttctcc 8887 89061 3 SEQ ID NO: 6118gagatgggcggaaacatca 7061 7080SEQ ID NO:6664tgatgacccatttcttctc 8886 8905,13 SEQ ID NO: 611 9ctagactctttcgagccgc 7112 7131 SEQ ID NO:6665gcggcgtgctgacgactag 8457 84761 3 SEQ ID NO: 6120 agactctttcgagccgct 7113 71321SEQ ID NO:6666agcgacgggtcttggtcta 7556 75751 3 SEQ ID NO: 61211agaatgaaatatccattgc 7149 7168SEQ ID NO:6667gcaaagaatgaggtttct 8030 80491 3 SEQ ID NO: 6122ttgcggcggagatcctgcg 7164 7183SEQ ID NO: 6668cgcacgatgcatctggcaa 8730 87491 3 SEQ ID NO: 6123agcgaggaggctggtgaga 7580 7599SEQ ID NO:6669tctcgtgcccgaccccgct 9305 93241 3 SEQ ID NO: 6124 gagagcgtcgtctgctgc 7594 7613SEQ ID NO: 6670gcagtaaagaccaagctca 9197 92161 3 SEQ ID NO: 6125gtcgtctgctgctcaatgt 7601 7620SEQ ID NO: 6671 acatggtctacgccacgac 7716 77351 3 SEQ ID NO: 6 1 26 tgcgccatcacaacatggt 7704 7723SEQ ID NO: 6672accatgtctcccccacgca 6123 61421 3 SEQ ID NO:6127cagaagaaggtcacctttg 7757 7776SEQ ID NO:6673caaagaatgaggttttctg 8031 80501 3 SEQ ID NO:E6l28cctggatgaccattaccgg 7789 7808SEQ ID NO:6674ccggaacctatccagcagg 7936 79551 3 SEQ ID NO:6129ggacgtgcttaaggagatg 7807 7826SEQ ID NO:6675catCgggccaggagcgtcc 9116 91351 3 SEQ ID NO:6130aaagaatgaggttttctgc 8032 8051 SEQ ID NO:6676gcagaagaaggtcaccttt 7756 77751 3 SEQ ID NO:6131agttcgtgtatgcgagaag 8110 8129SEQ ID NO:6677cttcatgcctcaggaaact 9069 908813 SEQ ID NO:6132ggctataaaatcgctcaca 8365 8384SEQ ID NO:6678tgtgaaaggtccgtgagcc 9551 95701 3 331 WO 2004/091515 PCT/US2004101 1255 SEQ ID NO:j61 33Itttccatccttctagctc 189001891 91SEQ ID NCO:16679gac9989gggatg agaail 71531 3~ EQ D O: 13 gctctgccaccccg 19303193221SEQ ID NO:16680cggggCgcgttccctgaca 13688137071113 332 WO 2004/091515 PCT/US2004/011255 Table 15. Sequences from human hepatitis C virus (HCV) (Direct Match Type) Source Start End Match Start End Match Index Index Index Index # SEQ ID NO: 5285 ttttttttttttttttttt 9446 9465 SEQ ID NO:5288 ttttttttttttttttttt 9466 9485 2 SEQ ID NO: 5286 tttttttttttttttttt 9446 9465 SEQ ID NO:5289 tttttttttttttttttt 9465 9484 1 SEQ ID NO: 5287 ttttttttttttttttttt 9447 9466 SEQ ID NO:5290 ttttttttttttttttttt 9466 9485 1 Table 16. Sequences of Exemplary Gene Targets gil45O21521reflNM_000384.1| Homo sapiens apolipoprotein B (including Ag(x) 5 antigen) (APOB) , mRNA ATTCCCACCGGGACCTGCGGGGCTGAGTGCCCTTCTCGGTTGCTGCCGCTGAGGAGCCCGCCCAGCCAGC CAGGGCCGCGAGGCCGAGGCCAGGCCGCAGCCCAGGAGCCGCCCCACCGCAGCTGGCGATGGACCCGCCG AGGCCCGCGCTGCTGGCGCTGCTGGCGCTGCCTGCGCTGCTGCTGCTGCTGCTGGCGGGCGCCAGGGCCG AAGAGGAAATGCTGGAAAATGTCAGCCTGGTCTGTCCAAAAGATGCGACCCGATTCAAGCACCTCCGGAA 10 GTACACATACAACTATGAGGCTGAGAGTTCCAGTGGAGTCCCTGGGACTGCTGATTCAAGAAGTGCCACC AGGATCAACTGCAAGGTTGAGCTGGAGGTTCCCCAGCTCTGCAGCTTCATCCTGAAGACCAGCCAGTGCA CCCTGAAAGAGGTGTATGGCTTCAACCCTGAGGGCAAAGCCTTGCTGAAGAAAACCAAGAACTCTGAGGA GTTTGCTGCAGCCATGTCCAGGTATGAGCTCAAGCTGGCCATTCCAGAAGGGAAGCAGGTTTTCCTTTAC CCGGAGAAAGATGAACCTACTTACATCCTGAACATCAAGAGGGGCATCATTTCTGCCCTCCTGGTTCCCC 15 CAGAGACAGAAGAAGCCAAGCAAGTGTTGTTTCTGGATACCGTGTATGGAAACTGCTCCACTCACTTTAC CGTCAAGACGAGGAAGGGCAATGTGGCAACAGAAATATCCACTGAAAGAGACCTGGGGCAGTGTGATCGC TTCAAGCCCATCCGCACAGGCATCAGCCCACTTGCTCTCATCAAAGGCATGACCCGCCCCTTGTCAACTC TGATCAGCAGCAGCCAGTCCTGTCAGTACACACTGGACGCTAAGAGGAAGCATGTGGCAGAAGCCATCTG CAAGGAGCAACACCTCTTCCTGCCTTTCTCCTACAACAATAAGTATGGGATGGTAGCACAAGTGACACAG 20 ACTTTGAAACTTGAAGACACACCAAAGATCAACAGCCGCTTCTTTGGTGAAGGTACTAAGAAGATGGGCC TCGCATTTGAGAGCACCAAATCCACATCACCTCCAAAGCAGGCCGAAGCTGTTTTGAAGACTCTCCAGGA ACTGAAAAAACTAACCATCTCTGAGCAAAATATCCAGAGAGCTAATCTCTTCAATAAGCTGGTTACTGAG CTGAGAGGCCTCAGTGATGAAGCAGTCACATCTCTCTTGCCACAGCTGATTGAGGTGTCCAGCCCCATCA CTTTACAAGCCTTGGTTCAGTGTGGACAGCCTCAGTGCTCCACTCACATCCTCCAGTGGCTGAAACGTGT 25 GCATGCCAACCCCCTTCTGATAGATGTGGTCACCTACCTGGTGGCCCTGATCCCCGAGCCCTCAGCACAG CAGCTGCGAGAGATCTTCAACATGGCGAGGGATCAGCGCAGCCGAGCCACCTTGTATGCGCTGAGCCACG CGGTCAACAACTATCATAAGACAAACCCTACAGGGACCCAGGAGCTGCTGGACATTGCTAATTACCTGAT GGAACAGATTCAAGATGACTGCACTGGGGATGAAGATTACACCTATTTGATTCTGCGGGTCATTGGAAAT ATGGGCCAAACCATGGAGCAGTTAACTCCAGAACTCAAGTCTTCAATCCTCAAATGTGTCCAAAGTACAA 30 AGCCATCACTGATGATCCAGAAAGCTGCCATCCAGGCTCTGCGGAAAATGGAGCCTAAAGACAAGGACCA GGAGGTTCTTCTTCAGACTTTCCTTGATGATGCTTCTCCGGGAGATAAGCGACTGGCTGCCTATCTTATG TTGATGAGGAGTCCTTCACAGGCAGATATTAACAAAATTGTCCAAATTCTACCATGGGAACAGAATGAGC AAGTGAAGAACTTTGTGGCTTCCCATATTGCCAATATCTTGAACTCAGAAGAATTGGATATCCAAGATCT GAAAAAGTTAGTGAAAGAAGCTCTGAAAGAATCTCAACTTCCAACTGTCATGGACTTCAGAAAATTCTCT 35 CGGAACTATCAACTCTACAAATCTGTTTCTCTTCCATCACTTGACCCAGCCTCAGCCAAAATAGAAGGGA ATCTTATATTTGATCCAAATAACTACCTTCCTAAAGAAAGCATGCTGAAAACTACCCTCACTGCCTTTGG ATTTGCTTCAGCTGACCTCATCGAGATTGGCTTGGAAGGAAAAGGCTTTGAGCCAACATTGGAAGCTCTT TTTGGGAAGCAAGGATTTTTCCCAGACAGTGTCAACAAAGCTTTGTACTGGGTTAATGGTCAAGTTCCTG ATGGTGTCTCTAAGGTCTTAGTGGACCACTTTGGCTATACCAAAGATGATAAACATGAGCAGGATATGGT 10 AAATGGAATAATGCTCAGTGTTGAGAAGCTGATTAAAGATTTGAAATCCAAAGAAGTCCCGGAAGCCAGA GCCTACCTCCGCATCTTGGGAGAGGAGCTTGGTTTTGCCAGTCTCCATGACCTCCAGCTCCTGGGAAAGC TGCTTCTGATGGGTGCCCGCACTCTGCAGGGGATCCCCCAGATGATTGGAGAGGTCATCAGGAAGGGCTC AAAGAATGACTTTTTTCTTCACTACATCTTCATGGAGAATGCCTTTGAACTCCCCACTGGAGCTGGATTA CAGTTGCAAATATCTTCATCTGGAGTCATTGCTCCCGGAGCCAAGGCTGGAGTAAAACTGGAAGTAGCCA 15 ACATGCAGGCTGAACTGGTGGCAAAACCCTCCGTGTCTGTGGAGTTTGTGACAAATATGGGCATCATCAT TCCGGACTTCGCTAGGAGTGGGGTCCAGATGAACACCAACTTCTTCCACGAGTCGGGTCTGGAGGCTCAT GTTGCCCTAAAAGCTGGGAAGCTGAAGTTTATCATTCCTTCCCCAAAGAGACCAGTCAAGCTGCTCAGTG GAGGCAACACATTACATTTGGTCTCTACCACCAAAACGGAGGTGATCCCACCTCTCATTGAGAACAGGCA 333 WO 2004/091515 PCT/US2004101 1255 GTCCTGGTCAGTTTGCAAGCAAGTCTTTCCTGGCCTGAATTACTGCACCTCAGGCGCTTACTCCAACGCC AGCTCCACAGACTCCGCCTCCTACTATCCGCTGACCGGGGACACCAGATTAGAGCTGGAACTGAGGCCTA CAGGAGAGATTGAGCAGTATTCTGTCAGCGCAACCTATGAGCTCCAGAGAGAGGACAGAGCCTTGGTGGA TACCCTGAAGTTTGTAA CTCAAGCAGAA-GGTGCGAAGCAGACTGAGGCTACCATGACATTCAAATATAAT 5 CGGCAGAGTATGACCTTGTCCAGTGAAGTCCAAATTCCGGATTTTGATGTTGACCTCGGAACAATCCTCA GAGTTAATGATGAATCTACTGAGGGCAAAACGTCTTACAGACTCACCCTGGACATTCAGAACAAGAAA-AT TACTGAGGTCGCCCTCATGGGCCACCTAAGTTGTGACACAAAGGAAGAAAGAAAAATCAAGGGTGTTATT TCCATACCCCGTTTGCAAGCAGAAGCCAGAAGTGAGATCCTCGCCCACTGGTCGCCTGCCAAACTGCTTC TCCAAATGGACTCATCTGCTACAGCTTATGGCTCCACAGTTTCCAAGAGGGTGGCATGGCATTATGATGA 10 AGAGAAGATTGAATTTGAATGGAACACAGGCACCAATGTAGATACCAAAALAATGACTTCCAATTTCCCT GTGGATCTCTCCGATTATCCTAAGAGCTTGCATATGTATGCTAATAGACTCCTGGATCACAGAGTCCCTG AAACAGACATACTTTCCGGCACGTGGGTTCCAATTATAGTTGCAATGAGCTCATGGCTTCAGAGGC ATCTGGGAGTCTTCCTTATACCCAGACTTTGCAAGACCACCTCAATAGCCTGAAGGAGTTCAACCTCCAG AACATGGGATTGCCAGACTTCCACATCCCAG1AAAACCTCTTCTTAAAALAGCGATGGCCGGGTCAAATATA 15 CCTTGAACAAGAACAGTTTGAAAATTGAGATTCCTTTGCCTTTTGGTGGCAAATCCTCCAGAGATCTAAA GATGTTAGAGACTGTTAGGACACCAGCCCTCCACTTCAAGTCTGTGGGATTCCATCTGCCATCTCGAGAG TTCCAAGTCCCTACTTTTACCATTCCCAALGTTGTATCAACTGCAAGTGCCTCTCCTGGGTGTTCTAGACC TCTCCACGAATGTCTACAGCAACTTGTACAACTGGTCCGCCTCCTACAGTGGTGGCAACACCAGCACAGX CCATTTCAGCCTTCGGGCTCGTTACCACATGAAGGCTGACTCTGTGGTTGACCTGCTTTCCTACAATGTG 20 CAAGGATCTGGAGAAACAACATATGACCACAAGAALTACGTTCACACTATCATGTGATGGGTCTCTACGCC2 ACAAATTTCTAGATTCGAATATCAA-TTCAGTATGTAGAAAAACTTGGAAACAACCCAGTCTCAAAAGG TTTACTAATATTCGATGCATCTAGTTCCTGGGGACCACAGATGTCTGCTTCAGTTCATTTGGACTCCAAA AAGAAACAGCATTTGTTTGTCAAAGAAGTCAAGATTGATGGGCAGTTCAGAGTCTCTTCGTTCTATGCTA AAGGCACATATGGCCTGTCTTGTCAGAGGGATCCTAACACTGGCCGGCTCAALTGGAGAGTCCAACCTGAG 25 GTTTAACTCCTCCTACCTCCAAGGCACCAACCAGATAACAGGAAGATATGAAGATGGAACCCTCTCCCTC ACCTCCACCTCTGATCTGCAAAGTGGCATCATTAAA1AATACTGCTTCCCTAAAGTATGAGAACTACGAGC TGACTTTAAAATCTGACACCAATGGGAAGTATAAGAACTTTGCCACTTCTAACAAGATGGATATGACCTT * CTCTAAGCAAAATGCACTGCTGCGTTCTGAATATCAGGCTGATTACGAGTCATTGAGGTTCTTCAGCCTG CTTTCTGGATCACTAAATTCCCATGGTCTTGAGTTAAATGCTGACATCTTAGGCACTGACAAAATTAATA 30 GTGGTGCTCACAGGCGACACTAAGGATTGGCCAAGATGGAATATCTACCAGTGCAACGACCAACTTG-AA GTGTAGTCTCCTGGTGCTGGAGAATGAGCTGAATGCAGAGCTTGGCCTCTCTGGGGCATCTATGAAATTA * ACAACAAATGGCCGCTTCAGGGAACACAATGCAAAATTCAGTCTGGATGGGAAAGCCGCCCCTCACAGAGC TATCACTGGGAAGTGCTTATCAGGCCATGATTCTGGGTGTCGACAGCAAAAACATTTTCAACTTCAAGGT CAGTCAAGAAGGACTTAAGCTCTCAAATGACATGATGGGCTCATATGCTGAAATGAAATTTGACCACACA 35 AACAGTCTGAACATTGCAGGCTTATCACTGGACTTCTCTTCAAAACTTGACAACATTTACAGCTCTGACA AGTTTTATAAGCAAACTGTTAATTTACAGCTACAGCCCTATTCTCTGGTAACTACTTTAAACAGTGACCT GAAATACAATGCTCTGGATCTCACCAACAATGGGAAACTACGGCTAGAACCCCTGAAGCTGCATGTGGCT GGTAACCTAAAAGGAGCCTACCAAAATA~ATGAAATAAAACACATCTATGCCATCTCTTCTGCTGCCTTAT CAGCAAGCTATAAAGCAGACACTGTTGCTAAGGTTCAGGGTGTGGAGTTTAGCCATCGGCTCAALCACAGA 40 CATCGCTGGGCTGGCTTCAGCCATTGACATGAGCACAAACTATAATTCAGACTCACTGCATTTCAGCAAT GTCTTCCGTTCTGTAATGGCCCCGTTTACCATGACCATCGATGCACATACAAATGGCAATGGGAAACTCG CTCTCTGGGGAGAACATACTGGGCAGCTGTATAGCAAATTCCTGTTGAAAGCAGAACCTCTGGCATTTAC TTTCTCTCATGATTACAAAGGCTCCAC1AAGTCATCATCTCGTGTCTAGGAAAAGCATCAGTGCAGCTCTT GAACACAAAGTCAGTGCCCTGCTTACTCCAGCTGAGCAGACAGGCACCTGGAAACTCAAGACCCAATTTA 45 ACAACAATGAATACAGCCAGGACTTGGATGCTTACAACACTAA.AGATAAAATTGGCGTGGAGCTTACTGG ACGAACTCTGGCTGACCTAACTCTACTAGACTCCCCAALTTAAALGTGCCACTTTTACTCAGTGAGCCCATC AATATCATTGATGCTTTAGAGATGAGAGATGCCGTTGAGAAGCCCCAAGAATTTACAATTGTTGCTTTTG TAAAGTATGATAAAAACCAAGATGTTCACTCCATTAACCTCCCATTTTTTGAGACCTTGCAAGAATATTT TGAGAGGAATCGACAAACCATTATAGTTGTAGTGGAAAACGTACAGAGAAACCTGAAGCACATCAATATT 50 GATCAATTTGTAAGAAAATACAGAGCAGCCCTGGGAA2AACTCCCACAGCAAGCTAATGATTATCTG3AATT CATTCAATTGGGAGAGACAAGTTTCACATGCCAAGGAGAAACTGACTGCTCTCACAAAAA-AGTATAGAAT TACAGAAAATGATATACAAATTGCATTAGATGATGCCAAAATCAACTTTAATGAAAAACTATCTCAACTG CAGACATATATGATACAATTTGATCAGTATATTAAAGATAGTTATGATTTACATGATTTGAAATAGCTA TTGCTAATATTATTGATGAAATCATTGAAA1AATTAAAAAGTCTTGATGAGCACTATCATATCCGTGTAAA 55 TTTAGTAAAAACAATCCATGATCTACATTTGTTTATTGAAAATATTGATTTTAACAAAGTGGAAGTAGT ACTGCATCCTGGATTCAAAATGTGGATACTAAGTACCAAATCAGAALTCCAGATACAAGAAAAACTGCAGC AGCTTAAGAGACACATACAGAATATAGACATCCAGCACCTAGCTGGAAAGTTAAAACAACACATTGAGGC TATTGATGTTAGAGTGCTTTTAGATCAATTGGGAACTACAATTTCATTTGAAAGAATAALATGATGTTCTT 334 WO 2004/091515 PCT/US200401 1255 GAGCATGTCAAACACTTTGTTATAATCTTATTGGGGATTTTGAAGTAGCTGAGAAATCAATGCCTTCA GAGCCAAGTCCATGAGTTAATCGAGAGGTATGAAGTAGACCAACAAATCCAGGTTTTAATGGATAAATT AGTAGAGTTGACCCACCAATACAGTTGAGGAGACTATTCAGAGCTAAGCA\TGTCCTACAACAGTT AAGATAAAGATTACTTTGAGAAATTGGTTGGATTTATTGATGATGCTGTGAAGAAGCTTAATGJATTAT 5 CTTTTAAACATTCATTGAAGATGTTAAAATTCCTTGACATGTTGATAAGAAATTAAGTCATTTGA TTACCACCAGTTTGTAGATGAAACCAATGACAAATCCGTGAGGTGACTCAGAGACTCAATGGTGATT CAGGCTCTGGAACTACCACAAAAAGCTGAAGCATTAAAACTGTTTTTAGAGGAA-ACCAAGGCCACAGTTG CAGTGTATCTGGAAAGCCTACAGGACACCA-AAATAACCTTAATCATCAATTGGTTACAGGAGGCTTTAjAG TTCAGCATCTTTGGCTCACATGAAGGCCAAAJTTCCGAGAGACTCTAGAAGATACACGAGACCGAJATGTAT 10 CAAITGGACATTCAGCAGGAACTTCAACGATACCTGTCTCTGGTAOGCCAG3GTTTATAGCACACTTGTCA CCTACATTTCTGATTGGTGGACTCTTGCTGCTAAGAACCTTACTGACTTTGCAGAGCAATATTCTATCCA AGATTGGGCTAAACGTATGAAAGCATTGGTAGAGCAAGGGTTCACTGTTCCTGPTCAGACCATCCTT GGGACCATGCCTGCCTTTGAAGTCAGTCTTCAGGCTCTTCAGAAAGCTACCTTCCAGACACCTGATTTTA TAGTCCCCCTAACAGATTTGAGGATTCCATCAGTTCAGATAACTTCAGACTTAATATAAAAAT 15 CCCATCCAGGTTTTCCACACCAGAATTTACCATCCTTAACACCTTCCACATTCCTTCCTTTACAATTGAC TTTGTCGAAATGAAAGTAAAGATCATCAGAACCATTGACCAGATGCAGAACAGTGAGCTGCAGTGGCCCG TTCCAGATATATATCTCAGGGATCTGAAGGTGGAGGACATTCCTCTAGCGAGAJATCACCCTGCCAGACTT CCTTCAAACCATCGATAATCCATTACTATATTAGTC GACCTTCACATACCAGAATTCCAGCTTCCCCACATCTCACACACAATTGAAGTACCTACTTTTGGCAAGC 20, TATACAGTATTCTGAAATCCAATCTCCTCTTTTCACATTAGATGCAAATGCTGACATAGGGATGGAJAC CACCTCAGCAAACGAAGCAGGTATCGCAGCTTCCATCACTGCCAAGGAGAGTCCAATTAGAGTTCTC AATTATTAGAAGAALTTAACCAGTATCCGCCG-GATA TGAAGTTCTCCAGCAAGTACCTGAGAACGGAGCATGGGAGTGAAATGCTGTTTTTTGGAA\ATGCTATTGA GGGAAAATCAAACACAGTGGCAAGTTTACACACAGAAAAATACACTGGAGCTTAGTATGGAGTGATT 25 GTAGTAAATACTCCGAACAATATCTCCATGAACCAA TGGACTTCTCTAGTCAGGCTGACCTGCGCAACGAGATCAAGACACTGTTGAGCTGGCCACATAGCATG GACTTCTTCTGGAAAGGGTCATGGAAATGGGCCTGCCCCAGATTCTCAGATGAGGGAACACATGAATCA CAATATTACTGAGCCTATCTTGCGCATAACAACACC TAAGAGTAAACCAAACTTGGTTTATGAATCTGGCTCCCTCAACTTTTCTAAACTTGAATTCJATCACA 30 AGTCGATTCCCAGCATGTGGGCCACAGTGTTCTAACTGCTAGGCATGGCACTGTTTGGAGAGGGAAG GCGGTATGAGAGTCCTTATGAAGTTGACTGAATCCT TCTTTTCAGCCCAGCCATTTGAGATCACGGCATCCACAALACAATGAAGGGAATTTGAAAGTTCGTTTTCC ATTAAGGTTAACAGGGAAGATAGACTTCCTGAATAACTATGCACTGTTTCTGAGTCCCAGTGCCCAGCAA GCAALGTTGGCAAGTAAGTGCTAGGTTCAATCAGTATAAGTACAACCATTTCTCTGCTGGACAACG 35. AGAACATTATGGAGGCCCATGTAGGAATAAATGGAGAAGCAAATCTGGATTTCTTAALACATTCCTTTAAC AATTCCTGAAATGCGTCTACCTTACACAATAATCACAACTCCTCCACTGAAJAGATTTCTCTCTATGGGAA AAAACAGGCTTGAAGGAATTCTTGAAAACGACAAAGCAATCATTTGATTTAAGTGTAuALGCTCAGTATA AGAAAAACAAACACAGGCATTCCATCACAAATCCTTTGGCTGTGCTTTGTGAGTTTATCAGTCAGAGCAT (CATCTGCGCTTGAAACGACAGATGTTGCCAACTTA 40 GAAACAAAAATTAAGTTTGATAAGTACAAAGCTGAAAAATCTCACGACGAGCTCCCCAGGACCTTTCAAA TTCCTGGATACACTGTTCCAGTTGTCAATGTTGAAGTGTCTCCATTCACCATAGAGATGTCGGCATTCGG CTATGTGTTCCCAAAAGCAGTCAGCATGCCTAGTTTCTCCATCCTAGGTTCTGACGTCCGTGTGCCTTCA TACACATTAATCCTGCCATCATTAGAGCTGCCAGTCCTTCATGTCCCTAGA2ATCTCAAGCTTTCTCTTC CACATTTCAAGGAATTGTGTACCATAAGCCATATTTTTATTCCTGCCATGGGCAATATTACCTATGATTT 45 CTCCTTTAAATCAGTGTCATCACACTGAATACCAATGCTGAALCTTTTTACCAGTCAGATATTGTTGCT CATCTCCTTTCTTCATCTTCATCTGTCATTGATGCACTGCAGTACAAATTAGAGGGCACCACAAGATTGA CAAGAAAAAGGGGATTGAAGTTAGCCACAGCTCTGTCTCTGAGCAACA'ATTTGTGGAGGGTAGTCATAA CAGTACTGTGAGCTTAACCACGAAATATGGAAGTGTCAGTGGCAAACCACAAAAGCCGAATTCCA ATTTTGAGAATGAATTTCAAGCAAGAACTTAATGAATACCAAGTCAAAACCTACTGTCTCTTCCTCCA 50 TGGAATTTAAGTATGATTTCAATTCTTCAATGCTGTACTCTACCGCTAAAGGAGCAGTTGACCACAAGCT TAGCTTGGAAAGCCTCACCTCTTACTTTTCCATTGAGTCATCTACCAAAGGAGATGTCAGGGTTCGGTT CTTTGGAATAGATTGTGGGGCAATATGATCAACCCG CTTCAGTGAAGCTGCAGGGCACTTCCAAAATTGATGATATCTGGAACCTTGAGTAAGAAATTTTGC TGGAGAAGCCACACTCCAACGCATATATTCCCTCTGGGAGCACAGTACGAAAACCACTTACAGCTAGAG 55 GGCCTCTTTTTCACCAACGGAGAACATACAAGCAAAGCCACCCTGGAACTCTCTCCATGGCAAATGTCAG CTCTTGTTCAGGTCCATGCAAGTCAGCCCAGTTCCTTCCATGATTTCCCTGACCTTGGCCAGGAGTGGC CCTGAATGCTAACACTAAGAACCAGAAGATCAGATGGAAAAATGAAGTCCGGATTCATTCTGGGTCTTTC CAGAGCCAGGTCGAGCTTTCCAATGACCAAGAAAAGGCACACCTTGACATTGCAGGATCCTTAGJAGGAC 335 WO 2004/091515 PCT/US2004/011255 ACCTAAGGTTCCTCAAAAATATCATCCTACCAGTCTATGACAAGAGCTTATGGGATTTCCTAAAGCTGGA TGTAACCACCAGCATTGGTAGGAGACAGCATCTTCGTGTTTCAACTGCCTTTGTGTACACCAAAAACCCC AATGGCTATTCATTCTCCATCCCTGTAAAAGTTTTGGCTGATAAATTCATTACTCCTGGGCTGAAACTAA ATGATCTAAATTCAGTTCTTGTCATGCCTACGTTCCATGTCCCATTTACAGATCTTCAGGTTCCATCGTG 5 CAAACTTGACTTCAGAGAAATACAAATCTATAAGAAGCTGAGAACTTCATCATTTGCCCTCAACCTACCA ACACTCCCCGAGGTAAAATTCCCTGAAGTTGATGTGTTAACAAAATATTCTCAACCAGAAGACTCCTTGA TTCCCTTTTTTGAGATAACCGTGCCTGAATCTCAGTTAACTGTGTCCCAGTTCACGCTTCCAAAAAGTGT TTCAGATGGCATTGCTGCTTTGGATCTAAATGCAGTAGCCAACAAGATCGCAGACTTTGAGTTGCCCACC ATCATCGTGCCTGAGCAGACCATTGAGATTCCCTCCATTAAGTTCTCTGTACCTGCTGGAATTGTCATTC 10 CTTCCTTTCAAGCACTGACTGCACGCTTTGAGGTAGACTCTCCCGTGTATAATGCCACTTGGAGTGCCAG TTTGAAAAACAAAGCAGATTATGTTGAAACAGTCCTGGATTCCACATGCAGCTCAACCGTACAGTTCCTA GAATATGAACTAAATGTTTTGGGAACACACAAAATCGAAGATGGTACGTTAGCCTCTAAGACTAAAGGAA CACTTGCACACCGTGACTTCAGTGCAGAATATGAAGAAGATGGCAAATTTGAAGGACTTCAGGAATGGGA AGGAAAAGCGCACCTCAATATCAAAAGCCCAGCGTTCACCGATCTCCATCTGCGCTACCAGAAAGACAAG 15 AAAGGCATCTCCACCTCAGCAGCCTCCCCAGCCGTAGGCACCGTGGGCATGGATATGGATGAAGATGACG ACTTTTCTAAATGGAACTTCTACTACAGCCCTCAGTCCTCTCCAGATAAAAAACTCACCATATTCAAAAC TGAGTTGAGGGTCCGGGAATCTGATGAGGAAACTCAGATCAAAGTTAATTGGGAAGAAGAGGCAGCTTCT GGCTTGCTAACCTCTCTGAAAGACAACGTGCCCAAGGCCACAGGGGTCCTTTATGATTATGTCAACAAGT ACCACTGGGAACACACAGGGCTCACCCTGAGAGAAGTGTCTTCAAAGCTGAGAAGAAATCTGCAGAACAA 20 TGCTGAGTGGGTTTATCAAGGGGCCATTAGGCAAATTGATGATATCGACGTGAGGTTCCAGAAAGCAGCC

AGTGGCACCACTGGGACCTACCAAGAGTGGAAGGACAAGGCCCAGAATCTGTACCAGGAACTGTTGACTC

AGGAAGGCCAAGCCAGTTTCCAGGGACTCAAGGATAACGTGTTTGATGGCTTGGTACGAGTTACTCAAAA ATTCCATATGAAAGTCAAGCATCTGATTGACTCACTCATTGATTTTCTGAACTTCCCCAGATTCCAGTTT CCGGGGAAACCTGGGATATACACTAGGGAGGAACTTTGCACTATGTTCATAAGGGAGGTAGGGACGGTAC 25 TGTCCCAGGTATATTCGAAAGTCCATAATGGTTCAGAAATACTGTTTTCCTATTTCCAAGACCTAGTGAT TACACTTCCTTTCGAGTTAAGGAAACATAAACTAATAGATGTAATCTCGATGTATAGGGAACTGTTGAAA GATTTATCAAAAGAAGCCCAAGAGGTATTTAAAGCCATTCAGTCTCTCAAGACCACAGAGGTGCTACGTA ATCTTCAGGACCTTTTACAATTCATTTTCCAACTAATAGAAGATAACATTAAACAGCTGAAAGAGATGAA ATTTACTTATCTTATTAATTATATCCAAGATGAGATCAACACAATCTTCAATGATTATATCCCATATGTT 30 TTTAAATTGTTGAAAGAAAACCTATGCCTTAATCTTCATAAGTTCAATGAATTTATTCAAAACGAGCTTC AGGAAGCTTCTCAAGAGTTACAGCAGATCCATCAATACATTATGGCCCTTCGTGAAGAATATTTTGATCC AAGTATAGTTGGCTGGACAGTGAAATATTATGAACTTGAAGAAAAGATAGTCAGTCTGATCAAGAACCTG TTAGTTGCTCTTAAGGACTTCCATTCTGAATATATTGTCAGTGCCTCTAACTTTACTTCCCAACTCTCAA GTCAAGTTGAGCAATTTCTGCACAGAAATATTCAGGAATATCTTAGCATCCTTACCGATCCAGATGGAAA 35 AGGGAAAGAGAAGATTGCAGAGCTTTCTGCCACTGCTCAGGAAATAATTAAAAGCCAGGCCATTGCGACG AAGAAAATAATTTCTGATTACCACCAGCAGTTTAGATATAAACTGCAAGATTTTTCAGACCAACTCTCTG ATTACTATGAAAAATTTATTGCTGAATCCAAAAGATTGATTGACCTGTCCATTCAAAACTACCACACATT TCTGATATACATCACGGAGTTACTGAAAAAGCTGCAATCAACCACAGTCATGAACCCCTACATGAAGCTT GCTCCAGGAGAACTTACTATCATCCTCTAATTTTTTAAAAGAAATCTTCATTTATTCTTCTTTTCCAATT 40 GAACTTTCACATAGCACAGAAAAAATTCAAACTGCCTATATTGATAAAACCATACAGTGAGCCAGCCTTG CAGTAGGCAGTAGACTATAAGCAGAAGCACATATGAACTGGACCTGCACCAAAGCTGGCACCAGGGCTCG GAAGGTCTCTGAACTCAGAAGGATGGCATTTTTTGCAAGTTAAAGAAAATCAGGATCTGAGTTATTTTGC TAAACTTGGGGGAGGAGGAACAAATAAATGGAGTCTTTATTGTGTATCATA (SEQ ID NO:6681) 45 >gil4557442|refINM_000078.11 Homo sapiens cholesteryl ester transfer protein, plasma (CETP), mRNA GTGAATCTCTGGGGCCAGGAAGACCCTGCTGCCCGGAAGAGCCTCATGTTCCGTGGGGGCTGGGCGGACA TACATATACGGGCTCCAGGCTGAACGGCTCGGGCCACTTACACACCACTGCCTGATAACCATGCTGGCTG CCACAGTCCTGACCCTGGCCCTGCTGGGCAATGCCCATGCCTGCTCCAAAGGCACCTCGCACGAGGCAGG 50 CATCGTGTGCCGCATCACCAAGCCTGCCCTCCTGGTGTTGAACCACGAGACTGCCAAGGTGATCCAGACC GCCTTCCAGCGAGCCAGCTACCCAGATATCACGGGCGAGAAGGCCATGATGCTCCTTGGCCAAGTCAAGT ATGGGTTGCACAACATCCAGATCAGCCACTTGTCCATCGCCAGCAGCCAGGTGGAGCTGGTGGAAGCCAA GTCCATTGATGTCTCCATTCAGAACGTGTCTGTGGTCTTCAAGGGGACCCTGAAGTATGGCTACACCACT GCCTGGTGGCTGGGTATTGATCAGTCCATTGACTTCGAGATCGACTCTGCCATTGACCTCCAGATCAACA 55 CACAGCTGACCTGTGACTCTGGTAGAGTGCGGACCGATGCCCCTGACTGCTACCTGTCTTTCCATAAGCT GCTCCTGCATCTCCAAGGGGAGCGAGAGCCTGGGTGGATCAAGCAGCTGTTCACAAATTTCATCTCCTTC 336 WO 2004/091515 PCT/US2004101 1255 ACCCTGAAGCTGGTCCTGAAGGGACAGATCTGCAAAGAGATCACGTCATCTCTAACATCATGGCCGATT TTGTCCAGACAAGGGCTGCCAGCATCCTTTCAGATGGAGACATTGGGGTGGACATTTCCCTGACAGGTGA TCCCGTCATCACAGCCTCCTACCTGGAGTCCCATCACAALGGGTCATTTCATCTACAAGAATGTCTCAGAG GACCTCCCCCTCCCCACCTTCTCGCCCACACTGCTGGGGGACTCCCGCATGCTGTACTTCTGGTTCTCTG 5 AGCGAGTCTTCCACTCGCTGGCCAAGGTAGCTTTCCAGGATGGCCGCCTCATGCTCAGCCTGATGGGAGA CGAGTTCAAGGCAGTGCTGGAGACCTGGGGCTTCAACACCAACCAGGAAATCTTCCAAGAGGTTGTCGGC GGCTTCCCCAGCCAGGCCCAAGTCACCGTCCACTGCCTCALAGATGCCCAAGATCTCCTGCCAAAACAAGG GAGTCGTGGTCAATTCTTCAGTGATGGTGA1AATTCCTCTTTCCACGCCCAGACCAGCAACATTCTGTAGC TTACACATTTGAAGAGGATATCGTGACTACCGTCCAGGCCTCCTATTCTAAGAAAAAGCTCTTCTTAAGC 10 CTCTTGGATTTCCAGATTACACCAAAGACTGTTTCCAACTTGACTGAGAGCAGCTCCGAGTCCATCCAGA GCTTCCTGCAGTCALATGATCACCGCTGTGGGCATCCCTGAGGTCATGTCTCGGCTCGAGGTAGTGTTTAC AGCCCTCATGAACAGCAAAGGCGTGAGCCTCTTCGACATCATCAACCCTGAGATTATCACTCGAGATGGC TTCCTGCTGCTGCAGATGGACTTTGGCTTCCCTGAGCACCTGCTGGTGGATTTCCTCCAGAGCTTGAGCT AGAAGTCTCCAAGGAGGTCGGGATGGGGCTTGTAGCAGAAGGCAAGCACCAGGCTCACAGCTGGAACCCT 15 GGTGTCTCCTCCAGCGTGGTGGAAGTTGGGTTAGGAGTACGGAGATGGAGATTGGCTCCCAACTCCTCCC TATCCTAAAGGCCCACTGGCATTAAAGTGCTGTATCCAAG (SEQ ID NO: G582) >gi 414668 IembIX75500.IjHSMTP H. sapiens mRNA for microsomal triglyceride 20 transfer protein TGCAGTTGAGGATTGCTGGTCAATATGATTCTTCTTGCTGTGCTTTTTCTCTGCTTCATTTCCTCATATT CAGCTTCTGTTAAAGGTCACACAACTGGTCTCTCATTAAATAATGACCGGCTGTACAAGCTCACGTACTC CACTGAAGTTCTTCTTGATCGGGGCAAAGGAAAACTGCAAGACAGCGTGGGCTACCGCATTTCCTCCAAC GTGGATGTGGCCTTACTATGGAGGAATCCTGATGGTGATGATGACCAGTTGATCCAAATAACGATGAAGG 25 ATGTAATGTTGAAAATGTGAATCAGCAGAGAGGAGAGAAGAGCATCTTCAAGGAAAAAGCCCATCTAA4 AATAATGGGAAAGGAAAACTTGGAAGCTCTGCAAAGACCTACGCTCCTTCATCTAATCCATGGAAAGGTC AAAGAGTTCTACTCATATCAAAATGAGGCAGTGGCCATAGAAAATATCAAGAGAGGTCTGGCTAGCCTAT TTCAGACACAGTTAAGCTCTGGAACCACCA.ATGAGGTAGATATCTCTGGAAATTGTAAAGTGACCTACCA GGCTCATCAAGACAAAGTGATCAAAATTAAGGCCTTGGATTCATGCAAAATAGCGAGGTCTGGATTTACG 30 ACCCCAAATCAGGTCTTGGGTGTCAGTTCAAAAGCTACATCTGTCACCACCTATAAGATAGAAGACAGCT TTGTTATAGCTGTGCTTGCTGAAGAAACACACAATTTTGGACTGAATTTCCTACAAACCATTAAGGGGAA AATAGTATCGAAGCAGAZAATTAGAGCTGAAGACAACCGAAGCAGGCCCAAGATTGATGTCTGGAAAGCAG GCTGCAGCCATAATCAAAGCAGTTGATTCAA~AGTACACGGCCATTCCCATTGTGGGGCAGGTCTTCCAGA GCCACTGTAALAGGATGTCCTTCTCTCTCGGAGCTCTGGCGGTCCACCAGGAAATACCTGCAGCCTGACAA 35 CCTTTCCAAGGCTGAGGCTGTCAGAAACTTCCTGGCCTTCATTCAGCACCTCAGGACTGCGAAGAAAGAA GAGATCCTTCAAATACTAALAGATGGAA1\ATAAGGAAGTATTACCTCAGCTGGTGGATGCTGTCACCTCTG CTCAGACCTCAGACTCATTAGAAGCCATTTTGGACTTTTTGGATTTCAAAAGTGACAGCAGCATTATCCT CCAGGAGAGGTTTCTCTATGCCTGTGGATTTGCTTCTCATCCCAATGAAGAACTCCTGAGAGCCCTCATT AGTAZXGTTCAAAGGTTCTATTGGTAGCAGTGACATCAGAGAAACTGTTATGATCATCACTGGGACACTTG 40 TCAGAAAGTTGTGTCAGAALTGAAGGCTGCAAACTCAAAGCAGTAGTGGAAGCTAAGAAGTTAATCCTGGG AGGACTTGAAAAAGCAGAGAAAAAAGAGGACACCAGGATGTATCTGCTGGCTTTGAAGAATGCCCTGCTT CCAGAAGGCATCCCAAGTCTTCTGAAGTATGCAGAAGCAGGAGAAGGGCCCATCAGCCACCTGGCTACCA CTGCTCTCCAGAGATATGATCTCCCTTTCATAACTGATGAGGTGAAGAAGACCTTAAACAGAA!TATACCA CCAAAACCGTAAAGTTCATGAAAAGACTGTGCGCACTGCTGCAGCTGCTATCATTTTAAATAACAATCCA 45 TCCTACATGGACGTCAAGALACATCCTGCTGTCTATTGGGGAGCTTCCCCAAGAAATGAATAAATACATGC TCGCCATTGTTCAAGACATCCTACGTTTTGA2AATGCCTGCAAGCAAAATTGTCCGTCGAGTTCTGAAGGA AATGGTCGCTCACAATTATGACCGTTTCTCCAGGAGTGGATCTTCTTCTGCCTACACTGGCTACATAGAA CGTAGTCCCCGTTCGGCATCTACTTACAGCCTAGACATTCTCTACTCGGGTTCTGGCATTCTAAGGAGAA GTAACCTGAACATCTTTCAGTACATTGGGAAGGCTGGTCTTCACGGTAGCCAGGTGGTTATTGAAGCCCA 50 AGGACTGGAAGCCTTAATCGCAGCCACCCCTGACGAGGGGGAGGAGAACCTTGACTCCTATGCTGGTATG TCAGCCATCCTCTTTGATGTTCAGCTCAGACCTGTCACCTTTTTC1AACGGATACAGTGATTTGATGTCCA AZATGCTGTCAGCATCTGGCGACCCTATCAGTGTGGTGAAAGGACTTATTCTGCTAATAGATCATTCTCA GGAACTTCAGTTACAATCTGGACTAAALAGCCAATATAGAGGTCCAGGGTGGTCTAGCTATTGATATTTCA GGTGCAATGGAGTTTAGCTTGTGGTATCGTGAGTCTAAAACCCGAGTGAAAAATAGGGTGACTGTGGTAA 55 TAACCACTGACATCACAGTGGACTCCTCTTTTGTGAAAGCTGGCCTGGAAACCAGTACAGAAACAGAA3C AGGCTTGGAGTTTATCTCCACAGTGCAGTTTTCTCAGTACCCATTCTTAGTTTGCATGCAGATGGACAAG 337 WO 2004/091515 PCT/US2004/011255 GATGAAGCTCCATTCAGGCAATTTGAGAAAAAGTACGAALAGGCTGTCCACAGGCAGAGGTTATGTCTCTC AGAABAGAAAGAAAGCGTATTAGCAGGATGTGAATTCCCGCTCCATCAGAGAACTCAGAGATGTGCAA AGTGGTGTTTGCCCCTCAGCCGGATAGTACTTCCAGCGGATGGTTTTGAAACTGACCTGTGATATTTTAC TTGAATTTGTCTCCccGAAAGGGACACAATGTGGCATGACTAAGTACTTGCTCTCTGAGAGCACAGCGTT 5 TACATATTTACCTGTATTTAAGATTTTTGTAAAAGCTACAACTGCAGTTTGATCAATTTGGGTA TATGCAGTATGCTACCCACAGCGTCATTTTGATCATCATGTGACGCTTTCACACGTTCTTAGTTTAC TTATACCTCTCTCAAATCTCATTTGGTACAGTCAGAATAGTTATTCTCTAGAGGAACTAGTGTTTGTT AAACAATAACAACCCAGGACCATTTTACATTGTATT TAGACCTAAGCTCTACTAGGAACPAAGTCTACGAAA 10 AAAAAAAATAAAAAAACTTTTCCTTTGATGGGCAGA AAGGGACAAGGCTTTTAAAAGACTTGTTAGCCAACTTCAAGAATTAATATTTATGTCTCTGTTALTTGTTA GTTTTAAGCCTTAALGGTAGAAGGCACATAGAAATAACATC (SEQ ID NO :6683) >gi 1217638jemblX9114B .1jHSMTTP H.sapiens mRNA for microsomal triglyceride 15 transfer protein TGCAGTTGAGGATTGCTGGTCAATATGATTCTTCTTGCTGTGCTTTTTCTCTGCTTCATTTCCTCATATT CACTTTAAGCCCATGCCCTTATAGCGCGAAGTAGAT CACTGAAGTTCTTCTTGATCGGGGCAAAGGAAAACTGCAAGACAGCGTGGGCTACCGCATTTCCTCCAAC GTGGATGTGGCCTTACTATGGAGGAATCCTGATGGTGATGATGACCAGTTGATCCAATCGATGAAGG 20 ATGTAAATGTTGAAATGTGAATCAGCAGAGAGGAGAGAAGAGCATCTTGGAAAGCCCATCTAA AATAATGGGAAAGGAAACTTGGAGCTCTGCAAAGACCTACGCTCCTTCATCTAATCCATGGAAAGGTC M-AAGAGTTCTACTCATATCAAAATGAGGCAGTGGCCATAGAAAATATCAAGAGAGGTCTGGCTAGCCTAT TTCAGACACAGTTAAGCTCTGGACCACCA2 TGAGGTAGATATCTCTGGAAATTGTAAGTGACCTACCA GGCTCATCAAIGACAAAGTGATCAAAATTAAGGCCTTGGATTCATGCAAAATAGCGAGGTCTGGATTTACG 25 ACCCCAAATCAGGTCTTGGGTGTCAGTTCAAGCTACATCTGTCACCACCTATAAGATAGAAGACAGCT TTGTTATAGCTGTGCTTGCTGAGAAACACACAATTTTGGACTGATTTCCTACACCATTAGGGGAA AATAGTATCGAGCAGAAATTA GAGCTGAGACAACCGAGCAGGCCCAGATTGATGTCTGGAGCAG GCTGCAGCCATAATCAAAGCAGTTGATTCAAAGTACACGGCCATTCCCATTGTGGGGCAGGTCTTCCAGA GCCACTGTAAAGGATGTCCTTCTCTCTCGGAGCTCTGGCGGTCCACCAGGATACCTGCAGCCTGACAA 30. CCTTTCCAAGGCTGAGGCTGTCAGAACTTCCTGGCCTTCATTCAGCACCTCAGGACTGCGGAGA GAGATCCTTCAAATACTAAAGATGGAAAATAAGGAI4GTATTACCTCAGCTGGTGGATGCTGTCACCTCTG CTCAGACCTCAGACTCATTAGAAGCCATTTTGGACTTTTTGGATTTCAAAAGTGACAGCAGCATTATCCT CCAGGAGAGGTTTCTCTATGCCTGTGGATTTGCTTCTCATCCCAATGAAGAACTCCTGAGAGCCCTCATT AGTAAGTTCAAAGGTTCTATTGGTAGCAGTGACATCAGAGAAACTGTTATGATCATCACTGGGACACTTG 35 TCAGAAAGTTGTGTCAGAATGAAGGCTGCACTCAAAGCAGTAGTGGAAGCTAGGTTATCCTGGG AGGACTTGAAAAAGCAGAGAAAAAGAGGACACCAGGATGTATCTGCTGGCTTTGATGCCCTGCTT CCAG2AAGGCATCCCAAGTCTTCTGAAGTATGCAGAAGCAGGAGAAGGGCCCATCAGCCACCTGGCTACCA CTCCCAAAAGTCCCTCTATAGGTAGAGCTAAAATTC ACCAAACCGTAAGTTCATGAAAGACTGTGCGCACTGCTGCAGCTGCTATCATTTTATAACATCC 40 ATCCTACATGGACGTCAAGAACATCCTGCTGTCTATTGGGGAGCTTCCCCAAGATGATATACATG CTCGCCATTGTTCAAGACATCCTACGTTTTGAATGCCTGCAAGCAAAATTGTCCGTCGAGTTCTGAGG AiATGGTCGCTCACAATTATGACCGTTTCTCCAGGAGTGGATCTTCTTCTGCCTACACTGGCTACATAGA ACGTAGTCCCCGTTCGGCATCTACTTACAGCCTAGACATTCTCTACTCGGGTTCTGGCATTCTAAGGAGA AGTACCTGACATCTTTCAGTACATTGGGAGGCTGGTCTTCACGGTAGCCAGGTGGTTATTGAAGCCC 45 AAGGACTGG2AAGCCTTAATCGCAGCCACCCCTGACGAGGGGGAGGAGAACCTTGACTCCTATGCTGGTAT GTCAGCCATCCTCTTTGATGTTCAGCTCAGACCTGTCACCTTTTTCAACGGATACAGTGATTTGATGTCC AAAATGCTGTCAGCATCTGGCGACCCTATCAGTGTGGTGAAAGGACTTATTCTGCTAATAGATCATTCTC AGGAACTTCAGTTACAATCTGGACTAAAAGCCAATATAGAGGTCCAGGGTGGTCTAGCTATTGATATTTC AGGTGCAATGGAGTTTAGCTTGTGGTATCGTGAGTCTAAAACCCGAGTGAAAAATAGGGTGACTGTGGTA 50 ATACCGCTAATGCCTTTGGAGTCCGAACATCGACGA CAGGCTTGGAGTTTATCTCCACAGTGCAGTTTTCTCAGTACCCATTCTTAGTTTGCATGCAGATGGACA GGATGAAGCTCCATTCAGGCAATTTGAGAAAAAGTACGAAAGGCTGTCCACAGGCAGAGGTTATGTCTCT CAGNAAAGAAAAGAAAGCGTATTAGCAGGATGTGAATTCCCGCTCCATCAAGAGAACTCAGAGATGTGCA AAGTGGTGTTTGCCCCTCAGCCGGATAGTACTTCCAGCGGATGGTTTTGAAACTGACCTGTGATATTTTA 55 CTTGAATTTGTCTCCCCGAAAGGGACACAATGTGGCATGACTAAGTACTTGCTCTCTGAGAGCACAGCGT TTACATATTTACCTGTATTTAAGA-TTTTTGTAAAAAGCTACAA~AAACTGCAGTTTGATCATTTGGGT ATATGCAGTATGCTACCCACAGCGTCATTTTATCATCATGTGACGCTTTCAACACGTTCTTAGTTTA 338 WO 2004/091515 PCT/US2004/011255 CTTATACCTCTCTCAAATCTCATTTGGTACAGTCAGAATAGTTATTCTCTAAGAGGAAACTAGTGTTTGT TAAAAACAAAAATAAAAACAAAACCACACAAGGAGAACCCAATTTTGTTTCAACAATTTTTGATCAATGT ATATGAAGCTCTTGATAGGACTTCCTTAAGCATGACGGGAAAACCAAACACGTTCCCTAATCAGGAAAAA AAAAAAAAAAGAAAAAGTAAGACACAAACAAACCATTTTTTTCTCTTTTTTTGGAGTTGGGGGCCCAGGG 5 AGAAGGGACAAGGCTTTTAAAAGACTTGTTAGCCAACTTCAAGAATTAATATTTATGTCTCTGTTATTGT TAGTTTTAAGCCTTAAGGTAGAAGGCACATAGAAATAACATCTCATCTTTCTGCTGACCATTTTAGTGAG GTTGTTCCAAAGAGCATTCAGGTCTCTACCTCCAGCCCTGCAAAAATATTGGACCTAGCACAGAGGAATC AGGAAAATTAATTTCAGAAACTCCATTTGATTTTTCTTTTGCTGTGTCTTTTTTGAGACTGTAATATGGT ACACTGTCCTCTAAGGACATCCTCATTTTATCTCACCTTTTTGGGGGTGAGAGCTCTAGTTCATTTAACT 10 GTACTCTGCACAATAGCTAGGATGACTAAGAGAACATTGCTTCAAGAAACTGGTGGATTTGGATTTCCAA AATATGAAATAAGGAGAAAAATGTTTTTATTTGTATGAATTAAAAGATCCATGTTGAACATTTGCAAATA TTTATTAATAAACAGATGTGGTGATAAACCCAAAACAAATGACAGGTGCTTATTTTCCACTAAACACAGA CACATGAAATGAAAGTTTAGCTAGCCCACTATTTGTTGTAAATTGAAAACGAAGTGTGATAAAATAAATA TGTAGAAATCAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:6684) 15 >gil213611251reflNM_001467.21 Homo sapiens glucose-6-phosphatase, transport (glucose-6-phosphate) protein 1 (GGPT1), mRNA GGCACGAGGGGCCACCGAGGCGCTGTCCCTGACCACCAGCACGAGACCCCTTTCTATCGCGCCAGTCCTG 20 TGGTCTCCGCACCTCTCCAGCTCCTGCACCCCCGGCCCCCGTGGTTCCCAGCCGCACAGTAGCGTGTCCT GGGTAGCGTGAGGACCCACGGGGCTGAGCAGGTGCCACGAGCCCGCCGCCTCTTCGCCGCCCGCCGCCTC TCCTCCTCTCCCGCCCGCCGCCTGGCCCTCCCCTACCAGGCTGAGCCTCTGGCTGCCAGAAGCGCGGGGC CTCCGGGAGAATACGTGCGGTCGCCCGCTCCGCGTGCGCCTACGCCTTCTGCTCCAGTTGCTTTCCCAAT TGAGCGGAAAAGCCGGGGCATGTTGCCGGGGCCCTGGGCGGGACGGTTGTGCCCTGCAGCCCGAAGCCCG 25 CCGGGGCACCTTCCCGCCCACGAGCTGCCCAGTCCCTCTGCTTGCGGCCCCTGCCAACGTCCCACAGGAC ACTGGGTCCCCTTGGAGCCTCCCCAGGCTTAATGATTGTCCAGAAGGCGGCTATAAAGGGAGCCTGGGAG GCTGGGTGGAGGAGGGAGCAGAAAAAACCCAACTCAGCAGATCTGGGAACTGTGAGAGCGGCAAGCAGGA ACTGTGGTCAGAGGCTGTGCGTCTTGGCTGGTAGGGCCTGCTCTTTTCTACCATGGCAGCCCAGGGCTAT GGCTATTATCGCACTGTGATCTTCTCAGCCATGTTTGGGGGCTACAGCCTGTATTACTTCAATCGCAAGA 30 CCTTCTCCTTTGTCATGCCATCATTGGTGGAAGAGATCCCTTTGGACAAGGATGATTTGGGGTTCATCAC CAGCAGCCAGTCGGCAGCTTATGCTATCAGCAAGTTTGTCAGTGGGGTGCTGTCTGACCAGATGAGTGCT CGCTGGCTCTTCTCTTCTGGGCTGCTCCTGGTTGGCCTGGTCAACATATTCTTTGCCTGGAGCTCCACAG TACCTGTCTTTGCTGCCCTCTGGTTCCTTAATGGCCTGGCCCAGGGGCTGGGCTGGCCCCCATGTGGGAA GGTCCTGCGGAAGTGGTTTGAGCCATCTCAGTTTGGCACTTGGTGGGCCATCCTGTCAACCAGCATGAAC 35 CTGGCTGGAGGGCTGGGCCCTATCCTGGCAACCATCCTTGCCCAGAGCTACAGCTGGCGCAGCACGCTGG CCCTATCTGGGGCACTGTGTGTGGTTGTCTCCTTCCTCTGTCTCCTGCTCATCCACAATGAACCTGCTGA TGTTGGACTCCGCAACCTGGACCCCATGCCCTCTGAGGGCAAGAAGGGCTCCTTGAAGGAGGAGAGCACC CTGCAGGAGCTGCTGCTGTCCCCTTACCTGTGGGTGCTCTCCACTGGTTACCTTGTGGTGTTTGGAGTAA AGACCTGCTGTACTGACTGGGGCCAGTTCTTCCTTATCCAGGAGAAAGGACAGTCAGCCCTTGTAGGTAG 40 CTCCTACATGAGTGCCCTGGAAGTTGGGGGCCTTGTAGGCAGCATCGCAGCTGGCTACCTGTCAGACCGG GCCATGGCAAAGGCGGGACTGTCCAACTACGGGAACCCTCGCCATGGCCTGTTGCTGTTCATGATGGCTG GCATGACAGTGTCCATGTACCTCTTCCGGGTAACAGTGACCAGTGACTCCCCCAAGCTCTGGATCCTGGT ATTGGGAGCTGTATTTGGTTTCTCCTCGTATGGCCCCATTGCCCTGTTTGGAGTCATAGCCAACGAGAGT GCCCCTCCCAACTTGTGTGGCACCTCCCACGCCATTGTGGGACTCATGGCCAATGTGGGCGGCTTTCTGG 45 CTGGGCTGCCCTTCAGCACCATTGCCAAGCACTACAGTTGGAGCACAGCCTTCTGGGTGGCTGAAGTGAT TTGTGCGGCCAGCACGGCTGCCTTCTTCCTCCTACGAAACATCCGCACCAAGATGGGCCGAGTGTCCAAG AAGGCTGAGTGAAGAGAGTCCAGGTTCCGGAGCACCATCCCACGGTGGCCTTCCCCCTGCACGCTCTGCG GGGAGAAAAGGAGGGGCCTGCCTGGCTAGCCCTGAACCTTTCACTTTCCATTTCTGCGCCTTTTCTGTCA CCCGGGTGGCGCTGGAAGTTATCAGTGGCTAGTGAGGTCCCAGCTCCCTGATCCTATGCTCTATTTAAAA 50 GATAACCTTTGGCCTTAGACTCCGTTAGCTCCTATTTCCTGCCTTCAGACAAACAGGAAACTTCTGCAGT CAGGAAGGCTCCTGTACCCTTCTTCTTTTCCTAGGCCCTGTCCTGCCCGCATCCTACCCCATCCCCACCT GAAGTGAGGCTATCCCTGCAGCTGCAGGGCACTAATGACCCTTGACTTCTGCTGGGTCCTAAGTCCTCTC AGCAGTGGGTGACTGCTGTTGCCAATACCTCAGACTCCAGGGAAAGAGAGGAGGCCATCATTCTCACTGT ACCACTAGGCGCAGTTGGATATAGGTGGGAAGAAAAGGTGACTTGTTATAGAAGATTAAAACTAGATTTG 55 ATACTG (SEQ ID NO:6685) 339 WO 2004/091515 PCT/US2004/011255 gil4503130|refINM_001904.11 Homo sapiens catenin (cadherin-associated protein), beta 1, 88kDa (CTNNB1), mRNA AAGCCTCTCGGTCTGTGGCAGCAGCGTTGGCCCGGCCCCGGGAGCGGAGAGCGAGGGGAGGCGGAGACGG 5 AGGAAGGTCTGAGGAGCAGCTTCAGTCCCCGCCGAGCCGCCACCGCAGGTCGAGGACGGTCGGACTCCCG CGGCGGGAGGAGCCTGTTCCCCTGAGGGTATTTGAAGTATACCATACAACTGTTTTGAAAATCCAGCGTG GACAATGGCTACTCAAGCTGATTTGATGGAGTTGGACATGGCCATGGAACCAGACAGAAAAGCGGCTGTT AGTCACTGGCAGCAACAGTCTTACCTGGACTCTGGAATCCATTCTGGTGCCACTACCACAGCTCCTTCTC TGAGTGGTAAAGGCAATCCTGAGGAAGAGGATGTGGATACCTCCCAAGTCCTGTATGAGTGGGAACAGGG 10 ATTTTCTCAGTCCTTCACTCAAGAACAAGTAGCTGATATTGATGGACAGTATGCAATGACTCGAGCTCAG AGGGTACGAGCTGCTATGTTCCCTGAGACATTAGATGAGGGCATGCAGATCCCATCTACACAGTTTGATG CTGCTCATCCCACTAATGTCCAGCGTTTGGCTGAACCATCACAGATGCTGAAACATGCAGTTGTAAACTT GATTAACTATCAAGATGATGCAGAACTTGCCACACGTGCAATCCCTGAACTGACAAAACTGCTAAATGAC GAGGACCAGGTGGTGGTTAATAAGGCTGCAGTTATGGTCCATCAGCTTTCTAAAAAGGAAGCTTCCAGAC 15 ACGCTATCATGCGTTCTCCTCAGATGGTGTCTGCTATTGTACGTACCATGCAGAATACAAATGATGTAGA AACAGCTCGTTGTACCGCTGGGACCTTGCATAACCTTTCCCATCATCGTGAGGGCTTACTGGCCATCTTT AAGTCTGGAGGCATTCCTGCCCTGGTGAAAATGCTTGGTTCACCAGTGGATTCTGTGTTGTTTTATGCCA TTACAACTCTCCACAACCTTTTATTACATCAAGAAGGAGCTAAAATGGCAGTGCGTTTAGCTGGTGGGCT GCAGAAAATGGTTGCCTTGCTCAACAAAACAAATGTTAAATTCTTGGCTATTACGACAGACTGCCTTCAA 20 ATTTTAGCTTATGGCAACCAAGAAAGCAAGCTCATCATACTGGCTAGTGGTGGACCCCAAGCTTTAGTAA ATATAATGAGGACCTATACTTACGAAAAACTACTGTGGACCACAAGCAGAGTGCTGAAGGTGCTATCTGT CTGCTCTAGTAATAAGCCGGCTATTGTAGAAGCTGGTGGAATGCAAGCTTTAGGACTTCACCTGACAGAT CCAAGTCAACGTCTTGTTCAGAACTGTCTTTGGACTCTCAGGAATCTTTCAGATGCTGCAACTAAACAGG AAGGGATGGAAGGTCTCCTTGGGACTCTTGTTCAGCTTCTGGGTTCAGATGATATAAATGTGGTCACCTG 25 TGCAGCTGGAATTCTTTCTAACCTCACTTCAATAATTATAAGAACAAGATGATGGTCTGCCAAGTGGGT GGTATAGAGGCTCTTGTGCGTACTGTCCTTCGGGCTGGTGACAGGGAAGACATCACTGAGCCTGCCATCT GTGCTCTTCGTCATCTGACCAGCCGACACCAAGAAGCAGAGATGGCCCAGAATGCAGTTCGCCTTCACTA TGGACTACCAGTTGTGGTTAAGCTCTTACACCCACCATCCCACTGGCCTCTGATAAAGGCTACTGTTGGA TTGATTCGAAATCTTGCCCTTTGTCCCGCAAATCATGCACCTTTGCGTGAGCAGGGTGCCATTCCACGAC 30 TAGTTCAGTTGCTTGTTCGTGCACATCAGGATACCCAGCGCCGTACGTCCATGGGTGGGACACAGCAGCA ATTTGTGGAGGGGGTCCGCATGGAAGAAATAGTTGAAGGTTGTACCGGAGCCCTTCACATCCTAGCTCGG GATGTTCACAACCGAATTGTTATCAGAGGACTAAATACCATTCCATTGTTTGTGCAGCTGCTTTATTCTC CCATTGAAAACATCCAAAGAGTAGCTGCAGGGGTCCTCTGTGAACTTGCTCAGGACAAGGAAGCTGCAGA AGCTATTGAAGCTGAGGGAGCCACAGCTCCTCTGACAGAGTTACTTCACTCTAGGAATGAAGGTGTGGCG 35 ACATATGCAGCTGCTGTTTTGTTCCGAATGTCTGAGGACAAGCCACAAGATTACAAGAAACGGCTTTCAG TTGAGCTGACCAGCTCTCTCTTCAGAACAGAGCCAATGGCTTGGAATGAGACTGCTGATCTTGGACTTGA TATTGGTGCCCAGGGAGAACCCCTTGGATATCGCCAGGATGATCCTAGCTATCGTTCTTTTCACTCTGGT GGATATGGCCAGGATGCCTTGGGTATGGACCCCATGATGGAACATGAGATGGGTGGCCACCACCCTGGTG CTGACTATCCAGTTGATGGGCTGCCAGATCTGGGGCATGCCCAGGACCTCATGGATGGGCTGCCTCCAGG 40 TGACAGCAATCAGCTGGCCTGGTTTGATACTGACCTGTAAATCATCCTTTAGCTGTATTGTCTGAACTTG CATTGTGATTGGCCTGTAGAGTTGCTGAGAGGGCTCGAGGGGTGGGCTGGTATCTCAGAAAGTGCCTGAC ACACTAACCAAGCTGAGTTTCCTATGGGAACAATTGAAGTAAACTTTTTGTTCTGGTCCTTTTTGGTCGA GGAGTAACAATACAAATGGATTTTGGGAGTGACTCAAGAAGTGAAGAATGCACAAGAATGGATCACAAGA TGGAATTTAGCAAACCCTAGCCTTGCTTGTTAAAATTTTTTTTTTTTTTTTTTTAAGAATATCTGTAATG 45 GTACTGACTTTGCTTGCTTTGAAGTAGCTCTTTTTTTTTTTTTTTTTTTTTTTTTTTGCAGTAACTGTTT TTTAAGTCTCTCGTAGTGTTAAGTTATAGTGAATACTGCTACAGCAATTTCTAATTTTTAAGAATTGAGT AATGGTGTAGAACACTAATTAATTCATAATCACTCTAATTAATTGTAATCTGAATAAAGTGTAACAATTG TGTAGCCTTTTTGTATAAAATAGACAAATAGAAAATGGTCCAATTAGTTTCCTTTTTAATATGCTTAAAA TAAGCAGGTGGATCTATTTCATGTTTTTGATCAAAAACTATTTGGGATATGTATGGGTAGGGTAAATCAG 50 TAAGAGGTGTTATTTGGAACCTTGTTTTGGACAGTTTACCAGTTGCCTTTTATCCCAAAGTTGTTGTAAC CTGCTGTGATACGATGCTTCAAGAGAAAATGCGGTTATAAAAAATGGTTCAGAATTAAACTTTTAATTCA TT (SEQ ID NO:6686) 340 WO 2004/091515 PCT/US2004/011255 giI18104977|refINM_002827.21 Homo sapiens protein tyrosine phosphatase, non receptor type 1 (PTPN1), mRNA GTGATGCGTAGTTCCGGCTGCCGGTTGACATGAAGAAGCAGCAGCGGCTAGGGCGGCGGTAGCTGCAGGG GTCGGGGATTGCAGCGGGCCTCGGGGCTAAGAGCGCGACGCGGCCTAGAGCGGCAGACGGCGCAGTGGGC 5 CGAGAAGGAGGCGCAGCAGCCGCCCTGGCCCGTCATGGAGATGGAAAAGGAGTTCGAGCAGATCGACAAG TCCGGGAGCTGGGCGGCCATTTACCAGGATATCCGACATGAAGCCAGTGACTTCCCATGTAGAGTGGCCA AGCTTCCTAAGAACAAAAACCGAAATAGGTACAGAGACGTCAGTCCCTTTGACCATAGTCGGATTAAACT ACATCAAGAAGATAATGACTATATCAACGCTAGTTTGATAAAAATGGAAGAAGCCCAAAGGAGTTACATT CTTACCCAGGGCCCTTTGCCTAACACATGCGGTCACTTTTGGGAGATGGTGTGGGAGCAGAAAAGCAGGG 10 GTGTCGTCATGCTCAACAGAGTGATGGAGAAAGGTTCGTTAAAATGCGCACAATACTGGCCACAAAAAGA AGAAAAAGAGATGATCTTTGAAGACACAAATTTGAAATTAACATTGATCTCTGAAGATATCAAGTCATAT TATACAGTGCGACAGCTAGAATTGGAAAACCTTACAACCCAAGAAACTCGAGAGATCTTACATTTCCACT ATACCACATGGCCTGACTTTGGAGTCCCTGAATCACCAGCCTCATTCTTGAACTTTCTTTTCAAAGTCCG AGAGTCAGGGTCACTCAGCCCGGAGCACGGGCCCGTTGTGGTGCACTGCAGTGCAGGCATCGGCAGGTCT 15 GGAACCTTCTGTCTGGCTGATACCTGCCTCTTGCTGATGGACAAGAGGAAAGACCCTTCTTCCGTTGATA TCAAGAAAGTGCTGTTAGAAATGAGGAAGTTTCGGATGGGGCTGATCCAGACAGCCGACCAGCTGCGCTT CTCCTACCTGGCTGTGATCGAAGGTGCCAAATTCATCATGGGGGACTCTTCCGTGCAGGATCAGTGGAAG GAGCTTTCCCACGAGGACCTGGAGCCCCCACCCGAGCATATCCCCCCACCTCCCCGGCCACCCAAACGAA TCCTGGAGCCACACAATGGGAAATGCAGGGAGTTCTTCCCAAATCACCAGTGGGTGAAGGAAGAGACCCA 20 GGAGGATAAAGACTGCCCCATCAAGGAAGAAAAAGGAAGCCCCTTAAATGCCGCACCCTACGGCATCGAA AGCATGAGTCAAGACACTGAAGTTAGAAGTCGGGTCGTGGGGGGAAGTCTTCGAGGTGCCCAGGCTGCCT CCCCAGCCAAAGGGGAGCCGTCACTGCCCGAGAAGGACGAGGACCATGCACTGAGTTACTGGAAGCCCTT CCTGGTCAACATGTGCGTGGCTACGGTCCTCACGGCCGGCGCTTACCTCTGCTACAGGTTCCTGTTCAAC AGCAACACATAGCCTGACCCTCCTCCACTCCACCTCCACCCACTGTCCGCCTCTGCCCGCAGAGCCCACG 25 CCCGACTAGCAGGCATGCCGCGGTAGGTAAGGGCCGCCGGACCGCGTAGAGAGCCGGGCCCCGGACGGAC GTTGGTTCTGCACTAAAACCCATCTTCCCCGGATGTGTGTCTCACCCCTCATCCTTTTACTTTTTGCCCC TTCCACTTTGAGTACCAAATCCACAAGCCATTTTTTGAGGAGAGTGAAAGAGAGTACCATGCTGGCGGCG CAGAGGGAAGGGGCCTACACCCGTCTTGGGGCTCGCCCCACCCAGGGCTCCCTCCTGGAGCATCCCAGGC GGGCGGCACGCCAACAGCCCCCCCCTTGAATCTGCAGGGAGCAACTCTCCACTCCATATTTATTTAAACA 30 ATTTTTTCCCCAAAGGCATCCATAGTGCACTAGCATTTTCTTGAACCAATAATGTATTAAAATTTTTTGA TGTCAGCCTTGCATCAAGGGCTTTATCAAAAAGTACAATAATAAATCCTCAGGTAGTACTGGGAATGGAA GGCTTTGCCATGGGCCTGCTGCGTCAGACCAGTACTGGGAAGGAGGACGGTTGTAAGCAGTTGTTATTTA GTGATATTGTGGGTAACGTGAGAAGATAGAACAATGCTATAATATATAATGAACACGTGGGTATTTAATA AGAAACATGATGTGAGATTACTTTGTCCCGCTTATTCTCCTCCCTGTTATCTGCTAGATCTAGTTCTCAA 35 TCACTGCTCCCCCGTGTGTATTAGAATGCATGTAAGGTCTTCTTGTGTCCTGATGAAAAATATGTGCTTG AAATGAGAAACTTTGATCTCTGCTTACTAATGTGCCCCATGTCCAAGTCCAACCTGCCTGTGCATGACCT GATCATTACATGGCTGTGGTTCCTAAGCCTGTTGCTGAAGTCATTGTCGCTCAGCAATAGGGTGCAGTTT TCCAGGAATAGGCATTTGCCTAATTCCTGGCATGACACTCTAGTGACTTCCTGGTGAGGCCCAGCCTGTC CTGGTACAGCAGGGTCTTGCTGTAACTCAGACATTCCAAGGGTATGGGAAGCCATATTCACACCTCACGC 40 TCTGGACATGATTTAGGGAAGCAGGGACACCCCCCGCCCCCCACCTTTGGGATCAGCCTCCGCCATTCCA AGTCAACACTCTTCTTGAGCAGACCGTGATTTGGAAGAGAGGCACCTGCTGGAAACCACACTTCTTGAAA CAGCCTGGGTGACGGTCCTTTAGGCAGCCTGCCGCCGTCTCTGTCCCGGTTCACCTTGCCGAGAGAGGCG CGTCTGCCCCACCCTCAAACCCTGTGGGGCCTGATGGTGCTCACGACTCTTCCTGCAAAGGGAACTGAAG ACCTCCACATTAAGTGGCTTTTTAACATGAAAAACACGGCAGCTGTAGCTCCCGAGCTACTCTCTTGCCA 45 GCATTTTCACATTTTGCCTTTCTCGTGGTAGAAGCCAGTACAGAGAAATTCTGTGGTGGGAACATTCGAG GTGTCACCCTGCAGAGCTATGGTGAGGTGTGGATAAGGCTTAGGTGCCAGGCTGTAAGCATTCTGAGCTG GGCTTGTTGTTTTTAAGTCCTGTATATGTATGTAGTAGTTTGGGTGTGTATATATAGTAGCATTTCAAAA TGGACGTACTGGTTTAACCTCCTATCCTTGGAGAGCAGCTGGCTCTCCACCTTGTTACACATTATGTTAG AGAGGTAGCGAGCTGCTCTGCTATATGCCTTAAGCCAATATTTACTCATCAGGTCATTATTTTTTACAAT 50 GGCCATGGAATAAACCATTTTTACAAAA (SEQ ID NO:6687) gil12831192|gblAF333324.11 Hepatitis C virus type lb polyprotein mRNA, complete cds 55 GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCA GAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCA 341 WO 2004/091515 PCT/US2004101 1255 TAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCG CTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCC TTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCATCATGAGCACA AATCCTAAACCTCAZAAGAAAAACCAAACGTAACACCAACCGCCGCCCACAGGACGTTAAGTTCCCGGGCG 5 GTGGTCAGATCGTTGGTGGAGTTTACCTGTTGCCGCGCAGGGGCCCCAGGTTGGGTGTGCGCGCGACTAG GAAGACTTCCGAGCGGTCGCAACCTCGTGGAAGGCGACAACCTATCCCCAAGGCTCGCCGGCCCGAGGGT AGGACCTGGGCTCAGCCCGGGTACCCTTGGCCCCTCTATGGCAACGAGGGTATGGGGTGGGCAGGATGGC TCCTGTCACCCCGTGGCTCTCGGCCTAGTTGGGGCCCCACAGACCCCC3GCGTAGGTCGCGTAATTTGGG TAAGGTCATCGATACCCTTACATGCGGCTTCGCCGACCTCATGGGGTACATTCCGCTTGTCGGCGCCCCC 10 CTAGGAGGCGCTGCCAGGGCCCTGGCGCATGGCGTCCGGGTTCTGGAGGACGGCGTGAACTATGCACAG GGAATCTGCCCGGTTGCTCTTTCTCTATCTTCCTCTTAGCTTTGCTGTCTTGTTTGACCATCCCAGCTTC CGCTTACGAGGTGCGCAACGTGTCCGGGATATACCATGTCACGAACGACTGCTCCAACTCAAGTATTGTG TATGAGGCAGCGGACATGATCATGCACACCCCCGGGTGCGTGCCCTGCGTCCGGGAGAGTAATTTCTCCC GTTGCTGGGTAGCGCTCACTCCCACGCTCGCGGCCAGGAACAGCAGCATCCCCACCACGACAATACGACG 15 CCACGTCGATTTGCTCGTTGGGGCGGCTGCTCTCTGTTCCGCTATGTACGTTGGGGATCTCTGCGGATCC GTTTTTCTCGTCTCCCAGCTGTTCACCTTCTCACCTCGCCGGTATGAGACGGTACAAGATTGCAAgFTGCT CAATCTATCCCGGCCACGTATCACGTCACCGCATGGCTTGGGATATGATGATGAACTGGTCACCTACpjAC GGCCCTAGTGGTATCGCAGCTACTCCGGATCCCACAAGCCGTCGTGGACATGGTGGCGGGGGCCCACTGG GGTGTCCTAGCGGGCCTTGCCTACTATTCCATGGTGGGGAA-CTGGGCTAAGGTCTTGATTGTGATGCTAC 20 TCTTTGCTGGCGTTGACGGGCACACCCACGTGACAGGGGGAAGGGTAGCCTCCAGCACCCAGAGCCTCGT GTCCTGGCTCTCACAAGGGCCATCTCAGAATCCAACTCGTGAACACCAACGGCAGCTGGCACATCAAC AGGACCGCTCTGAATTGCAATGACTCCCTCCAAACTGGGTTCATTGCTGCGCTGTTCTACGCACACAGGT TCAALCGCGTCCGGATGTCCAGAGCGCATGGCCAGCTGCCGCCCCATCGACAAGTTCGCTCAGGcGGTGG TCCCATCACTCACGTTGTGCCTAACATCTCGGACCAGAGGCCTTATTGCTGGCACTATGCACCCCAACCG 25 TGCGGT1ATTGTACCCGCGTCGCAGGTGTGTGGCCCAGTGTATTGCTTCACCCCGAGTCCTGTTGTGGTGG GGACGACCGACCGTTCCGGAGTCCCCACGTATAGCTGGGGGGAGAATGAGACAGACGTGCTGCTACTCAA CAACACGCGGCCGCCGCAAGGCAACTGGTTCGGCTGTACATGGATGAALTAGCACCGGGTTCACCAAGACG TGCGGGGGCCCCCCGTGTAACATCGGGGGGGTTGGCAACAACACCTTGATTTGCCCCACGGATTGCTTCC GAAAGCACCCCGAGGCCACTTACACCAAATGCGGCTCGGGTCCTTGGTTGACACCTAGGTGTCTAGTTGA 30 CTACCCATACAGACTTTGGCACTACCCCTGCACTATCAATTTTACCATCTTCAAGGTCAGGATGTACGTG GGGGGCGTGGAGCACAGGCTCAACGCCGCGTGCAATTGGACCCGAGGAGAGCGCTGTGACCTGGAGGACA GGGATAGATCAGAGCTTAGCCCGCTGCTATTGTCTACAACGGAGTGGCAGGTACTGCCCTGTTCCTTTAC CACCCTACCGGCTCTGTCCACTGGATTGATCCACCTCCATCAGA\TATCGTGGACGTGCAATACCTGTAC GGTGTAGGGTCAGTGGTTGTCTCCGTCGTAATCAA.ATGGGAGTATGTTCTGCTGCTCTTCCTTCTCCTGG 35 CGGACGCGCGCGTCTGTGCCTGCTTGTGGATGATGCTGCTGATAGCCCAGGCTGAGGCCACCTTAGAGAA CCTGGTGGTCCTCAATGCGGCGTCTGTGGCCGGAGCGCATGGCCTTCTCTCCTTCCTCGTGTTCTTCTGC GCCGCCTGGTACATCAAAGGCAGGCTGGTCCCTGGGGCGGCATATGCTCTCTATGGCGTATGGCCGTTGC TCCTGCTCTTGCTGGCTTTACCACCACGAGCTTATGCCATGGACCGAGAGATGGCTGCATCGTGCGGAGG CGCGGTTTTTGTAGGTCTGGTACTCTTGACCTTGTCACCATACTATAAGGTGTTCCTCGCTAGGCTCATA 40 TGGTGGTTACAATATTTTATCACCAGGGCCGAGGCGCACTTGCAAGTGTGGGTCCCCCCTCTTAATGTTC

GGGGAGGCCGCGATGCCATCATCCTCCTTACATGCGCGGTCCATCCAGAGCTAATCTTTGACATCACCA

ACTCCTGCTCGCCATACTCGGTCCGCTCATGGTGCTCCAAGCTGGCATAACCAGAGTGCCGTACTTCGTG CGCGCTCAAGGGCTCATTCATGCATGCATGTTAGTGCGGAAGGTCGCTGGGGGTCATTATGTCCAAATGG CCTTCATGAAGCTGGGCGCGCTGACAGGCACGTACATTTACAACCATCTTACCCCGCTACGGGATTGGGC 45 CCACGCGGGCCTACGAGACCTTGCGGTGGCAGTGGAGCCCGTCGTCTTCTCCGACATGGAGACCAAGATC ATCACCTGGGGAGCAGACACCGCGGCGTGTGGGGACATCATCTTGGGTCTGCCCGTCTCCGCCCGAGGG GAAAGGAGATACTCCTGGGCCCGGCCGATAGTCTTGAAGGGCGGGGGTGGCGACTCCTCGCGCCCATCAC GGCCTACTCCCAACAGACGCGGGGCCTACTTGGTTGCATCATCACTAGCCTTACAGGCCGGGACAGAAC CAGGTCGAGGGAGAGGTTCAGGTGGTTTCCACCGCAACACAIATCCTTCCTGGCGACCTGCGTCAACGGCG 50 TGTGTTGGACCGTTTACCATGGTGCTGGCTCAAAGACCTTAGCCGGCCCAAAGGGGCCAATCACCCAGAT GTACACTAATGTGGACCAGGACCTCGTCGGCTGGCAGGCGCCCCCCGGGGCGCGTTCCTTGACACCATGC ACCTGTGGCAGCTCAGACCTTTACTTGGTCACGAGACATGCTGACGTCATTCCGGTGCGCCGGCGGGGCG ACAGTAGGGGGAGCCTGCTCTCCCCCAGGCCTGTCTCCTACTTGAAGGGCTCTTCGGGTGGTCCACTGCT CTcGCCCTTCGGGGCACGCTGTGGGCATCTTCCGGGCTGCCGTATGCACCCGGGGGGTTGCGAAGGCGGTG 55 GACTTTGTGCCCGTAGAGTCCATGGAAACTACTATGCGGTCTCCGGTCTTCACGGACAACTCATCCCCCC CGGCCGTACCGCAGTCATTTCAAGTGGCCCACCTACACGCTCCCACTGGCAGCGGCAAGAGTACTAAAGT GCCGGCTGCATATGCAGCCCAAGGGTACAAGGTGCTCGTCCTCAATCCGTCCGTTGCCGCTACCTTAGGG TTTGGGGCGTATATGTCTAAGGCACACGGTATTGACCCCAACATCAG1AACTGGGGTAAGGACCATTACCA 342 WO 2004/091515 PCT/US2004101 1255 CAGGCGCCCCCGTCACATACTCTACCTATGGCAAGTTTCTTGCCGATGGTGGTTGCTCTGGGGGCGCTTA TGACJTCATAATATGTGATGAGTGCCATTCAACTGACTCGACTACAATCTTGGGCATCGGCACAGTCCTG GACCAAGCGGAGACGGCTGGAGCGCGGCTTGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCG TGCCACACCCAAACATCGAGGAGGTGGCCCTGTCTAATACTGGAGAGATCCCCTTCTATGGCAAGCCAT 5 CCCCATTGAAGCCATCAGGGGGGGAAGGCATCTCATTTTCTGTCATTCCAAGAAGAAGTGCGACGAGCTC GCCGCAAAGCTGTCAGGCCTCGGAATCAACGCTGTGGCGTATTACCGGGGGCTCGATGTGTCCGTCATAC CAACTATCGGAGACGTCGTTGTCGTGGCAACAGACGCTCTGATGACGGGCTATACGGGCGACTTTGACTC AGTGATCGACTGTAACACATGTGTCACCCAGACAGTCGACTTCAGCTTGGATCCCACCTTCACCATTGAG ACGACGACCGTGCCTCAAGCACGCAGTGTCGCGCTCGCAGCGGCGGGGTAGGACTGGCAGGGGTAGGAGAG 10 GCATCTACAGGTTTGTGACTCCGGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTCCTGTGTGAGTG CTATGACGCGGGCTGTGCTTGGTACGAGCTCACCCCCGCCGAGACCTCGGTTAGGTTGCGGGCCTACCTG AACACACCAGGGTTGCCCGTTTGCCAGGACCACCTGGAGTTCTGGGAGAGTGTCTTCACAGGCCTCACCC ACATAGATGCACACTTCTTGTCCCAGACCAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCA AGCCACGGTGTGCGCCAGGGCTCAGGCCCCACCTCCATCAtGGGATCAAA-TGTGGAAGTGTCTCATACGG 15 CTGAAACCTACGCTGCACGGGCCAACACCCTTGCTGTACAGGCTGGGAGCCGTCCAAATGAGGTCACCC TCACCCACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACTAGCACCTG GGTGCTGGTGGGCGGAGTCCTTGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGTGTGGTCATTGTG GGTAGGATTATC!TTGTCCGGGAGGCCGGCTATTGTTCCCGACAGGGAGCTTCTCTACCAGGAGTTCGATG AAATGGAAGAGTGCGCCACGCACCTCCCTTACATTGAGCAGGGAATGCAGCTCGCCGAGCAGTTCAAGCA 20 GAAAGCGCTCGGGTTACTGCAAACAGCCACCAAACAAGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAAG TGGCGAGCCCTTGAGACATTCTGGGCGAAGCACATGTGGAATTTCATCAGCGGGATACAGTACTTAGCAG GCTTATCCACTCTGCCTGGGAACCCCGCAATAGCATCATTGATGGCATTCACAGCCTCTATCACCAGCCC GCTCACCACCCAAAGTACCCTCCTGTTTAACATCTTGGGGGGGTGGGTGGCTGCCCAACTCGCCCCCCCC AGCGCCGCTTCGGCTTTCGTGGGCGCCGGCATCGCCGGTGCGGCTGTTGGCAGCATAGGCCTTGGojAGG 25 TGCTTGTGGACATTCTGGCGGGTTATGGAGCAGGAGTGGCCGGCGCGCTCGTGGCCTTTAAGGTCATGAG CGGCGAGATGCCCTCTACCGAGGACCTGGTCAATCTACTTCCTGCCATCCTCTCTCCTGGCGCCCTGGTC GTCGGGGTCGTGTGTGCAGCAATACTGCGTCGGCACGTGGGTCCGGGAGAGGGGGCTGTGCAGTGGATGA ACCGGCTGATAGCGTTCGCCTCGCGGGGTAATCACGTTTCCCCCACGCACTATGTGCCTGAGAGCGACGC CGCAGCGCGTGTTACTCAGATCCTCTCCAGCCTTACCATCACTCAGCTGCTGAAAAGGCTCCACCAGTGG 30 ATTAATGAGGACTGCTCCACACCGTGTTCCGGCTCGTGGCTAAGGGATGTTTGGGACTGGATATGCACGG TGTTGACTGACTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCAGCTACCGGGAGTCCCTTTTTTCTC GTGCCAACGCGGGTACAAGGGAGTCTGGCGGGGAGACGGCATCATGCAAACCACCTGCCCATGTGGAGCA CAGATCACCGGACATGTCAAAJXACGGTTCCATGAGGATCGTCGGGCCTAAGACCTGCAGCAACACGTGGC ATGGAACATTCCCCATCAACGCATACACCACGGGCCCCTGCACACCCTCTCCAGCGCCAAACTATTCTAG 35 GGCGCTGTGGCGGGTGGCCGCTGAGGAGTACGTGGAGGTCACGCGGGTGGGGGATTTCCACTACGTGACG GGCATGACCACTGACAACGTAAAGTGCCCATGCCAGGTTCCGGCTCCTGAATTCTTCTCGGAGGTGGACG GAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAGGCCTCTCCTACGGGAGGAGGTTACATTCCAGGTCGG GCTCAACCAATACCTGGTTGGGTCACAGCTACCATGCGAGCCCGAACCGGATGTAGCAGTGCTCACTTCC ATGCTCACCGACCCCTCCCACATCACAGCAGAAACGGCTAAGCGTAGGTTGGCCAGGGGGTCTCCCCCCT 40 CCTTGGCCAGCTCTTCAGCTAGCCAGTTGTCTGCGCCTTCCTTGAAGGCGACATGCACTACCCACCATGT CTCTCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGACATCACCCGC GTGGAGTCGGAGAACAAGGTGGTAGTCCTGGACTCTTTCGACCCGCTTCGAGCGGAGGAGGATGAGAGGG AAGTATCCGTTCCGGCGGAGATCCTGCGGAAATCCAAGAAGTTCCCCGCAGCGATGCCCATCTGGGCGCG CCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTGCACGGG 45 TGCCCGTTGCCACCTATCAAGGCCCCTCCAATACCACCTCCACGGAGAAGAGGACGGTTGTCCTAACAG AGTCCTCCGTGTCTTCTGCCTTAGCGGAGCTCGCTACTAAGACCTTCGGCAGCTCCG\ATCATCGGCCGT CGACAGCGGCACGGCGACCGCCCTTCCTGACCAGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAG TCGTACTCCTCCATGCCCCCCCTTGAGGGGGAACCGGGGGACCCCGATCTCAGTGACGGGTCTTGGTCTA CCGTGAGCGAGGAAGCTAGTGAGGATGTCGTCTGCTGCTCAATGTCCTACACATGGACAGGCGCCTTGAT 50 CACGCCATGCGCTGCGGAGGAAAGCAAGCTGCCCATCAACGCGTTGAGC ACTCTTTGCTGCGCCACCAT AACATGGTTTATGCCACAACATCTCGCAGCGCAGGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTGC AATCGAGCATCGGCTCCAGAAGAGGAGGCAATAGCA ACTCCTATCCGTAGAGGAAGCCTGCAAGCTGACGCCCCCACATTCGGCCA3AATCCAAGTTTGGCTATGGG GCAAAGGACGTCCGGAACCTATCCAGCAAGGCCGTTAACCACATCCACTCCGTGTGGAAGGACTTGCTGG 55 AAAATTAACATAACCACTGCAAAGGTTCGGCACAAA AGGAGGCCGTAAGCCAGCCCGCCTTATCGTATTCCCAGATCTGGGAGTCCGTGTATGCGAGAAGATGGCC CTCTATGATGTGGTCTCCACCCTTCCTCAGGTCGTGATGGGCTCCTCATACGGATTCCAGTACTCTCCTG GGCAGCGAGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAAAACCCCATGGGCTTTTCATATGACAC 343 WO 2004/091515 PCT/US2004/011255 TCGCTGTTTCGACTCAACGGTCACCGAGAACGACATCCGTGTTGAGGAGTCAATTTACCAATGTTGTGAC TTGGCCCCCGAAGCCAGACAGGCCATAAAATCGCTCACAGAGCGGCTTTATATCGGGGGTCCTCTGACTA ATTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCGAGCGGCGTGCTGACGACTAGCTGCGGTAA CACCCTCACATGTTACTTGAAGGCCTCTGCAGCCTGTCGAGCTGCGAAGCTCCAGGACTGCACGATGCTC 5 GTGAACGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGAACCCAAGAGGACGCGGCGAGCCTACGAG TCTTCACGGAGGCTATGACTAGGTACTCTGCCCCCCCCGGGGACCCGCCCCAACCAGAATACGACTTGGA GCTGATAACATCATGTTCCTCCAATGTGTCGGTCGCCCACGATGCATCAGGCAAAAGGGTGTACTACCTC ACCCGTGATCCCACCACCCCCCTCGCACGGGCTGCGTGGGAAACAGCTAGACACACTCCAGTTAACTCCT GGCTAGGCAACATTATCATGTATGCGCCCACTTTGTGGGCAAGGATGATTCTGATGACTCACTTCTTCTC 10 CATCCTTCTAGCACAGGAGCAACTTGAAAAAGCCCTGGACTGCCAGATCTACGGGGCCTGTTACTCCATT GAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACT CTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAGTCTGGAG ACATCGGGCCAGGAGCGTCCGCGCTAGGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAAGTAC CTCTTCAACTGGGCAGTGAAGACCAAACTCAAACTCACTCCAATCCCGGCTGCGTCCCAGCTGGACTTGT 15 CCGGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTG GTTCATGCTGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATCTACCTGCTCCCCAACCGATGAACGGGG AGCTAAACACTCCAGGCCAATAGGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCT TTTCCTTCTTTTTCCCTTTTTCTTTCTTCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTA GCTGTGAAAGGTCCGTGAGCCGCATGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGATCATGT 20 (SEQ ID NO:6688) gi 3062861gbIM96362.1|HPCUNKCDS Hepatitis C virus mRNA, complete cds TGCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGC AGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCC 25 ATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCC GCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGC CTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCAC GAATCCTAAACCTCAAAGAAAAACCAAACGTAACACCAACCGCCGCCCACAGGATATTAAGTTCCCGGGC GGTGGTCAGATCGTTGGTGGAGTTTACTTGTTGCCGCGCAGGGGCCCCAGGTTGGGTGTGCGCGCGACTA 30 GGAAGACTTCCGAGCGGTCGCAACCTCGTGGAAGGCGACAGCCTATCCCCAAGGCTCGCCGGCCCGAGGG CAGGGCCTGGGCTCAGCCCGGGTACCCTTGGCCCCTCTATGGCAATGAGGGCTTGGGGTGGGCAGGATGG CTCCTGTCACCCCGCGGCTCCCGGCCTAGTTGGGGCCCCACGGACCCCCGGCGTAAGTCGCGTAATTTGG GTAAGGTCATCGACACCCTCACATGCGGCTTCGCCGACCTCATGGGGTACATTCCGCTCGTCGGCGCCCC CCTAGGGGGCGTTGCCAGGGCCCTGGCACATGGTGTCCGGGTGCTGGAGGACGGCGTGAACTATGCAACA 35 GGGAATCTGCCCGGTTGCTCTTTCTCTATCTTCCTCTTGGCTCTGCTGTCTTGTTTGACCACCCCAGTTT CCGCTTATGAAGTGCGTAACGCGTCCGGGATGTACCATGTCACGAACGACTGCTCCAACTCAAGCATTGT GTATGAGGCAGCGGACATGATCATGCACACTCCCGGGTGCGTGCCCTGCGTTCGGGAGGACAACTCCTCC CGTTGCTGGGTGGCACTTACTCCCACGCTCGCGGCCAGGAATGCCAGCGTCCCCACTACGACATTGCGAC GCCATGTCGACTTGCTCGTTGGGGTAGCTGCTTTCTGTTCCGCTATGTACGTGGGGGACCTCTGCGGATC 40 TGTTTTCCTTGTTTCCCAGCTGTTCACCTTTTCGCCTCGCCGGCATGAGACGGTACAGGACTGCAACTGC TCAATCTATCCCGGCCGCGTATCAGGTCACCGCATGGCCTGGGATATGATGATGAACTGGTCGCCTACAA CAGCCCTAGTGGTATCGCAGCTACTCCGGATCCCACAAGCTGTCGTGGACATGGTGACAGGGTCCCACTG GGGAATCCTGGCGGGCCTTGCCTACTATTCCATGGTGGGGAACTGGGCTAAGGTCTTAATTGCGATGCTA CTCTTTGCCGGCGTTGACGGAACCACCCACGTGACAGGGGGGGCGCAAGGTCGGGCCGCTAGCTCGCTAA 45 CGTCCCTCTTTAGCCCTGGGCCGGTTCAGCACCTCCAGCTCATAAACACCAACGGCAGCTGGCATATCAA CAGGACCGCCCTGAGCTGCAATGACTCCCTCAACACTGGGTTTGTTGCCGCGCTGTTCTACAAATACAGG TTCAACGCGTCCGGGTGCCCGGAGCGCTTGGCCACGTGCCGCCCCATTGATACATTCGCGCAGGGGTGGG GTCCCATCACTTACACTGAGCCTCATGATTTGGATCAGAGGCCCTATTGCTGGCACTACGCGCCTCAACC GTGTGGTATTGTGCCCACGTTGCAGGTGTGTGGCCCAGTATACTGCTTCACCCCGAGTCCTGTTGCGGTG 50 GGGACTACCGATCGTTTCGGTGCCCCTACATACAGATGGGGGGCAAATGAGACGGACGTGCTGCTCCTTA ACAACGCCGGGCCGCCGCAAGGCAACTGGTTCGGCTGTACATGGATGAATGGCACTGGGTTCACCAAGAC ATGTGGGGGCCCCCCGTGTAACATCGGGGGGGTCGGCAACAATACCTTGACCTGCCCCACGGACTGCTTC CGAAAGCACCCCGGGGCCACTTACACCAAATGCGGTTCGGGGCCTTGGTTAACACCCAGGTGCTTAGTCG ACTACCCGTACAGGCTCTGGCATTACCCCTGCACTGTCAACTTTACCATCTTTAAGGTTAGGATGTACGT 55 GGGGGGCGCGGAGCACAGGCTCGACGCCGCATGCAACTGGACTCGGGGAGAGCGTTGTGACCTGGAGGAC AGGGATAGGTCAGAGCTTAGCCCGCTGCTGCTGTCTACAACAGAGTGGCAGGTACTGCCCTGTTCCTTCA CAACCCTACCGGCTCTGTCCACTGGTTTGATTCATCTCCATCAGAACATCGTGGACATACAATACCTGTA 344 WO 2004/091515 PCT/US2004/011255 CGGTATAGGGTCGGCGGTTGTCTCCTTTGCGATCAAATGGGAGTATATTGTGCTGCTCTTCCTTCTTCTG GCGGACGCGCGCGTCTGCGCTTGCTTGTGGATGATGCTGCTGGTAGCGCAAGCCGAGGCCGCCTTAGAGA ACCT'GGTGGTCCTCAATGCAGCGTCCGTGGCCGGAGCGCATGGCATTCTTTCCTTCATTGTGTTCTTCTG TGCTGCCTGGTACATCAAGGGCAGGCTGGTTCCCGGAGCGGCATACGCCCTCTATGGCGTATGGCCGCTG 5 CTTCTGCTTCTGCTGGCGTTACCACCACGGGCGTACGCCATGGACCGGGAGATGGCCGCATCGTGCGGAG GCGCGGTTTTTGTAGGTCTGGTACTCTTGACCTTGTCACCACACTATAAAGTGTTCCTTGCCAGGTTCAT ATGGTGGCTACAATATCTCATCAC2CAGAACCGAAGCGCATCTGCAAGTGTGGGTCCCCCCTCTCAACGTT CGGGGGGGTCGCGATGCCATCATCCTCCTCACATGCGTGGTCCACCCAGAGCTAATCTTTGACATCACAA AATATTTGCTCGCCATATTCGGCCCGCTCATGGTGCTCCAGGCCGGCATAACTAGAGTGCCGTACTTCGT 10 GCGCGCACAAGGGCTCATTCGTGCATGCATGTTGGCGCGGAAAGTCGTGGGGGGTCATTACGTCCAAATG GTCTTCATGAAGCTGGCCGCACTAGCAGGTACGTACGTTTATGACCATCTTACTCCACTGCGAGATTGGG CTCACACGGGCTTACGAGACCTTGCAGTGGCAGTAGAGCCCGTTGTCTTCTCTGACATGGAGACCAAAGT CATCACCTGGGGGGCAGACACCGCGGCGTGCGGGGACATCATCTTGGCCCTGCCTGCTTCCGCCCGAAGG GGGAAGGAGATACTTCTGGGACCGGCCGATAGTCTTGAAGGACAGGGGTGGCGACTCCTTGCGCCCATCA 15 CGGCCTACTCCCAACAAACGCGAGGCCTGCTTGGTTGCATCATCACTAGCCTTACAGGCCGGGACAAGAA CCAGGTTGAGGGGGAGGTTCAAGTGGTTTCCACCGCAACACAATCTTTCCTGGCGACCTGCATCAATGGC GTGTGTTGGACTGTCTTCCACGGCGCCGGCTCAAAGACCCTAGCCGGCCCAAAGGGTCCAATCACCCAAA TGTACACCAATGTAGACCAGGACCTTGTTGGCTGGCCGGCACCTCCTGGGGCGCGTTCCCTGACACCATG CACTTGCGGCTCCTCGGACCTTTACCTGGTCACGAGACATGCTGATGTCATTCCGGTGCGCCGGCGGGGT 20 GACGGTAGGGGGAGCCTACTCCCCCCCAGGCCTGTCTCCTACTTGAAGGGCTCCTCGGGTGGTCCACTGC TCTGCCCTTCGGGGCACGCTGTCGGCATACTTCCGGCTGCTGTATGCACCCGGGGGGTTGCCATGGCGGT GGAATTCATACCCGTTGAGTCTATGGA-AACTACTATGCGGTCTCCGGTCTTCACGGACAATCCGTCTCCC CCGGCTGTACCGCAGACATTCCAAGTGGCCCACTTACACGCTCCCACCGGCAGCGGCAAGAGCACTAGGG TGCCGGCTGCATATGCAGCCCAAGGGTACAAGGTGCTCGTCCTAAATCCGTCCGTCGCCGCCACCTTGGG 25 TTTTGGGGCGTATATGTCCAAGGCACATGGTATCGACCCCAACCTTAGAACTGGGGTAAGGACCATCACC ACAGGTGCCCCTATCACATACTCCACCTATGGCAAGTTCCTTGCCGACGGTGGCGGCTCCGGGGGCGCCT ATGACATCATAATGTGTGATGAGTGCCACTCAACTGACTCGACTACCATTTATGGCATCGGCACAGTCCT GGACCAAGCGGAGACGGCTGGAGCGCGGCTCGTGGTGCTCTCCACCGCTACGCCTCCGGGATCGGTCACC GTGCCACACCTCAATATCGAGGAGGTGGCCCTGTCTAATACTGGAGAGATCCCCTTCTACGGCAAAGCCA 30 TTCCCATCGAGGCTATCAAGGGGGGAAGGCATCTCATTTTCTGCCATTCCAAGAAGAAGTGTGACGAACT CGCCGCAA2AGCTGTCAGGCCTCGGACTCAATGCCGTAGCGTATTACCGGGGTCTTGACGTGTCCGTCATA CCGACCAGCGGAGACGTTGTTGTCGTGGCGACGGACGCTCTAATGACGGGCTTTACCGGCGACTTTGACT CAGTGATCGACTGTAATACGTGTGTCACCCAGACAGTCGATTTCAGCTTGGACCCCACCTTCACCATTGA GACGACGACCGTGCCCCAAGACGCAGTGTCGCGCTCGCAGAGGCGAGGCAGGACTGGTAGGGCAGGGCT 35 GGCATATACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGA-TTCTTCGGTCCTGTGTGAGT GTTATGACGCGGGTTGTGCGTGGTACGAACTCACGCCCGCTGAGACCTCGGTTAGGTTGCGGGCGTACCT AAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTCGGAGGGTGTCTTCACAGGCCTCACC CACATAGATGCCCACTTCTTATCCCAGACTAAACAGGCAGGAGAGAACTTCCCCTACTTGGTAGCATACC AGGCTACAGTGTGCGCCAGGGCTCAAGCCCCACCTCCATCGTGGGATGAAATGTGGAGGTGTCTCATACG 40 GCTGAAACCTACGCTGCACGGGCCAACACCCCTGCTGTATAGGTTAGGAGCCGTCCAAAATGAGGTCACC CTCACACACCCCATAACCAAATTCATCATGACATGTATGTCGGCTGACCTGGAGGTCGTCACCAGCACCT GGGTGCTGGTAGGCGGAGTCCTCGCAGCTCTGGCCGCGTACTGCCTGACAACAGGCAGCGTGGTCATTGT GGGCAGGATCATCCTGTCCGGGAAGCCGGCTATCATCCCCGATAGGGAAGTTCTCTACCAGGAGTTCGAC GAGATGGAGGAGTGTGCCTCACACCTCCCTTACTTCGAACAGGGAATGCAGCTCGCCGAGCAATTCAAAC 45 AGAAGGCGCTCGGGTTGCTGCAAACAGCCACCAAGCAGGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAA GTGGCGAGCCCTTGAGACCTTCTGGGCGAAGCACATGTGGAACTTCATTAGTGGGATACAGTACTTGGCA GGCTTGTCCACTCTGCCTGCGAACCCCGCAATACGATCACCGATGGCATTCACAGCCTCCATCACCAGCC CGCTCACCACCCAGCATACCCTCTTGTTTAACATCTTGGGGGGATGGGTGGCTGCCCAACTCGCCCCCCC CAGCGCTGCCTCAGCTTTCGTGGGCGCCGGCATCGCTGGAGCCGCTGTTGGCACGATAGGCCTTGGGAAG 50 GTGCTTGTGGACATTCTGGCAGGTTATGGAGCAGGGGTGGCGGGCGCACTTGTGGCCTTTAAGATCATGA GCGGCGAGATGCCTTCAGCCGAGGACATGGTCPAACTTACTCCCTGCCATCCTTTCTCCCGGTGCCCTGGT CGTCGGGATTGTGTGTGCAGCAATACTGCGTCGGCATGTGGGCCCAGGGGAAGGGGCTGTGCAGTGGATG AACCGGCTGATAGCGTTCGCCTCGCGGGGTAACCACGTCTCCCCCAGGCACTATGTGCCAGAGAGCGAGC CTGCAGCGCGTGTTACCCAGATCCTTTCCAGCCTCACCATCACTCAGCTGTTGAAGAGACTCCACCAGTG 55 GATTAATGAGGACTGCTCTACGCCATGCTCCAGCTCGTGGCTAAGGGAGATTTGGGACTGGATCTGCACG GTGTTGACTGACTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTACCGGGAGTCCCTTTTTTCT CATGCCAACGCGGGTATAAGGGAGTCTGGCGGGGGGACGGCATCATGCACACCACCTGCCCATGCGGAGC ACAGATCACCGGACACGTCAA7AACGGTTCCATGAGGATCGTTGGGCCTAA2AACCTGCAGCAACACGTGG 345 WO 2004/091515 PCT/US2004/011255 TACGGGACATTCCCCATCAACGCGTACACCACGGGCCCCTGCACACCCTCCCCGGCGCCAAACTATTCCA AGGCATTGTGGAGAGTGGCCGCTGAGGAGTACGTGGAGGTCACGCGGGTGGGAGATTTTCACTACGTGAC GGGCATGACCACTGACAACGTGAAGTGTCCATGCCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGAT GGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAGACCTCTCCTACGGGAGGAGGTCGTATTCCAGGTCG 5 GGCTCCACCAGTACCTGGTCGGGTCACAGCTCCCATGCGAGCCCGAACCGGATGTAGCAGTGCTCACTTC CATGCTCACTGACCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCCAGGGGGTCTCCCCCC TCCTTGGCCAGCTCTTCAGCTAGCCAGTTGTCTGCGCCTTCCTTGAAGGCGACATGCACTACCCATCATG ACTCCCCGGACGCTGACCTCATTGAGGCCAACCTCTTGTGGCGGCAAGAGATGGGCGGGAACATCACCCG CGTGGAGTCAGAGAATAAGGTGGTAATCCTGGACTCTTTCGACCCGCTCCGAGCGGAGGATGATGAGGGG 10 GAAATATCCGTTCCGGCGGAGATCCTGCGGAAATCCAGGAAATTCCCCCCAGCGCTGCCCATATGGGCGC CGCCGGATTACAACCCTCCGCTGCTAGAGTCCTGGAAGGACCCGGACTACGTTCCTCCGGTGGTACACGG GTGCCCGTTGCCGCCCACCAAGGCCCCTCCAATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGACA GAATCCACCGTGTCTTCTGCCTTGGCGGAGCTCGCTACTAAGACCTTCGGCAGCTCCGGATCGTCGGCCA TCGACAGCGGTACGGCGACCGCCCCTCCTGACCAAGCCTCCGGTGACGGCGACAGAGAGTCCGACGTTGA 15 GTCGTTCTCCTCCATGCCCCCCCTTGAGGGAGAGCCGGGGGACCCCGATCTCAGCGACGGATCTTGGTCC ACCGTGAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGTTCGATGTCCTACACATGGACAGGCGCCCTGA TCACGCCATGCGCTGCGGAGGAAAGCAAGTTGCCCATCAACCCGTTGAGCAATTCTTTGCTACGTCACCA CAACATGGTCTATGCTACAACATCCCGCAGCGCAGGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTG CAAGTCCTGGACGACCACTACCGGGACGTGCTTAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTA 20 AACTTCTATCTGTAGAAGAAGCCTGCAAACTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTACGG GGCGAAGGACGTCCGGAGCCTATCCAGCAGGGCCGTTACCCACATCCGCTCCGTGTGGAAGGACCTGCTG GAAGACACTGAAACACCAATTAGCACTACCATCATGGCAAAAAATGAGGTTTTCTGTGTCCAACCAGAGA AGGGAGGCCGCAAGCCAGCTCGCCTTATCGTGTTCCCAGATCTGGGAGTTCGTGTATGCGAGAAGATGGC CCTTTATGACGTGGTCTCCACCCTTCCTCAGGCCGTGATGGGCTCCTCATACGGATTCCAGTACTCTCCT 25 AAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCCATGGGCTTCTCATATGACA CCCGCTGTTTTGACTCAACGGTCACTGAGAATGACATCCGTGTTGAGGAGTCAATTTACCAATGTTGTGA CTTGGCCCCCGAAGCCAAACTGGCCATAAAGTCGCTCACAGAGCGGCTCTATATCGGGGGTCCCCTGACT AATTCAAAAGGGCAGAACTGCGGTTACCGCCGGTGCCGCGCGAGCGGCGTGCTGACGACTAGCTGCGGTA ATACCCTCACATGTTACCTGAAAGCCACTGCGGCCTGTCGAGCTGCGAAGCTCCGGGACTGCACGATGCT 30 CGTGAACGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGAACCCAAGAGGATGCGGCGAGCCTACGA GTCTTCACGGAGGCTATGACTAGGTACTCTGCCCCCCCTGGGGACCCGCCTCAACCGGAATACGACTTGG AGTTGATAACATCATGTTCCTCCAATGTGTCGGTCGCACACGATGCATCTGGTAAAAGGGTGTACTACCT CACCCGTGACCCTACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAACTCC TGGCTAGGCAACATCATCATGTATGCGCCCACCTTATGGGCAAGGATGATTCTGATGACTCATTTCTTCT 35 CCATCCTTCTAGCTCAGGAGCAACTTGAAAAAACCCTAGATTGTCAGATCTACGGGGCCTGTTACTCCAT TGAACCACTTGATCTACCTCAGATCATTGAGCGACTCCATGGTCTTAGCGCATTTTCACTCCATAGTTAC TCTCCAGGCGAGATCAATAGGGTGGCTTCATGCCTCAGAAAACTTGGGGTACCACCCTTGCGAGCCTGGA GACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAAGTA CCTCTTCAACTGGGCGGTGAGGACCAAGCTCAAACTCACTCCAATCCCAGCCGCGTCCCGGTTGGACTTG 40 TCCGGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCT GGTTCATGTTGTGCCTACTCCTACTTTCCGTGGGGGTAGGCATCTACCTGCTCCCCAACCGATGAATGGG GAGCTAAACACTCCAGGCCAATAGGCCGTTTCTC (SEQ ID NO:6689) 45 gil329739|gb|LO2836.1|HPCCGENOM Hepatitis C China virus complete genome ATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTA GCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGC GGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTG GAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTG 50 CCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACC TCAAAGAAAAACCAAACGTAACACCAACCGCCGCCCACAGGACGTCAAGTTCCCGGGCGGTGGTCAGATC GTTGGTGGAGTTTACCTGTTGCCGCGCAGGGGCCCCAGGTTGGGTGTGCGCGCGACTAGGAAGACTTCCG AGCGGTCGCAACCTCGTGGAAGGCGACAACCTATCCCCAAGGCTCGCCGACCCGAGGGCAGGACCTGGGC TCAGCCCGGGTATCCTTGGCCCCTCTATGGCAATGAGGGCTTTGGGTGGGCAGGATGGCTCCTGTCACCC 55 CGCGGCTCCCGGCCTAGTTGGGGCCCCACGGACCCCCGGCGTAGGTCGCGTAATTTGGGTAAGGTCATCG ATACCCTCACATGCGGCTTCGCCGACCTCATGGGGTACATTCCGCTCGTCGGCGCCCCCTTGGGGGGCGC 346 WO 2004/091515 PCT/US2004101 1255 TGCCAGGGCCCTGGCACATGGTGTCCGGGTTCTGGAGGACGGCGTGAA.CTATGCA.ACAGGGAATTTGCcC GGTTGCTCTTTCTCTATCTTCCTTTTAGCCTTGCTATCCTGTTTGACCACCCCAGCTTCCGCTTACGAAG TGCGTAACGTGTCCGGGATATACCATGTCACGAACGACTGCTCCAACTCAAGCATTGTGTATGAGGCAGC GGACCTGATCATGCATACCCCTGGGTGCGTGCCCTGCGTTCGGGAAGGCAACTCCTCCCGTTGCTGGGTA 5 GCGCTCACTCCCACGCTCGCGGCCAGGAACGCCACGATCCCCACTGCGACAGTACGACGGCATGTCGATC TGCTCGTTGGGGCGGCTGCTTTCTCTTCCGCCATGTACGTGGGGGATCTCTGCGGATCTGTTTTCCTTGT CTCTCAGCTGTTCACCTTCTCGCCTCGCCGGTATGAGACAATACAGGACTGCAATTGCTCAATCTATCCC GGCCACGTAACAGGTCACCGCATGGCTTGGGATATGATGATGAACTGGTCGCCTACAACAGCTCTAGTGG TGTCGCAGTTACTCCGGATCCCTCAAGCCGTCATGGACATGGTGGTGGGGGCCCACTGGGGAGTCCTGGC 10 GGGCCTTGCCTACTATGCCATGGTGGGGAATTGGGCTAAGGTTTTGATTGTGATGCTACTCTTCGCCGGC GTTGATGGGGATACCTACGCGTCTGGGGGGGCGCAGGGCCGCTCCACCCTCGGGTTCACGTCCCTCTTTA CACCTGGGGCCTCTCAGAAGATCCAGCTTATAAATACCAATGGTAGCTGGCATATCAACAGGACTGCCCT GAACTGCAATGACTCCCTCAATACTGGGTTTCTTGCCGCGCTGTTCTATACACACAGGTTCAACGCGTCC GGATGCGCAGAGCGCATGGCCAGCTGCCGCCCCATTGATACATTCGATCAGGGCTGGGGCCCCATCACTT 15 ATACTGAGCCTGATAGCTCGGACCAGAGGCCTTATTGCTGGCACTACGCGCCTCGAAAGTGCGGCATCGT ACCTGCGTCGGAGGTGTGCGGTCCAGTGTATTGTTTCACCCCAAGCCCTGTCGTCGTGGGGACGACCGAT CGTTTCGGTGTCCCCACATATAGCTGGGGGGAGAATGAGACAGACGTGCTGCTCCTCALACAACACGCGGC CGCCGCAAGGCAACTGGTTTGGCTGTACATGGATGAATGGCACTGGGTTCACCAAGACGTGCGGGGGGCC TCCGTGTAACATCGGGGGGGTCGGCAACAACACTTTGACTTGCCCCACGGATTGCTTTCGGAAGCACCCC 20 GAGGCTACGTATACAAGGTGTGGTTCGGGGCCTTGGCTGACACCTAGGTGCTTAGTTGACTACCCATACA GGCTCTGGCACTACCCCTGCACTGTCAACTTTGCCATCTTCAAAGTTAGGATGTATGTGGCGGGGCGTGGA GCACAGGCTCGATGCTGCATGCAACTGGACTCGAGGAGAGCGCTGTAACTTGGAGGACAGGGATAGATCA GAACTCAGCCCGCTGCTACTGTCTACAACAGAGTGGCAGATACTACCCTGCGCCTTCACCACCCTACCGG CTCTGTCCACTGGTTTAATCCATCTCCATCAGALACATCGTGGACGTGCAATACCTGTACGGTATAGGGTC 25 AGCGGTTGCCTCCTTTGCAATTAAATGGGAGTATGTCTTGTTGCTTTTCCTTCTACTAGCAGACGCGCGC GTATGTGCCTGCTTGTGGATGATGCTGCTGATAGCCCAGt3CCGAGGCCGCCTTAGAGAACCTGGTGGTCC TCAATGCGGCGTCCGTGGCCGACGCGCATGGCATCCTCTCCTTCCTTGTGTTCTTTTGTGCCGCCTGGTA CATTAAGGGCAGGCTGGTCCCCGGOGCAGCATACGCTTTCTACGGCGTGTGGCCGCTGCTCCTGCTCCTG CTGACATTACCACCACGAGCTTACGCCATGGACCGGGAGATGGCTGCATCGTGCGGAGGCGCGGTTTTTG 30 TAGGTCTGGTATTCCTGACTTTGTCACCATACTACAAGGTGTTCCTCGCTAGGCTCATATGGTGGTTGCA ATACTTCCTCACCATAGCCGAGGCGCACCTGCAAGTGTGGATCCCCCCTCTCAACATTCGAGGGGGCCGC GATGCCATCATCCTCCTCACGTGTGCAATCCACCCAGAGTCAATCTTTGACATCACCAAACTCCTGCTCG CCACGCTCGGTCCGCTCCTGGTGCTTCAGGCTGGCATAACTAGAGTGCCGTACTTTGTGCGCGCTCATGG GCTCATTCGCGCGTGCATGCTATTGCGGAAAGTTGCTGGGGGTCATTATGTCCAAATGGCCTTCATGAAG 35 CTGGGCGCACTGACAGGTACGTACGTCTATAACCATCTTACTCCGCTGCAGTATTOGCCACGCGCGGGTT TACGAGAACTCGCGGTGGCAGTAGAGCCCGTCATCTTCTCTGACATGGAGACCAAGATTATCACCTGGGG GGCAGACACTGCAGCGTGTGGAGACATCATCTTGGGTTTACCCGTCTCCGCCCGAAGGGGAAAGGAGATA CTCCTGGGGCCGGCCGATAGTCTTGAAGGGCAGGGGTGGCGACTCCTTGCGCCCATCACGGCCTACTCCC AACAGACGCGGGGCTTACTTGGTTGCATCATCACTAGCCTCACAGGCCGAGACAALGAACCAGGTCGAGGG 40 GGAGGTTC1AAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCATCAACGGTGTGTGTTGGACT GTCTATCATGGCGCCGGCTCAAAAACCTTAGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATG TAGACCAGGACCTCGTCGGCTGGCACCGGCCCCCCGGGGCGCGTTCCCTAACACCATGCACCTGCGGCAG CTCGGACCTTTACTTGGTCACGAGACATGCTGATGTCATTCCGGTGCGCCGTCGAGGCGACAGTAGGGGG AGTTTACTCTCCCCCAGGCCTGTCTCCTACCTGAAGGGCTCGTCGGGGGGCCCACTGCTCTGCCCCTTCG 45 GGCACGTTGCAGGCATCTTCCGGGCTGCTGTGTGCACCCGGGGGGTTGCGAAGGCGGTGGATTTTATACC CGTTGAGACCA TGGAAACTACCATGCGGTCCCCGGTCTTCACGGACAACTCATCCCCTCCTGCCGTACCG CAGACATTCCAAGTGGCCCATCTACACGCTCCCACTGGCAGCGGCAAAAGCACCAAGGTGCCGGCTGCAT ATGCAGCCCAAGGGTACAPAGGTACTTGTCTTGAACCCGTCTGTTGCCGCCACTTTAGGTTTTGGGGCGTA TIATGTCTA1GGCACATGGTGTCGACCCCAACATTAGAACCGGGGTAAGGACCATCACCACGGGCGCCCCC 50 ATCACATACTCTACCTATGGCAAGTTCCTTGCTGATGGTGGTTGCTCTGGGGGTGCCTATGACATTATAA TATGTGATGAGTGCCATTCAACTGACTCGACTACCATCTTGGGCATCGGCACGGTCCTGGACCAAGCGGA GACGGCTGGAGCGCGGCTTGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCA AACATCGAGGAGGTGGCCCTGTCCALATACTGGAGAGATCCCCTTCTATGGTAAAGCCATCCCCATCGAAG CCATCAGGGGGGGAAGGCATCTCATTTTCTGCCACTCCAAGAAGAAGTGTGACGAGCTTGCTGCAAAGCT 55 ATCATCGCTCGGGCTCAACGCTGTGGCGTACTACCGGGGGCTTGATGTGTCCGTCATACCATCTAGCGGA GACGTCGTTGTCGTGGCAACGGACGCTCTAATGACGGGCTTTACGGGCGACTTTGACTCAGTGATCGACT GTAACACATGTGTTACCCAAACAGTCGATTTCAGCTTGGACCCCACCTTCACCATCGAGACAACGACCGT GCCCCAAGACGCGGTGTCGCGCTCGCAGCGGCGAGGTAGGACTGGCAGGGGTAGGGAAGGCATCTACAGG 347 WO 2004/091515 PCT/US200401 1255 TTTGTTACTCCAGGAG1AACGGCCCTCGGGCATGTTCGACTCCTCAGTCCTGTGTGAGTGCTATGAcGCGG GCTGTGCTTGGTACGAGCTCACGCCGGCTGAGACCACGGTTAGGTTGCGGGCTTACCTAAATACACCAGG GTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGGGCGTCTTCACAGGTCTCACCCATATAGACGCT CACTTTCTGTCCCAGACCAAGCAAGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAAGCTACAGTGT 5 GTGCCAAGGCTCAGGCCCCACCTCCATCGTGGGATCAAATGTGGAAGTGCCTCACACGGCTAAAGccTAc GCTGCAGGGACCAACACCCCTGCTGTATAGGCTAGGAGCCGTCCAAAATGAGGTCACCCTCACACACCCC ATAACTAAATACATCATGACATGCATGTCGGCTGACCTGGAGGTCGTCACCAGCACCTGGGTGCTGGTGG GCGGAGTCCTTGCAGCTCTGGCCGCGTATTGCCTGACAACGGGCAGCGTGGTCATTGTGGGTAGGATTGT CTTGTCCGGAAGTCCGGCTATTGTTCCTGACAGGGAAGTTCTTTACCAAGACTTCGACGAGATGGAAGAG 10 TGTGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAGCAGTTCAAGCAGAA(G~CGCTCG GGTTGCTGCAAA.CAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAAGTGGCGAGCCCT CGAGACATTTTGGGAAAAACACATGTGGAATTTCATCAGCGGGATACAGTACTTAGCAGGCTTATCCACT CTGCCTGGGAACCCCGCAATGGCATCACTGATGGCATTCACAGCTTCTATCACCAGCCCGCTCACTACCC AACACACCCTCCTGTTTAACATCTTGGGTGGATGGGTGGCTGCCCAACTCGCTCCCCCCAGCGCCGCTTC 15 GGCCTTTGTGGGCGCCGGCATTGCCGGTGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGAC ATCCTGGCGGGTTATGGGGCGGGGGTGGCTGGCGCACTCGTGGCCTTTAAGGTCATGAGTGGCGAAATGC CCTCCACTGAGGACCTGGTTAATTTACTCCCTGCCATCCTCTCTCCTGGTGCCCTAGTCGTCGGGGTCGT GTGCGCAGCAATACTGCGCCGACACGTGGGCCCGGGAGAGGGGGCTGTGCAGTGGATGAACCGGCTGATA GCGTTCGCTTCGCGGGGTAACCATGTCTCCCCCACGCACTATGTGCCTGAAAGTGACGCCGCAGCGCGTG 20 TTACCCAGATCCTCTCCAGCCTTACCATCACTCAGCTGCTGAAAIAGACTTCACCAGTGGATTAATGAGGA CTGTTCCACACCATGCTCCGGCTCGTGGCTAAGGGATGTTTGGGATTGGATATGCACGGTGTTGACCGAT TTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGGTTGCCCGGAGTCCCTTTCCTCTCATGCCAACGCG GGTACAAGGGAGTCTGGCGGGGGGACGGTATTATGCAAACCACCTGTCCATGTGGAGCACAGATTACTGG ACATGTCAAAAALCGGTTCCATGAGAATCGTTGGGCCTAAGACTTGTAGCAACACGTGGCATGGAACATTC 25 CCCATCAA.CGCGTACACCACGGGCCCCTGCACACCCTCCCCGGCGCCGAACTATTCCAGGGCGCTGTGGC GGGTGGCTCCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCAC CGACAACGTGA2AATGCCCATGCCAAGTCCCGGCCCCTGAATTCTTCACGGAGGTGGATGGAGTACGGCTG CACAGGTACGCTCCGGCGTGCAAACCTCTCCTACGGGAGGAGGTCGTGTTCCAGGTCGGGCTCAACCAAT ACCTGGTTGGATCACAGCTCCCATGCGAGCCCGAGCCGGACGTAACAGTGCTCACTTCCATGCTTACCGA 30 CCCCTCCCACATCACAGCAGAGACGGCCAAGCGTAGGCTGGCCAGGGGGTCTCCCCCCTCCTTGGCCAGC TCTTCAGCTAGCCAATTGTCTGCGCCTTCTTTGAALGGCGACATGTACTACCCATCATGACTCCCCGGACG CCGACCTCATTGAGGCCA~ACCTCCTGTGGCGGCAGGAGATGGGCGGAAACATCACCCGTGTGGAGTCAGA AAATAAGGTAGTGATCCTGGACTCTTTCGACCCGCTTCGGGCGGAGGAGGACGAGAGGGAAGTATCCGTT GCGGCGGAGATCCTGCGGAAATCCAGGAAGTTCCCCTCAGCGCTGCCCATATGGGCACGCCCAGACTACA 35 ACCCTCCACTGCTAGAGTCCTGGAAGGACCCAGATTATGTCCCTCCGGTGGTACACGGGTGCCCGTTGCC GCCTACCACGGCCCCTCCAGTACCACCTCCACGGAGAAAAAGGACGGTCGTCCTAACAGAGTCATCCGTG TCTTCTGCCTTGGCGGAGCTCGCTACTAAGACCTTCGGCAGCTCTGAATCGTC4GCCGTCGACAGCGGCA CGGCGACTGCCCCTCCTGACGAGGCCTCCGGCGGCGGCGACAAAGGATCCGACGTTGAGTCGTACTCCTC CATGCCCCCCCTTGAGGGAGAGCCGGGGGACCCCGACCTCAGCGACGGGTCCTGGTCTACCGTGAGTGAG 40 GAGGCCAGTGAGGACGTCGTCTGCTGCTCAATGTCCTATACATGGACAGGCGCCTTGATCACGCCATGTG CTGCGGAGGAGAGCAAGCTGCCCATCAACCCGCTGAGCAACTCCTTGCTGCGTCACCACAACATGGTCTA TGCTACAACATCCCGCAGTGCAAGCCTACGGCAGAAGAAGGTCGCTTTTGACAGAATGCAAGTCCTGGAC GACCACTACCGGGACGTGCTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAACTCCTATCCA TAGAAGAGGCCTGCAAGCTGACGCCCCCACATTCAGCCAAATCCAALATTTGGCTATGGGGCAAAALGACGT 45 CCGGAACCTATCCAGCAGGCGTTAACCACATCCGCTCCGTGTGGAAGGACTTGTTGGAAGACAATGAG ACACCAATCA.ATACCACCATCATGGCAAAAAATGAGGTTTTCTGCGTCCAXCCAGAGAAAGGAGGCCGTA AGCCAGCTCGCCTTATCGTATTCCCAGACTTGGGAGTCCGTGTGTGCGAGAAGATGGCCCTTTATGACGT GGTCTCCACCCTTCCTCAGCCCGTGATGGGCTCCTCATACGGATTCCAGTACTCTCCTGGGCAGCGGGTC GAATTCCTGCTAAATGCCTGGAAATCAAAGGAAI\ACCCTATGGGCTTCTCATATGACACCCGCTGTTTTG 50 ACTCAALCGGTCACTCAGAACGACATCCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGA GGCCAGACGGGCCATAAAGTCGCTCACAGAGCGGCTCTATATCGGGGGTCCCCTGACTAATTCAAAAGGG CAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACCAGCTGCGGTAALTACCCTTACAT GTTACTTGAAGGCCTCTGCGGCCTGTCGAGCTGCGAAGCTGCAGGACTGCACGATGCTCGTGAACGGAGA CGACCTTGTCGTTATCTGTGAAAGCGCGGGAACTCAAGAGGATGCGGCGAGCCTACGAGTCTTCACGGAG 55 GCTATGACTAGGTACTCTGCCCCCCCTGGGGACCTGCCCCAACCAGAATACGACTTGGAGCTiAATAACAT CATGCTCCTCCAATGTGTCAGTCGCCCACGATGCATCTGGCAAAAGGGTGTACTACCTCACCCGTGACCC CACCATCCCCCTCGCGCGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAACTCCTGGCTAGGCAAC ATCATCATGTATGCGCCCACTCTATGGGCAAGGATGATTCTGATGACTCACTTCTTCTCCATCCTTCTAG 348 WO 2004/091515 PCT/US2004/011255 CTCAGGAGCAACTTGAGAAAGCCCTGGATTGCCAAATCTACGGGGCCTACTACTCCATTGAGCCACTTGA CCTACCTCAGATCATTGAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACTCTCCAGGTGAG ATCAATAGGGTGGCGTCATGTCTCAGGAAACTTGGGGTACCACCCTTGCGAGTCTGGAGACATCGGGCCA GAAGCGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAAGTACCTCTTCAACTG 5 GGCAGTAAAGACCAAGCTTAAACTCACTCCAATCCCGGCTGCGTCCCGGTTGGACTTGTCCGGCTGGTTC GTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGTTGGTTCATGTTGT GCCTACTCCTACTTTCTGTAGGGGTAGGCATCTACCTGCTCCCCAACCGATGAACGGGGAGATAAACACT CCAGGCCAATAGGCCATCCC (SEQ ID NO:6690) 10 giI15422182|gblAY051292.11 Hepatitis C virus from India polyprotein mRNA, complete cds GCCAGCCCCCTGATGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCA GAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCA 15 TAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCG CTCAATGCCTGGAGATTTGGGCGTGCCCCCGCAAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCC TTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACG AATCCTAAACCTCAAAGAAAAACCAAACGTAACACCAACCGACGCCCACAGAACGTTAAGTTCCCGGGTG GCGGCCAGATCGTTGGCGGAGTTTGCTTGTTGCCGCGCAGGGGTCCCAGAGTGGGTGTGCGCGCGACGAG 20 GAAGACTTCCGAGCGGTCACAACCTCGCGGAAGGCGTCAGCCTATTCCCAAGGCCCGCCGACCCGAGGGC AGGTCCTGGGCGCAGCCCGGGTACCCTTGGCCCCTCTATGGCAACGAGGGCTGTGGGTGGGCAGGATGGC TCTTGTCCCCCCGCGGCTCCCGGCCTAGTCGGGGCCCCTCTGACCCCCGGCGCAGGTCACGCAATTTGGG TAAGGTCATCGATACCCTCACGTGTGGCTTCGCCGACCTCATGGGGTACATCCCGCTCGTCGGTGCTCCT CTAGGGGGCGCTGCTAGGGCTCTGGCACATGGTGTTAGGGTTCTAGAAGACGGCGTAAATTACGCAACAG 25 GGAACCTTCCTGGTTGCTCTTTTTCTATCTTCTTGCTTGCTCTTCTCTCCTGCTTGACAGTCCCTGCTTC GGCCGTCGAAGTGCGCAACTCTTCGGGGATCTACCATGTCACCAATGATTGCCCCAATGCGTCTGTTGTG TACGAGACAGATAGCTTGATCATACATCTGCCCGGGTGTGTGCCCTGCGTACGCGAGGGCAACGCTTCGA GGTGCTGGGTCTCCCTTAGTCCTACTGTTGCCGCTAAGGATCCGGGCGTCCCCGTCAACGAGATTCGGCG TCACGTCGACCTGATTGTCGGGGCCGCTGCATTCTGTTCGGCTATGTATGTAGGGGACTTATGCGGTTCC 30 ATCTTCCTCGTTGGCCAGCTTTTCACCCTCTCCCCTAGGCGCCACTGGACAACACAAGACTGTAATTGCT CCATCTACCCAGGACATGTGACAGGCCATCGAATGGCTTGGGACATGATGATGAATTGGTCACCTACTGG CGCTTTGGTGGTAGCGCAGCTACTCCGGATCCCACAAGCCGTCTTGGATATGATAGCCGGTGCCCACTGG GGTGTCCTAGCGGGCCCGGCATACTACTCCATGGTGGGGAACTGGGCTAAGGTTTTGGTTGTGCTACTGC TCTTCGCTGGCGTCGATGCAACCACCCAAGTCACAGGTGGCACCGCGGGCCGTAATGCATATAGATTGGC 35 TAGCCTCTTCTCCACCGGCCCCAGCCAAAATATCCAGCTCATAAACTCCAATGGCAGCTGGCACATTAAC AGGACTGCCCTGAATTGCAATGACAGCCTGCACACCGGCTGGGTAGCAGCGCTGTTCTACTCCCACAAGT TCAACTCTTCGGGGCGTCCTGAGAGGATGGCTAGTTGTCGGCCTCTTACCGCCTTCGACCAAGGGTGGGG GCCCATCACTTACGGGGGGAAAGCTAGTAACGACCAGCGGCCGTATTGCTGGCACTATGCCCCACGCCCG TGCGGTATCGTGCCGGCGAAAGAGGTTTGCGGGCCTGTATACTGTTTCACACCCAGTCCCGTGGTAGTGG 40 GGACGACGGACAAGTACGGCGTTCCTACCTACACATGGGGCGAGAATGAGACGGATGTACTGCTCCTTAA CAACTCTAGGCCGCCAATAGGGAATTGGTTCGGGTGTACGTGGATGAATTCCACTGGTTTCACCAAGACG TGCGGGGCTCCTGCCTGTAACGTCGGCGGGAGCGAGACCAACACCCTGTCGTGCCCCACAGATTGCTTCC GCAGACATCCGGACGCAACATACGCTAAGTGCGGCTCTGGCCCTTGGCTTAACCCTCGATGCATGGTGGA CTACCCTTACAGGCTCTGGCACTATCCCTGCACAGTCAATTACACCATATTCAAGATCAGGATGTTCGTG 45 GGCGGGATTGAGCACAGGCTCACCGCCGCGTGCAACTGGACGCGGGGAGAGCGCTGCGACTTGGACGACA GGGATCGTGCCGAGTTGAGCCCGCTGTTGCTGTCCACCACGCAATGGCAGGTCCTCCCCTGCTCATTCAC AACGCTGCCCGCCCTGTCAACTGGCCTAATACATCTCCACCAGAACATCGTGGACGTGCAGTACCTCTAC GGGTTGAGCTCGGTAGTTACATCCTGGGCCATAAGGTGGGAGTATGTCGTGCTCCTTTTCTTGCTGTTAG CAGATGCCCGCATTTGTGCCTGCCTTTGGATGATGCTTCTCATATCCCAGGTAGAGGCGGCGCTGGAGAA 50 CCTGATAGTCCTCAACGCTGCTTCCCTGGCTGGGACACACGGCATCGTCCCTTTCTTCATCTTTTTTTGT GCAGCCTGGTATCTGAAAGGCAAGTGGGCCCCTGGACTCGTCTACTCCGTCTACGGAATGTGGCCGCTGC TCCTGCTTCTCCTGGCGTTGCCCCAACGGGCGTACGCCTTGGATCAGGAGTTGGCCGCGTCGTGTGGGGC CGTGGTCTTCATCAGCCTAGCGGTACTTACCCTGTCGCCGTACTACAAACAGTACATGGCCCGCGGCATC TGGTGGCTGCAGTACATGCTGACCAGAGCGGAGGCGCTCCTGCACGTCTGGGTCCCCTCGCTCAACGCCC 55 GGGGAGGGCGTGATGGTGCCATACTGCTCATGTGTGTGCTCCACCCGCACTTGCTCTTTGACATCACCAA AATCATGCTGGCCATTCTCGGGCCCCTGTGGATCTTGCAGGCCAGTCTGCTCAGGGTGCCGTACTTCGTG 349 WO 2004/091515 PCT/US2004101 1255 CGCGCCCACGGTCTCATTAGGCTCTGCATGCTGGTGCGCAAAACAGCGGGCGGTCACTATGTGCAGATGG CTCTGTTGAAGCTGGGGGCACTTACTGGCACTTACATTTACAACCACCTTTCCCCACTCCAAGACTGGGC TCATGGCAGCTTGCGTGATCTAGCGGTGGCCACCGAGCCCGTCATCTTCTCCCGGATGGAGATCAAGACT ATCACCTGGGGGGCAGACACCGCGGCCTGTGGAGACATCATCAACGGGCTGCCTGTTTCTGCTCGGAGGG 5 GGAGAGAGGTGTTGTTGGGACCAGCCGATGCCCTGACTGACAAGGGATGGAGGCTTTTAGCCCCCATCAC AGCTTACGCCCAACAGACACGAGGTCTCTTGGGCTGTATTGTCACCAGCCTCACCGGTCGGGACAAAAAT CAAGTGGAGGGGGA]AATCCAGATTGTGTCTACCGCAACCCAGACGTTCTTGGCCACTTGCATCAACGGAG CTTGCTGGACTGTTTATCATGGGGCCGGATCGAGGACCATCGCTTCGGCGTCGGGTCCTGTGGTCCGGAT GTACACCAATGTGGACCAGGATTTGGTGGGCTGGCCAGCGCCTCAGGGAGCGCGCTCCCTGACGCCGTGC 10 ACGTGCGGTGCCTCGGATCTGTACTTGGTCACGAGGCACGCGGATGTCATCCCAGTGCGGCGTCGAGGCG ATAACAGGGGAAGCTTGCTTTCTCCCCGGCCCATCTCATACCTAAAAGGATCCTCGGGAGGCCCTCTGCT CTGCCCCATGGGACATGTCGCGGGCATTTTTAGGGCCGCGGTGTGCACCCGTGGGGTTGCAGGCGGTC GACTTTGTGCCCGTTGAGTCCTTAGAGACCACCATGAGGTCCCCAGTGTTTACTGACAATTCCAGCCCTC CAACAGTGCCCCAGAGTTACCAGGTGGCACATCTACATGCACCCACTGGGAGTGGCAAGAGCACGAAGGT 15 GCCGGCCGCTTACGCAGCTCAAGGGTACAAGGTACTTGTGCTGAACCCGTC!TGTTGCTGCCACCTTAGGG TTCGGTGCTTATATGTCAAAGGCCCATGGGATTGACCCAAACGTCAGGACCGGCGTGAGGACCATTACCA CAGGCTCCCCCATCACCTACTCCACCTACGGGAAATTTTTGGCTGATGGCGGATGCCCAGGAGGTGCGTA CGACATCATAATATGTGACGAATGTCACTCAGTGGACGCCACCTCGATTCTGGGCATAGGGACCGTCTTG GACCAAGCGGAGACGGCGGGGGTTAGGCTCACTGTCCTTGCCACCGCTACACCACCTGGCTTGGTCACCG 20 TGCCACATTCCAACATCGAGGAAGTTGCACTGTCCGCTGACGGGGAGAAACCATTTTATGGTAAGGCCAT CCCCCTAAACTACATCAAGGGGGGGAGGCATCTCATTTTCTGTCATTCCAAGAAGAAGTGCGACGAGCTC GCTGCAAAGCTGGTCGGTCTGGGCGTCAACGCGGTGGCCTTTTACCGTGGCCTCGACGTATCTGTCATTC CAACTACAGGAGACGTCGTTGTTGTAGCGACCGACGCCTTGATGACTGGCTTCACCGGCGATTTCGACTC TGTGATAGACTGCAACACCTGTGTCGTCCAGACAGTCGACTTCAGCCTAGACCCTATATTCTCTATTGAG 25 ACTTCCACCGTGCCCCAGGACGCCGTGTCCCGCTCCCAACGGAGGGGTAGGACCGGTCGAGGGAAGCATG GTATTTACAGATATGTGTCACCCGGGGAGCGGCCGTCTGGCATGTTCGACTCCGTGGTCCTCTGTGAGTG CTATGACGCGGGTTGTGCTTGGTACGAGCTTACACCCGCCGAGACCACAGTCAGGCTACGGGCATACCTT AACACCCCAGGATTGCCCGTGTGCCAGGACCACTTGGAGTTCTGGGAGAGTGTCTTCACCGGCCTCACCC ACATAGATGCCCACTTCCTGTCCCAGACGAAACAGAGTGGGGAGAACTTCCCCTACCTAGTCGCATACCA 30 AGCCACCGTGTGCGCTAGAGCTAGAGCTCCTCCCCCGTCATGGGACCAAATGTGGAAGTGCCTGATACGG CTCAAGCCCACCCTCACTGGGGCTACCCCATTACTATACAGACTGGGTAGTGTACAGAATGAGATCACCT TAACACACCCAATCACCCAATACATCATGGCTTGCATGTCGGCGGACCTGGAGGTCGTCACTAGCACGTG GGTGTTGGTGGGCGGCGTCCTAGCCGCTTTGGCCGCTTACTGCCTGTCCACAGGCAGCGTGGTCATAGTG GGCAGGATAATCCTAGGTGGGAAGCCGGCAGTCATACCTGACAGGGAGGTTCTCTACCGAGAGTTTGATG 35 AGATGGAGGAGTGCGCCGCCCACGTCCCCTACCTCGAGCAGGGGATGCATTTGGCTGGACAGTTCAAGCA GAAAGCTCTCGGGTTGCTCCAGACAGCATCCAiAGCAAGCGGAGACGATCACTCCCACTGTCCGCACCAAC TGGCAGAAACTCGAGTCCTTCTGGGCTAAGCACATGTGGAACTTCGTTAGCGGGATACAATACCTGGCGG GCCTGTCAACGCTGCCCGGGAACCCCGCTATAGCGTCGCTGATGTCGTTTACGGCCGCGGTGACGAGTCC ACTAACCACCCAGCAAACCCTCTTCTTTAACATCTTAGGGGGGTGGGTGGCGGCCCAGCTTGCTTCCCCA 40 GCTGCCGCTACTGCTTTTGTCGGTGCTGGTATTACTGGCGCCGTTGTTGGCAGTGTGGGCCTAGGGAAGG TCCTAGTGGACATTATTGCTGGCTACGGGGCTGGTGTGGCGGGGGCCCTCGTGGCTTTCAAAATCATGAG CGGGGAGACCCCCACCACCGAGGATCTAGTCAACCTTCTGCCTGCCATCCTATCGCCAGGAGCTCTCGTT GTCGGCGTGGTGTGCGCAGCAATACTACGCCGGCACGTGGGCCCTGGCGAGGGCGCCGTGCAGTGGATGA ACCGGCTGATAGCGTTTGCTTCTCGGGGTAACCACGTCTCCCCTACACACTACGTGCCGGAGAGCGACGC 45 GTCGGCTCGTGTCACACAAATTCTCACCAGCCTCACTGTTACTCAGCTTCTGAAAAGGCTCCACGTGTGG ATAAGCTCGGATTGCATCGCCCCGTGTGCTAGTTCTTGGCTTAAAGATGTCTGGGACTGGATATGCGAGG TGCTGAGCGACTTCAT&GAATTGGCTGAAGGCCAAACTTGTACCACAACTGCCCGGGATCCCATTCGTATC CTGCCAACGCGGGTACCGTGGGGTCTGGCGGGGCGAGGGCATCGTGCACACTCGTTGCCCGTGTGGGGCC AATATAACTGGACATGTCAAGADACGGTTCGATGAGAATCGTCGGGCCTAAGACTTGCAGCAACACCTGGC 50 GTGGGTCGTTCCCCATTAACGCTTACACTACAGGCCCGTGCACGCCCTCCCCGGCGCCGAALCTATACGTT CGCGCTATGGAGGGTGTCTGCAGAGGAGTATGTGGAGGTAAGGCGGCTGGGGGACTTCCATTACGTCACG GGGGTGACCACTGATAAACTCAAGTGTCCATGCCAGGTCCCCTCACCCGAGTTCTTCACAGAGGTGGACG GGGTGCGCCTGCATAGGTACGCCCCCCCCTGCAAACCCCTGCTGCGAGAAGAGGTGACGTTTAGCATCGG GCTCAATGAATACTTGGTGGGGTCCCAGTTGCCCTGCGAGCCCGAGCCAGACGTAGCTGTACTGACATCA 55 ATGCTTACAGACCCCTCCCACATCACTGCAGAGACGGCAGCGCGTAGGCTGAAGCGGGGGTCTCCCCCCT CCCTGGCCAGCTCTTCCGCCAGCCAGCTGTCCGCGCCGTCACTGAAGGCALACATGCACCACTCACCACGA CTCTCCAGACGCTGACCTCATAGAAGCCAACCTCCTGTGGAGACAGGAGATGGGGGGGAACATCACTAGG GTGGAGTCGGAGAACAAGATTGTCGTTCTGGATTCTTTCGACCCGCTCGTAGCGGAGGAGGATGATCGGG 350 WO 2004/091515 PCT/US2004/011255 AGATCTCTATTCCAGCTGAGATTCTGCGGAAGTTCAAGCAGTTTCCTCCCGCTATGCCCATATGGGCACG GCCAGATTATAATCCTCCCCTTGTGGAACCGTGGAAGCGCCCGGACTATGAGCCACCCTTAGTCCACGGG TGCCCCCTACCACCTCCCAAGCCAACTCCGGTGCCGCCACCCCGGAGAAAGAGGACGGTGGTGCTGGACG AGTCTACAGTATCATCTGCTCTGGCTGAGCTTGCCACTAAGACCTTCGGCAGCTCTACAACCTCAGGCGT 5 GACAAGTGGTGAAGCGACTGAATCGTCCCCGGCGCCCTCCTGCGGCGGTGAGCTGGACTCCGAAGCTGAA TCTTACTCCTCCATGCCCCCTCTCGAGGGGGAGCCGGGGGACCCCGATCTCAGCGACGGGTCTTGGTCTA CCGTGAGCAGTGATGGTGGCACGGAAGACGTTGTGTGCTGCTCGATGTCTTACTCGTGGACGGGCGCTTT AATCACGCCCTGTGCCTCAGAGGAAGCCAAGCTCCCTATCAACGCATTGAGCAACTCGCTGCTGCGCCAC CACAACTTGGTGTATTCCACCACCTCTCGCAGCGCTGGCCAGAGACAGAAAAAAGTCACATTTGACAGAG 10 TGCAAGTCCTGGACGACCATTACCGGGACGTGCTCAAGGAGGCTAAGGCCAAGGCATCCACGGTGAAGGC TAGACTGCTATCCGTTGAGGAAGCGTGTAGCCTGACGCCCCCACACTCCGCCAGATCAAAATTTGGCTAT GGGGCGAAGGATGTCCGAAGCCATTCCAGTAAGGCTATACGCCACATCAACTCCGTGTGGCAGGACCTTC TGGAGGACAATACAACACCCATAGACACTACCATCATGGCAAAGAATGAGGTCTTCTGTGTGAAGCCCGA AAAGGGGGGCCGCAAGCCCGCTCGTCTTATCGTGTACCCCGACCTGGGAGTGCGCGTATGCGAGAAGAGG 15 GCTTTGTATGACGTAGTCAAACAGCTCCCCATTGCCGTGATGGGAGCCTCCTACGGGTTCCAGTACTCAC CAGCGCAGCGGGTCGACTTCCTGCTTAAAGCGTGGAAATCTAAGAAAGTCCCCATGGGGTTTTCCTATGA CACCCGTTGCTTTGACTCAACAGTCACTGAGGCTGATATCCGTACGGAGGAAGACCTCTACCAATCTTGT GACCTGGCCCCTGAGGCTCGCATAGCCATAAGGTCCCTCACAGAGAGGCTTTACATCGGGGGCCCACTCA CCAATTCTAAGGGACAAAACTGCGGCTATCGGCGATGCCGCGCAAGCGGCGTGCTGACCACTAGCTGCGG 20 TAACACCATAACCTGCTTCCTCAAAGCCAGTGCAGCCTGTCGAGCTGCGAAGCTCCAGGACTGCACCATG CTCGTGTGCGGCGACGACCTCGTCGTTATCTGTGAGAGCGCCGGTGTCCAGGAGGACGCTGCGAGCCTGA GAGCCTTCACGGAGGCTATGACCAGGTACTCCGCCCCCCCGGGAGACCCGCCTCAACCAGAATACGACTT GGAGCTTATAACATCCTGCTCCTCCAATGTGTCGGTCGCGCGCGACGGCGCTGGCAAAAGGGTCTATTAT CTGACCCGTGACCCTGAGACTCCCCTCGCGCGTGCCGCTTGGGAGACAGCAAGACACACTCCAGTGAACT 25 CCTGGCTAGGCAACATCATCATGTTTGCCCCCACTCTGTGGGTACGGATGGTCCTCATGACCCATTTTTT CTCCATACTCATAGCTCAGGAGCACCTTGGAAAGGCTCTAGATTGTGAAATCTATGGAGCCGTACACTCC GTCCAACCGTTGGACTTACCTGAAATCATCCAAAGACTCCACAGCCTCAGCGCGTTTTCGCTCCACAGTT ACTCTCCAGGTGAAATCAATAGGGTGGCTGCATGCCTCAGGAAGCTTGGGGTTCCGCCCTTGCGAGCTTG GAGACACCGGGCCCGGAGCGTTCGCGCCACACTCCTATCCCAGGGGGGGAAAGCCGCTATATGCGGTAAG 30 TACCTCTTCAACTGGGCGGTGAAAACCAAACTCAAACTCACTCCATTACCGTCCATGTCTCAGTTGGACT TGTCCAACTGGTTCACGGGCGGTTACAGCGGGGGAGACATTTATCACAGCGTGTCTCATGCCCGGCCCCG TTTGTTCCTCTGGTGCCTACTCCTACTTTCAGTAGGGGTAGGCATCTATCTCCTTCCCAACCGATAGACG GNTGGGCAACCACTCCGGGTCTTTAGGCCCTATTTAAACACTCCAGGCCTTTAGGCCCCGT (SEQ ID NO:6691) 35 gil235104191refINM_000043.31 Homo sapiens tumor necrosis factor receptor superfamily, member 6 (TNFRSF6), transcript variant 1, mRNA CCTACCCGCGCGCAGGCCAAGTTGCTGAATCAATGGAGCCCTCCCCAACCCGGGCGTTCCCCAGCGAGGC. TTCCTTCCCATCCTCCTGACCACCGGGGCTTTTCGTGAGCTCGTCTCTGATCTCGCGCAAGAGTGACACA 40 CAGGTGTTCAAAGACGCTTCTGGGGAGTGAGGGAAGCGGTTTACGAGTGACTTGGCTGGAGCCTCAGGGG CGGGCACTGGCACGGAACACACCCTGAGGCCAGCCCTGGCTGCCCAGGCGGAGCTGCCTCTTCTCCCGCG GGTTGGTGGACCCGCTCAGTACGGAGTTGGGGAAGCTCTTTCACTTCGGAGGATTGCTCAACAACCATGC TGGGCATCTGGACCCTCCTACCTCTGGTTCTTACGTCTGTTGCTAGATTATCGTCCAAAAGTGTTAATGC CCAAGTGACTGACATCAACTCCAAGGGATTGGAATTGAGGAAGACTGTTACTACAGTTGAGACTCAGAAC 45 TTGGAAGGCCTGCATCATGATGGCCAATTCTGCCATAAGCCCTGTCCTCCAGGTGAAAGGAAAGCTAGGG ACTGCACAGTCAATGGGGATGAACCAGACTGCGTGCCCTGCCAAGAAGGGAAGGAGTACACAGACAAAGC CCATTTTTCTTCCAAATGCAGAAGATGTAGATTGTGTGATGAAGGACATGGCTTAGAAGTGGAAATAAAC TGCACCCGGACCCAGAATACCAAGTGCAGATGTAAACCAAACTTTTTTTGTAACTCTACTGTATGTGAAC ACTGTGACCCTTGCACCAAATGTGAACATGGAATCATCAAGGAATGCACACTCACCAGCAACACCAAGTG 50 CAAAGAGGAAGGATCCAGATCTAACTTGGGGTGGCTTTGTCTTCTTCTTTTGCCAATTCCACTAATTGTT TGGGTGAAGAGAAAGGAAGTACAGAAAACATGCAGAAAGCACAGAAAGGAAAACCAAGGTTCTCATGAAT CTCCAACCTTAAATCCTGAAACAGTGGCAATAAATTTATCTGATGTTGACTTGAGTAAATATATCACCAC TATTGCTGGAGTCATGACACTAAGTCAAGTTAAAGGCTTTGTTCGAAAGAATGGTGTCAATGAAGCCAAA ATAGATGAGATCAAGAATGACAATGTCCAAGACACAGCAGAACAGAAAGTTCAACTGCTTCGTAATTGGC 55 ATCAACTTCATGGAAAGAAAGAAGCGTATGACACATTGATTAAAGATCTCAAAAAAGCCAATCTTTGTAC TCTTGCAGAGAAAATTCAGACTATCATCCTCAAGGACATTACTAGTGACTCAGAAAATTCAA.ACTTCAGA AATGAAATCCAAAGCTTGGTCTAGAGTGAAAAACAACAAATTCAGTTCTGAGTATATGCAATTAGTGTTT 351 WO 2004/091515 PCT/US2004/011255 GAAAAGATTCTTAATAGCTGGCTGTAAATACTGCTTGGTTTTTTACTGGGTACATTTTATCATTTATTAG CGCTGAAGAGCCAACATATTTGTAGATTTTTAATATCTCATGATTCTGCCTCCAAGGATGTTTAAAATCT AGTTGGGAAAACAAACTTCATCAAGAGTAAATGCAGTGGCATGCTAAGTACCCAAATAGGAGTGTATGCA GAGGATGAAAGATTAAGATTATGCTCTGGCATCTAACATATGATTCTGTAGTATGAATGTAATCAGTGTA 5 TGTTAGTACAAATGTCTATCCACAGGCTAACCCCACTCTATGAATCAATAGAAGAAGCTATGACCTTTTG CTGAA7ATATCAGTTACTGAACAGGCAGGCCACTTTGCCTCTAAATTACCTCTGATAATTCTAGAGATTTT ACCATATTTCTAZ4ACTTTGTTTATAACTCTGAGAAGATCATATTTATGTAAAGTATATGTATTTGAGTGC AGAATTTAAATAAGGCTCTACCTCAAAGACCTTTGCACAGTTTATTGGTGTCATATTATACALATATTTCA ATTGTGAATTCACATAGAAAACATTAAATTATAATGTTTGACTATTATATATGTGTATGCATTTTACTGG 10 CTCAAAACTACCTACTTCTTTCTCAGGCATCAAAAGCATTTTGAGCAGGAGAGTATTACTAGAGCTTTGC CACCTCTCCATTTTTGCCTTGGTGCTCATCTTAATGGCCTAATGCACCCCCAAACATGGAAATATCACCA AAAAATACTTAATAGTCCACCAAAAGGCAAGACTGCCCTTAGAAATTCTAGCCTGGTTTGGAGATACTAA CTGCTCTCAGAGAAAGTAGCTTTGTGACATGTCATGAACCCATGTTTGCAATCAAAGATGATAAAATAGA TTCTTATTTTTCCCCCACCCCCGAAAATGTTCAATAATGTCCCATGTAAAACCTGCTACAAATGGCAGCT 15 TATACATAGCAATGGTAAAATCATCATCTGGATTTAGGAATTGCTCTTGTCATACCCCCAAGTTTCTAAG ATTTAAGATTCTCCTTACTACTATCCTACGTTTAAATATCTTTGAAAGTTTGTATTAAATGTGAATTTTA AGAAATAATATTTATATTTCTGTAAATGTAAACTGTGAAGATAGTTATAAACTGAAGCAGATACCTGGAA CCACCTAAAGAACTTCCATTTATGGAGGATTTTTTTGCCCCTTGTGTTTGGATTATAAAATATAGGTAA AATCTATATAGTTG 20 AA\A (SEQ ID NO:6692) giJ35 9l01embIX12387.1IHSRCYP3 Human mRNA for cytochrome P-450 (cyp3 locus) GAATTCCCAAAGAGCAACACAGAGCTGAAAGGAAGACTCAGAGGAGAGAGATAAiGTAAGGAAAGTAGTGA 25 TGGCTCTCATCCCAGACTTGGCCATGGAAACCTGGCTTCTCCTGGCTGTCAGCCTGGTGCTCCTCTATCT ATATGGAACCCATTCACATGGACTTTTTAAGAAGCTTGGAATTCCAGGGCCCACACCTCTGCCTTTTTTG GGAAATATTTTGTCCTACCATAAGGGCTTTTGTATGTTTGACATGGAATGTCATAAAAAGTATGGAAAAG TGTGGGGCTTTTATGATGGTCAACAGCCTGTGCTGGCTATCACAGATCCTGACATGATCAAAACAGTGCT AGTGAAAGAATGTTATTCTGTCTTCACAAACCGGAGGCCTTTTGGTCCAGTGGGATTTATGAAAAGTGCC 30 ATCTCTATAGCTGAGGATGAAGAATG3GAAGAGATTACGATCATTGCTGTCTCCAACCTTCACCAGTGGAA AACTCAAGGAGATGGTCCCTATCATTGCCCAGTATGGAGATGTGTTGGTGAGAAATCTGAGGCGGGAAGC AGAGACAGGCAAGCCTGTCACCTTGAAAGACGTCTTTGGGGCCTACAGCATGGATGTGATCACTAGCACA TCATTTGGAGTGAACATCGACTCTCTCAACAATCCACAAGACCCCTTTGTGGAAAACACCAAGAAGCTTT TAZAGATTTGATTTTTTGGATCCATTCTTTCTCTCAATAACAGTCTTTCCATTCCTCATCCCAATTCTTGA 35 AGTATTAAATATCTGTGTGTTTCCAAGAGAAGTTACAA.ATTTTTTAAGAAAATCTGTAAAAAGGATGAAA GAAAGTCGCCTCGAAGATACACAAA7AGCACCGAGTGGATTTCCTTCAGCTGATGATTGACTCTCAGAATT CAAAAGAAACTGAGTCCCACAAAGCTCTGTCCGATCTGGAGCTCGTGGCCCAATCAATTATCTTTATTTT TGCTGGCTATGAAACCACGAGCAGTGTTCTCTCCTTCATTATGTATGAACTGGCCACTCACCCTGATGTC CAGCAGAAACTGCAGGAGGAAATTGATGCAGTTTTACCCAATAAGGCACCACCCACCTATGATACTGTGC 40 TACAGATGGAGTATCTTGACATGGTGGTGAATGAAACGCTCAGATTATTCCCAATTGCTATGAGACTTGA GAGGGTCTGCAAAAAAGATGTTGAGATC1AATGGGATGTTCATTCCCAAAGGGTGGGTGGTGATGATTCCA AGCTATGCTCTTCACCGTGACCCAAAGTACTGGACAGAGCCTGAGAAGTTCCTCCCTGAALAGATTCAGCA AGAAGAACAAGGACAACATAGATCCTTACATATACACACCCTTTGGAAGTGGACCCAGAAACTGCATTGG CATGAGGTTTGCTCTCATGAACATGAZAACTTGCTCTAATCAGAGTCCTTCAGAACTTCTCCTTCAAACCT 45 TGTAAAGAAACACAGATCCCCCTGAAATTAAGCTTACGAGGACTTCTTCAACCAGAAAAACCCGTTGTTC TAAAGGTTGAGTCAAGGGATGGCACCGTAAGTGGAGCCTGAATTTTCCTAAGGACTTCTGCTTTGCTCTT CAAGAATCTGTGCCTGAGACACCAGAGACCTCALATTACTTTGTGAATAGAACTCTGAAATGAAGATG GGCTTCATCCAATGGACTGCATAAATAACCGGGGATTCTGTACATGCATTGAGCTCTCTCATTGTCTGTG TAGAGTGTTATACTTGGGAATATAAAGGAGGTGACCAA.ATCAGTGTGAGGAGGTAGATTTGGCTCCTCTG 50 CTTCTCACGGGACTATTTCCACCACCCCCAGTTAGCACCATTAACTCCTCCTGAGCTCTGATAASGAGAAT CAACATTTCTCAATAATTTCCTCCACAAATTATTAATGAAAATAAGAATTATTTTGATGGCTCTAACAAT GACATTTATATCACATGTTTTCTCTGGAGTATTCTATAGTTTTATGTTAAATCAATAALAGACCACTTTAC AAAGTATTATCAGATGCTTTCCTGCACATTA\QGAGATCTATAGAACTGAATGAGAACCAACAAGTAA ATATTTTTGGTCATTGTAATCACTGTTGGCGTGGGGCCTTTGTCA-GAACTAGAATTTGATTATTAACATA 55 GGTGAAAGTTAATCCACTGTGACTTTGCCCATTGTTTAGAPAGAATATTCATAGTTTAATTATGCCTTTT TTGATCAGGCACATGGCTCACGCCTGTAATCCTAGCAGTTTGGGAGGCTGAGCCGGGTGGATCGCCTGAG 352 WO 2004/091515 PCT/US2004/011255 GTCAGGAGTTCAAGACAAGCCTGGCCTACATGGTGAAACCCCATCTCTACTAAAAATACACAAATTAGCT AGGCATGGTGGACTCGCCTGTAATCTCACTACACAGGAGGCTGAGGCAGGAGAATCACTTGAACCTGGGA GGCGGATGTTGAAGTGAGCTGAGATTGCACCACTGCACTCCAGTCTGGGTGAGAGTGAGACTCAGTCTTA AAAAAATATGCCTTTTTGAAGCACGTACATTTTGTAACAAAGAACTGAAGCTCTTATTATATTATTAGTT 5 TTGATTTAATGTTTTCAGCCCATCTCCTTTCATATTTCTGGGAGACAGAAAACATGTTTCCCTACACCTC TTGCTTCCATCCTCAACACCCAACTGTCTCGATGCAATGAACACTTAATAAAAAACAGTCGATTGGTCAA AA AGAATTC (SEQ ID NO:6693) 10 gilI339549|gbjM19154-11HUMTGFB2A Human transforming growth factor-beta-2 mRNA, complete cds GCCCCTCCCGTCAGTTCGCCAGCTGCCAGCCCCGGGACCTTTTCATCTCTTCCCTTTTGGCCGGAGGAGC CGAGTTCAGATCCGCCACTCCGCACCCGAGACTGACACACTGAACTCCACTTCCTCCTCTTAAATTTATT TCTACTTAATAGCCACTCGTCTCTTTTTTTCCCCATCTCATTGCTCCAAGAATTTTTTTCTTCTTACTCG 15 CCAAAGTCAGGGTTCCCTCTGCCCGTCCCGTATTAATATTTCCACTTTTGGAACTACTGGCCTTTTCTTT TTAAAGGAATTCAAGCAGGATACGTTTTTCTGTTGGGCATTGACTAGATTGTTTGCAAAAGTTTCGCATC AAAAACAACAACAACAAAAAACCAAACAACTCTCCTTGATCTATACTTTGAGAATTGTTGATTTCTTTTT TTTATTCTGACTTTTAAAAACAACTTTTTTTTCCACTTTTTTAAAAAATGCACTACTGTGTGCTGAGCGC TTTTCTGATCCTGCATCTGGTCACGGTCGCGCTCAGCCTGTCTACCTGCAGCACACTCGATATGGACCAG 20 TTCATGCGCAAGAGGATCGAGGCGATCCGCGGGCAGATCCTGAGCAAGCTGAAGCTCACCAGTCCCCCAG AAGACTATCCTGAGCCCGAGGAAGTCCCCCCGGAGGTGATTTCCATCTACAACAGCACCAGGGACTTGCT CCAGGAGAAGGCGAGCCGGAGGGCGGCCGCCTGCGAGCGCGAGAGGAGCGACGAAGAGTACTACGCCAAG GAGGTTTACAAAATAGACATGCCGCCCTTCTTCCCCTCCGAAACTGTCTGCCCAGTTGTTACAACACCCT CTGGCTCAGTGGGCAGCTTGTGCTCCAGACAGTCCCAGGTGCTCTGTGGGTACCTTGATGCCATCCCGCC 25 CACTTTCTACAGACCCTACTTCAGAATTGTTCGATTTGACGTCTCAGCAATGGAGAAGAATGCTTCCAAT TTGGTGAAAGCAGAGTTCAGAGTCTTTCGTTTGCAGAACCCAAAAGCCAGAGTGCCTGAACAACGGATTG AGCTATATCAGATTCTCAAGTCCAAAGATTTAACATCTCCAACCCAGCGCTACATCGACAGCAAAGTTGT GAAAACAAGAGCAGAAGGCGAATGGCTCTCCTTCGATGTAACTGATGCTGTTCATGAATGGCTTCACCAT AAAGACAGGAACCTGGGATTTAAAATAAGCTTACACTGTCCCTGCTGCACTTTTGTACCATCTAATAATT 30 ACATCATCCCAAATAAAAGTGAAGAACTAGAAGCAAGATTTGCAGGTATTGATGGCACCTCCACATATAC CAGTGGTGATCAGAAAACTATAAAGTCCACTAGGAAAAAAAACAGTGGGAAGACCCCACATCTCCTGCTA ATGTTATTGCCCTCCTACAGACTTGAGTCACAACAGACCAACCGGCGGAAGAAGCGTGCTTTGGATGCGG CCTATTGCTTTAGAAATGTGCAGGATAATTGCTGCCTACGTCCACTTTACATTGATTTCAAGAGGGATCT AGGGTGGAAATGGATACACGAACCCAAAGGGTACAATGCCAACTTCTGTGCTGGAGCATGCCCGTATTTA' 35 TGGAGTTCAGACACTCAGCACAGCAGGGTCCTGAGCTTATATAATACCATAAATCCAGAAGCATCTGCTT CTCCTTGCTGCGTGTCCCAAGATTTAGAACCTCTAACCATTCTCTACTACATTGGCAAAACACCCAAGAT TGAACAGCTTTCTAATATGATTGTAAAGTCTTGCAAATGCAGCTAAAATTCTTGGAAAAGTGGCAAGACC AAAATGACAATGATGATGATAATGATGATGACGACGACAACGATGATGCTTGTAACAAGAAAACATAAGA GAGCCTTGGTTCATCAGTGTTAAAAAATTTTTGAAAAGGCGGTACTAGTTCAGACACTTTGGAAGTTTGT 40 GTTCTGTTTGTTAAAACTGGCATCTGACACAAAAAAAGTTGAAGGCCTTATTCTACATTTCACCTACTTT GTAAGTGAGAGAGACAAGAAGCAAATTTTTTTTAAAGAAAAAAATAAACACTGGAAGAATTTATTAGTGT TAATTATGTGAACAACGACAACAACAACAACAACAACAAACAGGAAAATCCCATTAAGTGGAGTTGCTGT ACGTACCGTTCCTATCCCGCGCCTCACTTGATTTTTCTGTATTGCTATGCAATAGGCACCCTTCCCATTC TTACTCTTAGAGTTAACAGTGAGTTATTTATTGTGTGTTACTATATAATGAACGTTTCATTGCCCTTGGA 45 AAATAAAACAGGTGTATAAAGTGGAGACCAAATACTTTGCCAGAAACTCATGGATGGCTTAAGGAACTTG AACTCAAACGAGCCAGAAAAAAAGAGGTCATATTAATGGGATGAAAACCCAAGTGAGTTATTATATGACC GAGAAAGTCTGCATTAAGATAAAGACCCTGAAAACACATGTTATGTATCAGCTGCCTAAGGAAGCTTCTT GTAAGGTCCAAAAACTAAAAAGACTGTTAATAAAAGAAACTTTCAGTCAG (SEQ ID NO:6694) 50 gilB66241gbIJ04111.1|HUMJUNA Human c-jun proto oncogene (JUN), complete cds, clone hCJ-1 CCCGGGGAGGGGACCGGGGAACAGAGGGCCGAGAGGCGTGCGGCAGGGGGGAGGGTAGGAGAAAGAAGGG CCCGACTGTAGGAGGGCAGCGGAGCATTACCTCATCCCGTGAGCCTCCGCGGGCCCAGAGAAGAATCTTC 353 WO 2004/091515 PCT/US2004/011255 TAGGGTGGAGTCTCCATGGTGACGGGCGGGCCCGCCCCCCTGAGAGCGACGCGAGCCAATGGGAAGGCCT TGGGGTGACATCATGGGCTATTTTTAGGGGTTGACTGGTAGCAGATAAGTGTTGAGCTCGGGCTGGATAA GGGCTCAGAGTTGCACTGAGTGTGGCTGAAGCAGCGAGGCGGGAGTGGAGGTGCGCGGAGTCAGGCAGAC AGACAGACACAGCCAGCCAGCCAGGTCGGCAGTATAGTCCGAACTGCAAATCTTATTTTCTTTTCACCTT 5 CTCTCTAACTGCCCAGAGCTAGCGCCTGTGGCTCCCGGGCTGGTGGTTCGGGAGTGTCCAGAGAGCCTTG TCTCCAGCCGGCCCCGGGAGGAGAGCCCTGCTGCCCAGGCGCTGTTGACAGCGGCGGAAAGCAGCOGTAC CCCACGCGCCCGCCGGGGGACGTCGGCGAGCGGCTGCAGCAGCAAAGAACTTTCCCGGCGGGGAGGACCG GAGACAAGTGGCAGAGTCCCGGAGCGAACTTTTGCAAGCCTTTCCTGCGTCTTAGGCTTCTCCACGGCGG TAAAGACCAGAAGGCGGCGGAGAGCCACGCAAGAGAAGAAGGACGTGCGCTCAGCTTCGCTCGCACCGGT 10 TGTTGAACTTGGGCGAGCGCGAGCCGCGGCTGCCGGGCGCCCCCTCCCCCTAGCAGCGGAGGAGGGGACA AGTCGTCGGAGTCCGGGCGGCCAAGACCCGCCGCCGGCCGGCCACTGCAGGGTCCGCACTGATCCGCTCC GCGGGGAGAGCCGCTGCTCTGGGAAGTGAGTTCGCCTGCGGACTCCGAGGAACCGCTGCGCCCGAAGAGC GCTCAGTGAGTGACCGCGACTTTTCAAAGCCGGGTAGCGCGCGCGAGTCGACAAGTAAGAGTGCGGGAGG CATCTTAATTAACCCTGCGCTCCCTGGAGCGAGCTGGTGAGGAGGGCGCAGCGGGGACGACAGCCAGCGG 15 GTGCGTGCGCTCTTAGAGAAACTTTCCCTGTCAAAGGCTCCGGGGGGCGCGGGTGTCCCCCGCTTGCCAG AGCCCTGTTGCGGCCCCGAAACTTGTGCGCGCACGCCAAACTAACCTCACGTGAAGTGACGGACTGTTCT ATGACTGCAAAGATGGAAACGACCTTCTATGACGATGCCCTCAACGCCTCGTTCCTCCCGTCCGAGAGCG GACCTTATGGCTACAGTAACCCCAAGATCCTGAAACAGAGCATGACCCTGAACCTGGCCGACCCAGTGGG GAGCCTGAAGCCGCACCTCCGCGCCAAGAACTCGGACCTCCTCACCTCGCCCGACGTGGGGCTGCTCAAG 20 CTGGCGTCGCCCGAGCTGGAGCGCCTGATAATCCAGTCCAGCAACGGGCACATCACCACCACGCCGACCC CCACCCAGTTCCTGTGCCCCAAGAACGTGACAGATGAGCAGGAGGGGTTCGCCGAGGGCTTCGTGCGCGC CCTGGCCGAACTGCACAGCCAGAACACGCTGCCCAGCGTCACGTCGGCGGCGCAGCCGGTCAACGGGGCA GGCATGGTGGCTCCCGCGGTAGCCTCGGTGGCAGGGGGCAGCGGCAGCGGCGGCTTCAGCGCCAGCCTGC ACAGCGAGCCGCCGGTCTACGCAAACCTCAGCAACTTCAACCCAGGCGCGCTGAGCAGCGGCGGCGGGGC 25 GCCCTCCTACGGCGCGGCCGGCCTGGCCTTTCCCGCGCAACCCCAGCAGCAGCAGCAGCCGCCGCACCAC CTGCCCCAGCAGATGCCCGTGCAGCACCCGCGGCTGCAGGCCCTGAAGGAGGAGCCTCAGACAGTGCCCG AGATGCCCGGCGAGACACCGCCCCTGTCCCCCATCGACATGGAGTCCCAGGAGCGGATCAAGGCGGAGAG GAAGCGCATGAGGAACCGCATCGCTGCCTCCAAGTGCCGAAAAAGGAAGCTGGAGAGAATCGCCCGGCTG GAGGAAAAAGTGAAAACCTTGAAAGCTCAGAACTCGGAGCTGGCGTCCACGGCCAACATGCTCAGGGAAC 30 AGGTGGCACAGCTTAAACAGAAAGTCATGAACCACGTTAACAGTGGGTGCCAACTCATGCTAACGCAGCA GTTGCAAACATTTTGAAGAGAGACCGTCGGGGGCTGAGGGGCAACGAAGAAAAAAAATAACACAGAGAGA CAGACTTGAGAACTTGACAAGTTGCGACGGAGAGAAAAAAGAAGTGTCCGAGAACTAAAGCCAAGGGTAT CCAAGTTGGACTGGGTTCGGTCTGACGGCGCCCCCAGTGTGCACGAGTGGGAAGGACTTGGTCGCGCCCT CCCTTGGCGTGGAGCCAGGGAGCGGCCGCCTGCGGGCTGCCCCGCTTTGCGGACGGGCTGTCCCCGCGCG 35 AACGGAACGTTGGACTTTCGTTAACATTGACCAAGAACTGCATGGACCTAACATTCGATCTCATTCAGTA

TTAAAGGGGGGAGGGGGAGGGGGTTACAAACTGCAATAGAGACTGTAGATTGCTTCTGTAGTACTCCTTA

AGAACACAAAGCGGGGGGAGGGTTGGGGAGOGGCGGCAGGAGGGAGGTTTGTGAGAGCGAGGCTGAGCCT ACAGATGAACTCTTTCTGGCCTGCTTTCGTTAACTGTGTATGTACATATATATATTTTTTAATTTGATTA AAGCTGATTACTGTCAATAAACAGCTTCATGCCTTTGTAAGTTATTTCTTGTTTGTTTGTTTGGGTATCC 40 TGCCCAGTGTTGTTTGTAAATAAGATTTGGAGCACTCTGAGTTTACCATTTGTAATAAAGTATATAAT TTTTTTATGTTTTGTTTCTGAAAATTCCAGAAAGGATATTTAAGAAAATACAATAAACTATTGGAAAGTA CTCCCCTAACCTCTTTTCTGCATCATCTGTAGATCCTAGTCTATCTAGGTGGAGTTGAAAGAGTTAAGAA TGCTCGATAAAATCACTCTCAGTGCTTCTTACTATTAAGCAGTAAAAACTGTTCTCTATTAGACTTAGAA ATAAATGTACCTGATGTACCTGATGCTATGTCAGGCTTCATACTCCACGCTCCCCCAGCGTATCTATATG 45 GAATTGCTTACCAAAGGCTAGTGCGATGTTTCAGGAGGCTGGAGGAAGGGGGGTTGCAGTGGAGAGGGAC AGCCCACTGAGAAGTCAAACATTTCAAAGTTTGGATTGCATCAAGTGGCATGTGCTGTGACCATTTATAA TGTTAGAAATTTTACAATAGGTGCTTATTCTCAAAGCAGGAATTGGTGGCAGATTTTACAAAAGATGTAT CCTTCCAATTTGGAATCTTCTCTTTGACAATTCCTAGATAAAAAGATGGCCTTTGTCTTATGAATATTTA TAACAGCATTCTGTCACAATAAATGTATTCAAATACCAATAACAGATCTTGAATTGCTTCCCTTTACTAC 50 TTTTTTGTTCCCAAGTTATATACTGAAGTTTTTATTTTTAGTTGCTGAGGTT (SEQ ID NO:6695) gil1799821gbIM57729.1 HUMCCC5 Human complement component CS mRNA, complete cds CTACCTCCAACCATGGGCCTTTTGGGAATACTTTGTTTTTTAATCTTCCTGGGGAAAACCTGGGGACAGG 55 AGCAAACATATGTCATTTCAGCACCAAAAATATTCCGTGTTGGAGCATCTGAAAATATTGTGATTCAAGT TTATGGATACACTGAAGCATTTGATGCAACAATCTCTATTAAAAGTTATCCTGATAAAAAATTTAGTTAC 354 WO 2004/091515 PCT/US2004/011255 TCCTCAGGCCATGTTCATTTATCCTCAGAGAATAAATTCCAAAACTCTGCATCTTAAATACAACCAA AACAATTGCCTGGAGGACAAAACCCAGTTTCTTATGTGTATTTGGAAGTTGTATCAAAGCATTTTTCAAA ATCAAAAAGAATGCCAATAACCTATGACAATCGATTTCTCTTCATTCATACAGACAAACCTGTTTATACT CCAGACCAGTCAGTAAGTTAGAGTTTATTCGTTGATGACGACTTGAGCCAGCCAAGAGAAACTG 5 TCTTAACCTTCATAGATCCTGAAGGATCAGAGTTGACATGGTAGAGAATTGATCATATTGGATTAT CTCTTTTCCTGACTTCAAGATTCCGTCTAATCCTAGATATGGTATGTGGACGATCAAGGCTAAATATAALA GAGGACTTTTCAACAACTGGAACCGCATATTTTGAAGTTAA-AGAATATGTCTTGCCACATTTTTCTGTCT CATGGCGAAATTATGTCAA.TTAATTGATATTAACA ATATTTTTATAATAAAGTAGTCACTGAGGCTGACGTTTATATCACATTTGGAATAGAGAAGACTTAAAA 10 GATGATCAAAAGAATGATGCAACAGCATGCA.AACACAATGTTGATAATGGATTGCTCA4GTCA CATTTGATTCTGAAACAGCAGTCAAAGAACTGTCATACTACAGTTTAGAAGATTTAACAACAAGTACCT TTATATTGCTGTAACAGTCATAGAGTCTACAGGTGGATTTTCTGAAGAGGCAGAAATACCTGGCATCAAA TATGTCCTCTCTCCCTACAAACTGAALTTTGGTTGCTACTCCTCTTTTCCTGAAGCCTGGGATTCCATATC CCATCAGGTGCAGGTTAAAGATTCGCTTGACCAGTTGGTAGGAGGAGTCCCAGTAATACTGAATGCACA 15 AACAATTGATGTAAACCAAG1AGACATCTGACTTGGATCCAAGCAAAAGTGTAACACGTGTTGATGATGGA GTAGCTTCCTTTGTGCTTAATCTCCCATCTGGAGTGACGGTGCTGGAGTTTAATGTCAAACTGATGCTC CAGATCTTCCAGAAGAAAATCAGGCCAGGGAAGGTTACCGAGCAATAGCATACTCATCTCTCAGCCAAAG TTACCTTTATATTGATTGGACTGATAXCCATAAGGCTTTGCTAGTGGGAGAACATCTGAATATTATTGTT ACCCCCAAJAAGCCCATATATTGACAAAATAACTCACTATAATTACTTGATTTTATCCAAGGGCAAATTA 20 TCCATTTTGGCACGAGGGAGAAATTTTCAGATGCATCTTATCAAAGTATAAACATTCCAGTAACACAGAA CATGGTTCCTTCATCCCGACTTCTGGTCTATTATATCGTCACAGGAGAACAGACAGCAGAATTAGTGTCT GATTCAGTCTGGTTAAATATTGAAGAAAAATGTGGCAACCAGCTCCAGGTTCATCTGTCTCCTGATGCAG ATGCATATTCTCCAGGCCAAACTGTGTCTCTTAATATGGCAACTGGAATGGATTCCTGGGTGGCATTAGC AGCAGTGGACAGTGCTGTGTATGGAGTCCAAGAGGAGCCAAAAGCCCTTGGAAAGAGTATTTCATTC 25 TTAGAGAAGAGTGATCTGGGCTGTGGGGCAGGTGGTGGCCTCAACAATGCCAATGTGTTCCACCTAGCTG GACTTACCTTCCTCACTAhATGCAAATGCAGATGACTCCCAAGAAAATGATGAACCTTGTAAAGAAATTCT CAGGCCAAGAAGAACGCTG AAAGTGAAAACTGCTAAATATAAACATTCAGTAGTGAAG AAATGTTGTTACGATGGAGCCTGCGTTAATAATGATGAAACCTGTGAGCAGCGAGCTGCACGGATTAGTT TAGGGCCAZGATGCATCAAAGCTTTCACTGAATGTTGTGTCGTCGCAAGCCAGCTCCGTGCTAATATCTC 30 TCATAAAGACATGCAATTGGGAAGGCTACACATGAA GACCCTGTTACCAGTAAGCAAGCCAGAAATTCGG AGTTATTTTCCAGAAAGCTGGTTGTGGGAAGTTCATCTTGTTCCCAGAAGAAAACAGTTGCAGTTTGCCC TACCTGATTCTCTAACCACCTGGGAAATTCAAGGCATTGGCATTTCAALACACTGGTATATGTGTTGCTGA TACTGTCAAGGCAAAGGTGTTCAAAGATGTCTTCCTGGAAATGAATATACCATATTCTGTTGTACGAGGA GAACAGATCCAATTGAAAGGAACTGTTTACAACTATAGGACTTCTGGGATGCAGTTCTGTGTTAAAATGT 35 CTGCTGTGGAGGGAATCTGCACTTCGGAAAGCCCAGTCATTGATCATCAGGGCACAAAGTCCTCCAAATG TGTGCGCCAGAAAGTAGAGGGCTCCTCCAGTCACTTGGTGACATTCACTGTGCTTCCTCTGGAAATTGGC CTTCACAACATCAATTTTTCACTGGAGACTTGGTTTGGAAAAGAAATCTTAGTAAALAACATTACGAGTGG TGCCAGAAGGTGTCAAAAGGGAAAGCTATTCTGGTGTTACTTTGGATCCTAGGGGTATTTATGGTACCAT TAGCAGACGAAAGGAGTTCCCATACAGGATACCCTTAGATTTGGTCCCCAAAACAGAAATCA.AAAGGATT 40 TTGAGTGTAAAAGGACTGCTTGTAGGTGAGATCTTGTCTGCAGTTCTAAGTCAGGAAGGCATCAATATCC TAACCCACCTCCCCAAAGGGAGTGCAGAGGCGGAGCTGATGAGCGTTGTCCCAGTATTCTATGTTTTTCA CTACCTGGA2 ACAGGAAATCATTGGAACATTTTTCATTCTGACCCATTAATTGAAAAGCAGAAACTGAAG A-A-AAATTAAAAGAAGGGATGTTGAGCATTATGTCCTACAGAAATGCTGACTACTCTTACAGTGTGTGGA AGGGTGGAAGTGCTAGCACTTGGTTAACAGCTTTTGCTTTAAGAGTACTTGGACAAGTAALATAAATACGT 45 AGAGCAGAACCAAPJ\TTCAATTTGTAATTCTTTATTGTGGCTAGTTGAGAATTATCAATTAGATAATGGA TCTTTCAAGGAAAATTCACAGTATCAACCAATAAAATTACAGGGTACCTTGCCTGTTGAAGCCCGAGAGA ACAGCTTATATCTTACAGCCTTTACTGTGATTGGAATTAGAAAGGCTTTCGATATATGCCCCCTGGTGA AATCGACACAGCTCTAATTAAAGCTGACAACTTTCTGCTTGAAAATACACTGCCAGCCCAGAGCACCTTT ACATTGGCCATTTCTGCGTATGCTCTTTCCCTGGGAGATAAAACTCACCCACAGTTTCGTTCAATTGTTT 50 CAGCTTTGAAGAGAGAAGCTTTGGTTAAAGGTAALTCCACCCATTTATCGTTTTTGGAAAGACAATCTTCA GCATAALAGACAGCTCTGTACCTAACACTGGTACGGCACGTATGGTAGAAACAACTGCCTATGCTTTACTC ACCAGTCTGAACTTGAAAGATATAAATTATGTTAACCCAGTCATCAAATGGCTATCAGAAGAGCAGAGGT ATGGAGGTGGCTTTTATTCAACCCAGGACACCATCAATGCCA-TTGAGGGCCTGACGGAATATTCACTCCT GGTTAAACAACTCCGCTTGAGTATGGACATCGATGTTTCTTACAAGCATAAAGGTGCCTTACATAATTAT 55 AAAATGACAGACAAGAATTTCCTTGGGAGGCCAGTAGAGGTGCTTCTCAATGATGACCTCATTGTCAGTA CAGGATTTGGCAGTGGCTTGGCTACAGTACATGTAACAACTGTAGTTCACAALAACCAGTACCTCTGAGGA AGTTTGCAGCTTTTATTTGAAA-ATCGATACTCAGGATATTGAAGCATCCCACTACAGAGGCTACGGAAAC TCTGATTACAALACGCATAGTAGCATGTGCCAGCTACAAGCCCAGCAGGGAAGAATCATCATCTGGATCCT 355 WO 2004/091515 PCT/US2004101 1255 CTCATGCGGTGATGGACATCTCCTTGCCTACTGGAATCAGTGCAAATGAAGAAGACTTAAAAGCCCTTGT GGAAGGGGTGGATCAACTATTCACTGATTACCAAATCAAAGATGGACATGTTATTCTGCAACTGAATTCG ATTCCCTCCAGTGATTTCCTTTGTGTACGATTCCGGATATTTGAACTCTTTGAAGTTGGGTTTCTCAGTC CTGCCACTTTCACAGTTTACGAATACCACAGACCAGATAAACAGTGTACCATGTTTTATAGCACTTCCAA 5 TATCAAAATTCAGAAAGTCTGTGAAGGAGCCGCGTGCAAGTGTGTAGAAGCTGATTGTGGGCAAATGCAG GAAGAATTGGATCTGACAATCTCTGCAGAGACAAGAAAACAAACAGCATGTAALACCAGAGATTGCATATG CTTATAAAGTTAGCATCACATCCATCACTGTAGAAAATGTTTTTGTCAAGTACAAGGCAACCCTTCTGGA TATCTACAAAACTGGGGAAGCTGTTGCTGAGAAAGACTCTGAGATTACCTTCATTAAAAALGGTAACCTGT ACTAACGCTGAGCTGGTAAAAGGAAGACAGTACTTAATTATGGGTAAAGAAGCCCTCCAGATAAAATACA 10 ATTTCAGTTTCAGGTACATCTACCCTTTAGATTCCTTACCTGATTGAATACTGGCCTAGAGACACAAC ATGTTCATCGTGTCAAGCATTTTTAGCTAATTTAGATGAATTTGCCGAAGATATCTTTTTAAATGGATGC TAAAATTCCTGA7AGTTCAGCTGCATACAGTTTGCACTTATGGACTCCTGTTGTTGAAGTTCGTTTTTTTG TTTTCTTCTTTTTTTAAACATTCATAGCTGGTCTTATTTGTAAAGCTCACTTTACTTAGAATTAGTGGCA CTTGCTTTTATTAGAGAATGATTTCAAATGCTGTAACTTTCTGA.AATACATGGCCTTGGAGGGCATGAA 15 GACAGATACTCCTCCAA\GGTTATTGGACACCGGAAACAATAAATTGGAACACCTCCTCAAACCTACCACT CAGGAATGTTTGCTGGGGCCGAAAGAACAGTCCATTGAAAGGGAGTATTACAAAAACATGGCCTTTGCTT GAAAGAA.AATACCAAGGAACAGGAAACTGATCATTAAAGCCTGAGTTTGCTTTC (SEQ ID NO: 6696) 20 gill899441gbiLO5144.1jHUMPHOCAR Homo sapiens (clone lamda-hPEC-3) phosphoenolpyruvate carboxykinase (PCK1) mRNA, complete cds TGGGAACACAAACTTGCTGGCGGGAAGAGCCCGGAAAGAZAACCTGTGGATCTCCCTTCGAGATCATCCAA AGAGAAGAAAGGTGACCTCACATTCGTGCCCCTTAGCAGCACTCTGCAGAAATGCCTCCTCAGCTGCAAA ACGGCCTGAACCTCTCGGCCAAAGTTGTCCAGGGAAGCCTGGACAGCCTGCCCCAGGCAGTGAGGGAGTT 25 TCTCGAGAATAACGCTGAGCTGTGTCAGCCTGATCACATCCACATCTGTGACGGCTCTGAGGAGGAGAA.T GGGCGGCTTCTGGGCCAGATGGAGGAAGAGGGCATCCTCAGGCGGCTGAAGAAGTATGACAACTGCTGGT TGGCTCTCACTGACCCCAGGGATGTGGCCAGGATCGAAAGCAAGACGGTTATCGTCACCCAAGAGCAAAG AGACACAGTGCCCATCCCCAAA-ACAGGCCTCAGCCAGCTCGGTCGCTGGATGTCAGAGGAGGATTTTGAG AAAGCGTTCAATGCCAGGTTCCCAGGGTGCATGAAAGGTCGCACCATGTACGTCATCCCATTCAGCATGG 30 GGCCGCTGGGCTCACCTCTGTCGAAGATCGGCATCGAGCTGACGGATTCGCCCTACGTGGTGGCCAGCAT GCGGATCATGACGCGGATGGGCACGCCCGTCCTGGAAGCACTGGGCGATGGGGAGTTTGTCAAATGCCTC CATTCTGTGGGGTGCCCTCTGCCTTTACAAAAGCCTTTGGTCAACAACTGGCCCTGCAACCCGGAGCTGA CGCTCATCGCCCACCTGCCTGACCGCAGAGAGATCATCTCCTTTGGCAGTGGGTACGGCGGGAACTCGCi GCTCGGGAAGAAGTGCTTTGCTCTCAGGATGGCCAGCCGGCTGGCAGAGGAGGAAGGGTGGCTGGCAGAG 35 CACATGCTGATTCTGGGTATAACCAACCCTGAGGGTGAGAAGAAGTACCTGGCGGCCGCATTTCCCAGCG CCTGCGGGAAGACCAACCTGGCCATGATGAACCCCAGCCTCCCCGGGTGGAAGGTTGAGTGCGTCGGGGA TGACATTGCCTGGATGAAGTTTGACGCACAAGGTCATTTAAGGGCCATCAACCCAGAAAATGGCTTTTTC GGTGTCGCTCCTGGGACTTCAGTGAAGACCAACCCCATGCCATCAAGCCATCCAGAAGAACACAATCT TTACCA ATGTGGCCGAGACCAGCGACGGGGGCGTTTACTGGGAAGGCATTGATGAGCCGCTAGCTTCAGG 40 CGTCACCATCACGTCCTGGAAGAATAAGGAGTGGAGCTCAGAGGATGGGGAACCTTGTGCCCACCCCAAC TCGAOOTTCTGCACCCCTGCCAGCCAGTGCCCCATCATTGATGCTGCCTGGGAGTCTCCGGAAGGTGTTC CCATTGAAGGCATTATCTTTGGAGGCCGTAGACCTGCTGGTGTCCCTCTAGTCTATGAAGCTCTCAGCTG GCAACATGGAGTCTTTGTGGGGGCGGCCATGAGATCAGAGGCCACAGCGGCTGCAGAACATAAAGGCAAA ATCATCATGCATGACCCCTTTGCCATGCGGCCCTTCTTTGGCTACAACTTCGGCAAATACCTGGCCCACT 45 GGCTTAGCATGGCCCAGCACCCAGCAGCCAAACTGCCCAAGATCTTCCATGTCAACTGGTTCCGGAAGGA CAAGGAAGGCAAATTCCTCTGGCCAGGCTTTGGAGAGAACTCCAGGGTGCTGGAGTGGATGTTCAACCGG ATCGATGGAAAAGCCAGCACCAACGTCACGCCCATAGGCTACATCCCCAAGGAGGATGCCCTGAACCTGA AAGGCCTOGGGCACATCAACATOATGGAGCTTTTCAGCATCTCCAAGGAATTCTGGGACAAGGAGGTGGA AGACATCGAGAAGTATCTGGTGGATCAAGTCAATGCCGACCTCCCCTGTGAAATCGAGAGAGAGATCCTT 50 GCCTTGAAGCAAAGAATAAGCCAGATGTAATCAGGGCCTGAGAATAAGCCAGATGTAATCAGGGCCTGAG TGCTTTACCTTTAAAATCATTAAATTAAAATCCATAAGGTGCAGTAGGAGCAAGAGAGGGCAAGTGTTCC CAATTGACGCCACCTAATAATCATCACCACACCGGGAGCAGATCTGAAGGCACACTTTGATTTTTTTAA GGATAAGAACCACAGAACACTGGGTAGTAGCTAATGAAATTGAGAAGGGAAATCTTAGCATGCCTCCAA.A AATTCACATCCAATGCATACTTTGTTCAAATTTAAGGTTACTCAGGCATTGATCTTTTCAGTGTTTTTTC 55 ACTTAGCTATGTGGATTAGCTAGAATGCACACCAAAAAGATACTTGAGCTGTATATATATATGTGTGTGT GTGTGTGTGTGTGTGTGTGTGTGCATGTATGTGCACATGTGTCTGTGTGATATTTGGTATGTGTATTTGT 356 WO 2004/091515 PCT/US200401 1255 ATGTACTGTTATTCAAAATATATTTAATACCTTTGGAAAATCTTGGGCAAGATGACCTACTAGTTTTCCT TGAAAAAAAGTTGCTTTGTTATTAATATTGTGCTTAALATTATTTTTATACACCATTGTTCCTTACCTTTA CATAATTGCAATATTTCCCCCTTACTACTTCTTGGAAAAAAATTAGAAAATGAAGTTTATAGAAAAG (SEQ ID NQ:6697) 5 gij66798921refiNM_008061.11 Mus musculus glucose-6--phosphatase, catalytic (G~pc), mRNA AGCAGAGGGATCGGGGCCAACCGGGCTTGGACTCACTGCACGGGCTCTGCTGGCAGCTTCCTGAGGTACC 10 AAGGGAGGAAGGATGGAGGAAGGAATGAACATTCTCCATGACTTTGGGATCCAGTCGACTCGCTATCTCC AAGTGAATTACCAAGACTCCCAGGACTGGTTCATCCTTGTGTCTGTGATTGCTGACCTGAGGAACGCCTT CTATGTCCTCTTTCCCATCTGGTTCCATCTTAAAGAGACTGTGGGCATCAATCTCCTCTGGGTGGCAGTG GTCGGAGACTGGTTCAACCTCGTCTTCAAGTGGATTCTGTTTGGACAACGCCCGTATTGGTGGGTCCTGG ACACCGACTACTACAGCAACAGCTCCGTGCCTATAATAAAGCAGTTCCCTGTCACCTGTGAGACCGGACC 15 AGGAAGTCCCTCTGGCCATGCCATGGGCGCAGCAGGTGTATACTATGTTATGGTCACTTCTACTCTTGCT ATCTTTCGAGGAAAGAAAAAGCCAACGTATGGATTCCGGTGTTTGA7ACGTCATCTTGTGGTTGGGATTCT GGGCTGTGCAGCTGAACGTCTGTCTGTCCCGGATCTACCTTGCTGCTCACTTTCCCCACCAGGTCGTGGC TGGAGTCTTGTCAGGCATTGCTGTGGCTGAAACTTTCAGCCACATCCGGGGCATCTACAATGCCAGCCTC CGGAAGTATTGTCTCATCACCATCTTCTTGTTTGGTTTCGCGCTTGGATTCTACCTGCTACTAAAAGGGC 20 TAGGGGTGGACCTCCTGTGGACTTTGGAGAAAGCCAAGAGATGGTGTGAGCGGCCAGAATGGGTCCACCT TGACACTACACCCTTTGCCAGCCTCTTCAAAAACCTGGGAACCCTCTTGGGGTTGGGGCTGGCCCTCAAC TCCAGCATGTAzCCGGAAGAGCTGCAAGGGAGAACTCAGCAAGTCGTTCCCATTCCGCTTCGCCTGCATTG TGGCTTCCTTGGTCCTCCTGCATCTCTTTGACTCTCTGAAGCCCCCATCCCAGGTTGAGTTGATCTTCTA CATCTTGTCTTTCTGCAAGAGCGCAACAGTTCCCTTTGCATCTGTCAGTCTTATCCCATACTGCCTAGcC 25 CGGATCCTGGGACAGACACACAAGAAGTCTTTGTAAGGCATGCAGAGTCTTTGGTATTTAAAGTCAACCG CCATG CAAAGGACTAGGAACAACTAAAGCCTCTGAAACCCATTGTGAGG.CCAGAGGTGTTGACATCGGCC CTGGTAGCCCTGTCTTTCTTTGCTATCTTAACCAAAAGGTGAATTTTTACAAAGCTTACAGGGCTGTTTG AGGAAALGTGTGAATGCTGGAAACTGAGTCATTCTGGATGGTTCCCTGAAGATTCGCTTACCAGCCTCCTG TCAGATACAGAALGAGCAAGCCCAGGCTAGAGATCCCAACTGAGAATGCTCTTGCGGTGCAGA.ATCTTCCG 30 GCTGGGAA1AAGGAAAAGAGCACCATGCATTTGCCAGGAAGAGAAAGAAGGATCGGGAGGAGGGAGAGTGT, TTTATGTATCGAGCAAACCAGATGCAATCTATGTCTAACCGGCTTCAGTTGTGTCTGCGTCTTTAGATAC GACACACTCAATAATAATAATAGACCAACTAGTGTAATGAGTAGCCAGTTAAAGGCGATTAATTCTGCTT CCAGATAGTCTCCACTGTACATAAAGTCACACTGTGTGCTTGCATTCCTGTATGTAGTGGTGACTGTC TCTCACACCACCTTCTCTATCACGTCACAGTTTTCTCCTCCTCAGCCTATGTCTGCATTCCCCAGAATTC 35 TCCACTTGTTCCCTGGCCCTGCTGCTGGACCCTGCTGTGTCTGGTAGGCAACTGTTTGTTGGTGCTTTTG TAGGGTTAAGTTAAACTCTGAGATCTTGGGCAAAATGGCAAGGAGACCCAGGATTCTTCTCTCCAAAGGT CACTCCGATGTTATTTTTGATTCCTGGGGCAGAAATATGACTCCTTTCCCTAGCCCAAGCCAGCCAAGAG CTCTCATTCTTAGAAGAAAAGGCAGCCCCTTGGTGCCTGTCCTCCTGCCTCGGCTGATTTGCAGAGTACT TCTTCAAAAAGAAAAAAATGGTAAAGCTATTTATTAAAAATTCTTTGTTTTTTGCTACAAATGATGCATA 40 TATTTTCACCCACACCAAGCACTTTGTTTCTAATATCTTTGATAAGAAALACTACATGTGCAGTATTTTAT TAAAGCAACATTTTATTTA (SEQ ID NO:6698) giJ7llO6821refINM_-011044.11 Mus musculus phasphoenolpyruvate carboxykinase 1 45 cytosolic (Pcki), mRNA ACAGTTGGCCTTCCCTCTGGGAACACACCCTCGGTCAACAGGGGAAATCCGGCAAGGCGCTCAGCGATCT CTGATCCAGACCTTCCAAAAGGAAGAAAGGTGGCACCAGAGTTCCTGCCTCTCTCCACACCATTGCAATT ATGCCTCCTCAGCTGCATAACGGTCTGGACTTCTCTGCCAAGGTTATCCAGGGCAGCCTCGACAGCCTGC CCCAGGCAGTGAGGAAGTTCGTGGAAGGCAATGCTCAGCTGTGCCAGCCGGAGTATATCCACATCTGCGA 50 TGGCTCCGAGGAGGAGTACGGGCAGTTGCTGGCCCACATGCAGGAGGAGGGTGTCATCCGCAAGCTGAAG AAATATGACAACTGTTGGCTGGCTCTCACTGACCCTCGAGATGTGGCCAGGATCGAAAGCAAGACAGTCA TCATCACCCAAGAGCAGAGAGACACAGTGCCCATCCCCAAAACTGGCCTCAGCCAGCTGGGCCGCTGGAT GTCGGAAGAGGACTTTGAGAAAGCATTCAACGCCAGGTTCCCAGGGTGCATGAAAGGCCGCACCATGTAT GTCATCCCATTCAGCATGGGGCCACTGGGCTCGCCGCTGGCCAAGATTGGTATTGAACTGACAGACTCGC 357 WO 2004/091515 PCT/US2004/011255 CCTATGTGGTGGCCAGCATGCGGATCATGACTCGGATGGGCATATCTGTGCTGGAGGCCCTGGGAGATGG GGAGTTCATCAAGTGCCTGCACTCTGTGGGGTGCCCTCTCCCCTTAAAAAAGCCTTTGGTCAACAACTGG GCCTGCAACCCTGAGCTGACCCTGATCGCCCACCTCCCGGACCGCAGAGAGATCATCTCCTTTGGAAGCG GATATGGTGGGAACTCACTACTCGGGAAGAAATGCTTTGCGTTGCGGATCGCCAGCCGTCTGGCTAAGGA 5 GGAAGGGTGGCTGGCGGAGCATATGCTGATCCTGGGCATZAACTAACCCCGAAGGCAAGAAGAAATACCTG GCCGCAGCCTTCCCTAGTGCCTGTGGGAAGACTAACTTGGCCATGATGAACCCCAGCCTGCCCGGGTGGA AGGTCGAATGTGTGGGCGATGACATTGCCTGGATGAAGTTTGATGCCCAAGGCAACTTAAGGGCTATCAA CCCAGAAAACGGGTTTTTTGGAGTTGCTCCTGGCACCTCAGTGAAGACAAATCCAALATGCCATTAAALACC ATCCAGAAAAACACCATCTTCACCAACGTGGCCGAGACTAGCGATGGGGGTGTTTACTGGGAAGGCATCG 10 ATGAGCCGCTGGCCCCGGGAGTCACCATCACCTCCTGGAAGACAAGGAGTGGAGACCGCAGGACGCGGA ACCATGTGCCCATCCCAACTCGAGATTCTGCACCCCTGCCAGCCAGTGCCCCATTATTGACCCTGCCTGG GAATCTCCAGAAGGAGTACCCATTGAGGGTATCATCTTTGGTGGCCGTAGACCTGAAGGTGTCCCCCTTG TCTATGAAGCCCTCAGCTGGCAGCATGGGGTGTTTGTAGGAGCAGCCATGAGATCTGAGGCCACAGCTGC TGCAGAACACAAGGGCAAGATCATCATGCACGACCCCTTTGCCATGCGACCCTTCTTCGGCTACAACTTC 15 GGCAAATACCTGGCCCACTGGCTGAGCATGGCCCACCGCCCAGCAGCCAAGTTGCCCAAGATCTTCCATG TCAACTGGTTCCGGAAGGACAAAGATGGCAAGTTCCTCTGGCCAGGCTTTGGCGAGAACTCCCGGGTGCT GGAGTGGATGTTCGGGCGGATTGAAGGGGAAGACAGCGCCAAGCTCACGCCCATCGGCTACATCCCTAAG GAAAACGCCTTGAACCTGAAAGGCCTGGGGGGCGTCAACGTGGAGGAGCTGTTTGGGATCTCTAAGGAGT TCTGGGAGAAGGAGGTGGAGGAGATCGACAGGTATCTGGAGGACCAGGTCAACACCGACCTCCCTTACGA 20 AATTGAGAGGGAGCTCCGAGCCCTGAAACAGAGAATCAGCCAGATGTAAATCCC4ATGGGGGCGTCTCGA GAOTCACCCCTTCCCACTCACAGCATCGCTGAGATCTAGGAGAAAGCCAGCCTGCTCCAGCTTTGAGATA GCGGCACAATCGTGAGTAGATCAGAAAAGCACCTTTTAATAGTCAGTTGAGTAGCACAGAGAACAGGCTA GGGGCAAATAAGATTGGGAGGGGAAATCACCGCATAGTCTCTGAAGTTTGCATTTGACACCAATGGGGGT TTTGGTTCCACTTCAAGGTCACTCAGGAATCCAGTTCTTCACGTTAGCTGTAGCAGTTAGCTAAAATGCA 25 CAGAAAACATACTTGAGCTGTATATATGTGTGTGAACGTGTCTCTGTGTGAGCATGTGTGTGTGTGTGTG TGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTACATGCCTGTCTGTCCCATTGTCCACAGTATATTTAA AACCTTTGGGGAAAAATCTTGGGCAAATTTGTAGCTGTAACTAGAGAGTCATGTTGCTTTGTTGCTAGTA TGTATGTTTAAATTATTTTTATACACCGCCCTTACCTTTCTTTACATAATTGAAATTGGTATCCGGACCA CTTCTTGGGAAAAAAATTACAAAATAAA (SEQ ID NO:6699) 30 358 WO 2004/091515 PCT/US2004/011255 Example 5. siRNAs decrease mRNA levels in vivo Male CMV-Luc mice (8- 10 weeks old) from Xenogen (Cranbury, NJ) were administered cholesterol conjugated siRNA (see Table 17). 5 Table 17. Solutions adminstered to mice Group N Injection Mix 1 7 Buffer (PBS [pH 7.4]) Cholesterol conjugated siRNA 2 8 (ALN-3001) Table 18. Test iRNA agents targeting Luciferase siRNA Seguence 5'-GAA CUG UGU GUG AGA GGU CCU-3' (SEQ ID NO:5277) ALN-1070 3'-CG CUUT GAC ACA CAC UCU CCA GGA-5' (SEQ ID NO:5278) 5'-GAA CUG UGU GUG AGA GGU CCU-GS-3' (SEQ ID NO:5279) ALN-1000 3'-CG CUU GAC ACA CAC UCU CCA GGA-5' (SEQ ID NO:5280) 5'-GAA CUG UGU GUG AGA GGU CCU-3' (SEQ ID NO:5281) ALN-3000 3'-Cs 1 Gs' CUU GAC ACA CAC UCU CCA GGA-5' (SEQ ID NO:5282) 5'-GAA CUG UGU GUG AGA GGU CCU-chol.

2 -3' (SEQ ID NO:5283) ALN-3001 3'-Cs'Gs 1 CUU GAC ACA CAC UCU CCA GGA-5' (SEQ ID NO:5284) 2' O-Me group is attached to the nucleotide and the nucleotides have phosphorothioate linkages (indicated by 10 "s") 2 cholesterol is conjugated to the antisense strand via the linker: U-pyrroline carrier-C(O)-(CH 2

)

5

-NHC(O)

cholesterol (via cholesterol C-3 hydroxyl). Animals were injected (tail vein) with a volume of 200-250 [l test solution containing buffer 15 or an siRNA solution. Group 1 received buffer and group 2 received cholesterol conjugated siRNA (ALN-3001) at a dose of 50 mg/kg body weight. Twenty-two hours after injection, animals were sacrificed and livers collected. Organs were snap frozen on dry ice, then pulverized in a mortar and pestle. For Luciferase mRNA analysis (by the QuantiGene Assay (Genospectra, Inc.; Fremont, 20 CA)), approximately 10 mg of tissue powder was resuspended in tissue lysis buffer, and processed according to the manufacturer's protocol. Samples of the lysate were hybridized with probes specific for Luciferase or GAPDH (designed using ProbeDesigner software (Genospectra, Inc., Fremont, CA) in triplicate, and processed for luminometric analysis. Values for Luciferase were normalized to GAPDH. Mean values were plotted with error bars corresponding to the standard 25 deviation of the Luciferase measurements. 359 WO 2004/091515 PCT/US2004/011255 Results indicated that the level of luciferase RNA in animals injected with cholesterol conjugated siRNA was reduced by about 70% as compared to animals injected with buffer (see FIGs. 8A and 8B). 5 In Vitro Activity HeLa cells expressing luciferase were transfected with each of the siRNAs listed in Table 18. ALN-1000 siRNAs were most effective at decreasing luciferase mRNA levels (~0.6 nM siRNA decreased mRNA levels to about -65% the original expression level, and 1.0 nM siRNA decreased levels to about ~20% the original expression level); ALN-3001 siRNAs were least effective 10 (-0.6 nM siRNA had a negligible effect on mRNA levels, and 1.0 nM siRNA decreased levels to about -40% the original expression level). Pharmacokinetics/Biodistribution Pharmacokinetic analyses were performed in mice and rats. Test siRNA molecules were 15 radioactively labeled with 3 3 P on the antisense strand by splint ligation. Labeled siRNAs (50mg/kg) were administered by tail vein injection, and plasma levels of siRNA were measured periodically over 24 hrs by scintillation counting. Cholesterol conjugated siRNA (ALN-3001) was discovered to circulate in mouse plasma for a longer period of time than unconjugated siRNA (ALN-3000) (FIG. 9). RNAse protection assays indicated that cholesterol-conjugated siRNA (ALN-3001) was 20 detectable in mouse plasma 12 hours after injection, whereas unconjugated siRNA (ALN-3000) was not detectable in mouse plasma within two hours after injection. Similar results were observed in rats. Mouse liver was harvested at varying time points (ranging from 0.08-24 hours) following injection with siRNA, and siRNA localized to the liver was quantified. Over the time period tested, 25 the amount of cholesterol-conjugated siRNA (ALN-3001) detected in the liver ranged from 14.3 3.55 percent of the total dose administered to the mouse. The amount of unconjugated siRNA (ALN-3000) detected in the liver was lower, ranging from 3.91-1.75 percent of the total dose administered (FIG. 10). 30 Detection of siRNA in Different Tissues Various tissues and organs (fat, heart, kidney, liver, and spleen) were harvested from two CMV-Luc mice 22 hours following injection with 50 mg/kg ALN-3001. The antisense strand of the 360 WO 2004/091515 PCT/US2004/011255 siRNA was detected by RNAse protection assay. The liver contained the greatest concentration of siRNA (-8-10 pg siRNA/g tissue); the spleen, heart and kidney contained lesser amounts of siRNA (-2-7 pg siRNA/g tissue); and fat tissue contained the least amount of siRNA (<- pg siRNA/g tissue) (FIG. 11). 5 Glucose-6-phosphatase siRNA detection by RNAse Protection Assay Balbc mice were injected with U/U, 3'C/U, or 3' C/3' C siRNA (4 mg/kg) targeting glucose-6-phosphatase (G6Pase) (see Table 19). Administration was by hydrodynamic tail vein injection (hd) or non-hydrodynamic tail vein injection (iv), and siRNA was subsequently detected in 10 the liver by RNAse protection assay. Table 19. Test iRNA agents targeting glucose-6-phosphatase siRNA Description U/U No cholesterol; dinucleotide 3' overhangs on sense and antisense strands dinucleotide 3' overhangs on sense and antisense strands; cholesterol 3'C/U conjugated to 3' end of sense strand (mono-conjugate) dinucleotide 3' overhangs on sense and antisense strands; cholesterol 3'C/3'C conjugated to 3' end of both sense and antisense strands (bis-conjugate) 15 Unconjugated siRNA (U/U) delivered by hd was detected by 15 min. post-injection (the earliest determined time-point) and was still detectable in the liver 18 hours post-injection (FIG. 12). Delivery by normal iv administration resulted in the greatest concentration of 3'C/3'C siRNA (the bis-cholesterol-conjugate) in the liver 1 hour post injection (as compared to the mono cholesterol-conjugate 3'C/3'U siRNA). At 18 hours post injection, 3'C/3'C siRNAs and 3'C/U 20 siRNA were still detectable in the liver with the bis-conjugate at higher levels compared to the mono-conjugate (FIG. 13). Example 6. siRNAs decrease protein activity levels in vivo Male CMV-Luc mice were bred by Charles River Laboratories, Inc. (Wilmington, MA). 25 Mice (6-7 weeks old) were administered cholesterol conjugated siRNA (see Tables 20-22). 361 WO 2004/091515 PCT/US2004/011255 Table 20. Test groups for in vivo siRNA assays-experiment 1 Group N Injection Mix 1 10 Buffer (PBS [pH 7.4]) Cholesterol conjugated siRNA 2 11 (ALN-3001) Table 21. Test groups for in vivo siRNA assays-experiment 2 Group N Injection Mix 1 8 Buffer (PBS [pH 7.4]) Cholesterol conjugated siRNA 2 8 (ALN-3001) 5 Table 22. Test groups for in vivo siRNA assays-experiment 3 Group N Iniection Mix 1 8 Buffer (PBS [pH 7.4]) Cholesterol conjugated siRNA 2 8 (ALN-3001) Animals were injected (tail vein) with a volume of 200-250 L test solution containing buffer 10 or an siRNA solution. Group 1 received buffer and group 2 received cholesterol conjugated siRNA (ALN-3001) at a dose of 75 mg/kg body weight. Nineteen to 22 hours after injection, animals were sacrificed and livers collected. Organs were snap frozen on dry ice, then pulverized in a mortar and pestle. For Luciferase activity analysis, approximately 50 mg of tissue powder was resuspended in 15 0.5 ml Cell Lysis Buffer (Promega, Inc.). Samples were vortexed vigorously for three minutes, snap frozen in liquid nitrogen, then thawed in a 37 degree water bath. This process was repeated twice more. After the final thaw, samples were vortexed for three minutes. Insoluble material was removed by centrifugation in a microcentrifuge (4 degrees) at full speed for four minutes. Supernatants were collected. Twenty to 25 microliters of each sample were pipetted into assay tubes 20 in triplicate, and allowed to come to room temperature. For activity measurements, a luminometer (Berthold, Inc.) was programmed to deliver 200 microliters of "Bright Glow" assay reagent (Promega, Inc.) to the test sample, and record light emission over a ten second period. To measure total protein, samples of supernatant were diluted thirty fold, and five microliter samples were measured in triplicate in a Bradford protein microassay (Bio-Rad). Bovine 25 Serum Albumin was used to generate a standard curve. 362 Luciferase activity was determined as the mean of the luminometry reading normalized to mean protein content. Mean normalized values were then calculated for the buffer and siRNA treated groups in each experiment. For each experiment, the normalized Luc level of the siRNA treated group is expressed as a percentage of the buffer control (which was set to 100%). Error bars 5 indicate standard deviations. Results indicated that the level of luciferase activity in animals injected with cholesterol conjugated siRNA was reduced by about 55% as compared to animals injected with buffer (see FIG. 14). OTHER EMBODIMENTS 10 While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. 363

Claims

1. An iRNA agent comprising a sense strand and an antisense strand, wherein the sense and antisense strands are complementary to each other, and wherein the sense strand comprises a sequence that is substantially identical to a sequence provided in s Table 13, and the antisense strand comprises a sequence that is substantially identical to a sequence provided in Table 13, and wherein each strand of the iRNA agent is less than 30 nucleotides in length.

2. The iRNA agent of claim 1, wherein the sense strand and the antisense strand are io selected from the group consisting of SEQ ID NO: 5497 and SEQ ID NO: 5544; SEQ ID NO: 5499 and SEQ ID NO: 5546; SEQ ID NO: 5530 and SEQ ID NO: 5577; 15 SEQ ID NO: 5533 and SEQ ID NO: 5580; SEQ ID NO: 5535 and SEQ ID NO: 5582; SEQ ID NO: 5558 and SEQ ID NO: 5511; SEQ ID NO: 5503 and SEQ ID NO: 5550; SEQ ID NO: 5585 and SEQ ID NO: 5538; 20 SEQ ID NO: 5573 and SEQ ID NO: 5526; SEQ ID NO: 5556 and SEQ ID NO: 5509; and SEQ ID NO: 5548 and SEQ ID NO: 5501.

3. The iRNA agent of claim 2, wherein the sense strand and the antisense strand are 25 selected from the group consisting of SEQ ID NO: 5497 and SEQ ID NO: 5544; SEQ ID NO: 5530 and SEQ ID NO: 5577; SEQ ID NO: 5533 and SEQ ID NO: 5580; 30 SEQ ID NO: 5535 and SEQ ID NO: 5582; SEQ ID NO: 5558 and SEQ ID NO: 5511; SEQ ID NO: 5585 and SEQ ID NO: 5538; and SEQ ID NO: 5548 and SEQ ID NO: 5501.

2664219.1 (GHMatters) P55824.AU 365

4. The iRNA agent of any one of claims 1 to 3, for use in a method for reducing beta-catenin levels in a subject comprising administering to the subject the iRNA agent.

5 5. A method for reducing beta-catenin levels in a subject comprising administering to the subject an iRNA agent of any one of claims I to 3.

6. Use of an iRNA agent of any one of claims I to 3 in the manufacture of a medicament for reducing beta-catenin levels in a subject. 10

7. The iRNA agent of claim 4, the method of claim 5, or the use of claim 6, wherein the subject has a disorder characterized by unwanted cellular proliferation in the liver or in a tissue of the liver. is

8. The iRNA agent, method or use of claim 7, wherein said disorder is chosen from the group consisting of a hepatocellular carcinoma, a hepatic metastasis, and a hepatoblastoma.

9. The iRNA agent, method or use of any one of claims 1 to 8, wherein said iRNA 20 agent comprises one or more cholesterol moieties.

10. The iRNA agent, method or use of claim 9, wherein at least one cholesterol moiety is coupled to a sense strand of the iRNA agent. 25

11. The iRNA agent, method or use of any one of claims 1 to 10, wherein the sense strand and the antisense strand are at least 15 nucleotides in length.

12. The iRNA agent, method or use of any one of claims 1 to 11, wherein a duplex region of the iRNA agent is at least 15 nucleotides in length. 30

13. The iRNA agent, method or use of claim 12, wherein a duplex region of the iRNA agent is 19 to 21 nucleotides in length.

14. The iRNA agent, method or use of any one of claims I to 13, wherein the iRNA 35 agent comprises an overhang at one or both ends of the iRNA agent.

15. The iRNA agent, method or use of claim 14, wherein the overhang at one or both ends of the iRNA agent is two nucleotides in length. 26U4219_1 (GHMatters) P58824.AU 366

16. The iRNA agent of claim 1, the method of claim 5, or the use of claim 6, substantially as hereinbefore described with reference to any one of the Examples. 2084219_1 (GHMatters) PS8824 AU