Patent Publication Number: US-2022213475-A1

Title: DUAL TARGETING siRNA AGENTS

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. application Ser. No. 16/803,738, filed Feb. 27, 2020, which is a continuation of U.S. application Ser. No. 16/521,422, filed Jul. 24, 2019 (abandoned), which is a continuation of U.S. application Ser. No. 15/724,175, filed Oct. 3, 2017 (abandoned), which is a continuation of U.S. application Ser. No. 14/885,342, filed Oct. 16, 2015 (abandoned), which is a continuation of U.S. application Ser. No. 13/497,226, with a 371(c) filing date of Oct. 10, 2012, now U.S. Pat. No. 9,187,746, issued Nov. 17, 2015, which is a National Stage of International Application No. PCT/US2010/049868, filed Sep. 22, 2010, which claims the benefit of U.S. Provisional Application No. 61/244,859, filed Sep. 22, 2009, and claims the benefit of U.S. Provisional Application No. 61/313,584, filed Mar. 12, 2010, all of which are hereby incorporated in their entirety by reference. 
    
    
     REFERENCE TO A SEQUENCE LISTING 
     This application includes a Sequence Listing with 4166 sequences submitted electronically as a text file named AYL108C4_sequencelisting.txt, created on Feb. 20, 2020, with a size of 1,351,680 bytes. The sequence listing is incorporated by reference. 
     FIELD OF THE INVENTION 
     The invention relates to a composition of two covalently linked siRNAs, e.g., a dual targeting siRNA agent. At least one siRNA is a dsRNA that targets a PCSK9 gene. The covalently linked siRNA agent is used in methods of inhibition of PCSK9 gene expression and methods of treatment of pathological conditions associated with PCSK9 gene expression, e.g., hyperlipidemia. 
     BACKGROUND OF THE INVENTION 
     Proprotein convertase subtilisin kexin 9 (PCSK9) is a member of the subtilisin serine protease family. The other eight mammalian subtilisin proteases, PCSK1-PCSK8 (also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and SIP/SKI-1) are proprotein convertases that process a wide variety of proteins in the secretory pathway and play roles in diverse biological processes (Bergeron, F. (2000)  J. Mol. Endocrinol.  24, 1-22, Gensberg, K., (1998) 30  Semin. Cell Dev. Biol.  9, 11-17, Seidah, N. G. (1999)  Brain Res.  848, 45-62, Taylor, N. A., (2003)  FASEB J.  17, 1215-1227, and Zhou, A., (1999)  J. Biol. Chem.  274, 20745-20748). PCSK9 has been proposed to play a role in cholesterol metabolism. PCSK9 mRNA expression is down-regulated by dietary cholesterol feeding in mice (Maxwell, K. N., (2003)  J. Lipid Res.  44, 2109-2119), up-regulated by statins in HepG2 cells (Dubuc, G., (2004)  Arterioscler. Thromb. Vasc. Biol.  24, 1454-1459), and up-regulated in sterol regulatory element binding protein (SREBP) transgenic mice (Horton, J. D., (2003)  Proc. Natl. Acad. Sci. USA  100, 12027-12032), similar to the cholesterol biosynthetic enzymes and the low-density lipoprotein receptor (LDLR). Furthermore, PCSK9 missense mutations have been found to be associated with a form of autosomal dominant hypercholesterolemia (Hchola3) (Abifadel, M., et al. (2003)  Nat. Genet.  34, 154-156, Timms, K. M., (2004)  Hum. Genet.  114, 349-353, Leren, T. P. (2004)  Clin. Genet.  65, 419-422). PCSK9 may also play a role in determining LDL cholesterol levels in the general population, because single-nucleotide polymorphisms (SNPs) have been associated with cholesterol levels in a Japanese population (Shioji, K., (2004)  J. Hum. Genet.  49, 109-114). 
     Autosomal dominant hypercholesterolemias (ADHs) are monogenic diseases in which patients exhibit elevated total and LDL cholesterol levels, tendon xanthomas, and premature atherosclerosis (Rader, D. J., (2003)  J. Clin. Invest.  111, 1795-1803). The pathogenesis of ADHs and a recessive form, autosomal recessive hypercholesterolemia (ARH) (Cohen, J. C., (2003)  Curr. Opin. Lipidol.  14, 121-127), is due to defects in LDL uptake by the liver. ADH may be caused by LDLR mutations, which prevent LDL uptake, or by mutations in the protein on LDL, apolipoprotein B, which binds to the LDLR. ARH is caused by mutations in the ARH protein that are necessary for endocytosis of the LDLR-LDL complex via its interaction with clathrin. Therefore, if PCSK9 mutations are causative in Hchola3 families, it seems likely that PCSK9 plays a role in receptor-mediated LDL uptake. 
     Overexpression studies point to a role for PCSK9 in controlling LDLR levels and, hence, LDL uptake by the liver (Maxwell, K. N. (2004)  Proc. Natl. Acad. Sci. USA  101, 7100-7105, Benjannet, S., et al. (2004)  J. Biol. Chem.  279, 48865-48875, Park, S. W., (2004)  J. Biol. Chem.  279, 50630-50638). Adenoviral-mediated overexpression of mouse or human PCSK9 for 3 or 4 days in mice results in elevated total and LDL cholesterol levels; this effect is not seen in LDLR knockout animals (Maxwell, K. N. (2004)  Proc. Natl. Acad. Sci. USA  101, 7100-7105, Benjannet, S., et al. (2004)  J. Biol. Chem.  279, 48865-48875, Park, S. W., (2004)  J. Biol. Chem.  279, 50630-50638). In addition, PCSK9 overexpression results in a severe reduction in hepatic LDLR protein, without affecting LDLR mRNA levels, SREBP protein levels, or SREBP protein nuclear to cytoplasmic ratio. 
     Loss of function mutations in PCSK9 have been designed in mouse models (Rashid et al., (2005)  PNAS,  102, 5374-5379), and identified in human individuals (Cohen et al. (2005)  Nature Genetics  37:161-165). In both cases loss of PCSK9 function lead to lowering of total and LDLc cholesterol. In a retrospective outcome study over 15 years, loss of one copy of PCSK9 was shown to shift LDLc levels lower and to lead to an increased risk-benefit protection from developing cardiovascular heart disease (Cohen et al., (2006)  N. Engl. J. Med.,  354:1264-1272). 
     X-box binding protein 1 (XBP-1) is a basic leucine zipper transcription factor that is involved in the cellular unfolded protein response (UPR). XBP-1 is known to be active in the endoplasmic reticulum (ER). The ER consists of a system of folded membranes and tubules in the cytoplasm of cells. Proteins and lipids are manufactured and processed in the ER. When unusual demands are placed on the ER, “ER stress” occurs. ER stress can be triggered by a viral infection, gene mutations, exposure to toxins, aggregation of improperly folded proteins or a shortage of intracellular nutrients. The result can be Type II diabetes, metabolic syndrome, a neurological disorder or cancer. 
     Two XBP-1 isoforms are known to exist in cells: spliced XBP-1S and unspliced XBP-1U. Both isoforms of XBP-1 bind to the 21-bp Tax-responsive element of the human T-lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) in vitro and transactivate HTLV-1 transcription. HTLV-1 is associated with a rare form of blood dyscrasia known as Adult T-cell Leukemia/lymphoma (ATLL) and a myelopathy, tropical spastic paresis. 
     Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) disclosed the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in  C. elegans . dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.),  Drosophila  (see, e.g., Yang, D., et al.,  Curr. Biol . (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.). This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene. 
     A description of siRNA targeting PCSK9 can be found in U.S. patent application Ser. No. 11/746,864 filed on May 10, 2007 (now U.S. Pat. No. 7,605,251) and International Patent Application No. PCT/US2007/068655 filed May 10, 2007 (published as WO 2007/134161). Additional disclosure can be found in U.S. patent application Ser. No. 12/478,452 filed Jun. 4, 2009 (published as US 2010/0010066) and International Patent Application No. PCT/US2009/032743 filed Jan. 30, 2009 (published as WO 2009/134487). 
     A description of siRNA targeting XPB-1 can be found in U.S. patent application Ser. No. 12/425,811 filed on Apr. 17, 2009 and published as US 2009-0275638. 
     Dual targeting siRNAs can be found in International patent application publication no. WO/2007/091269. 
     SUMMARY OF THE INVENTION 
     Described herein are dual targeting siRNA agent in which a first siRNA targeting PCSK9 is covalently joined to a second siRNA targeting a gene implicated in cholesterol metabolism, e.g., XBP-1. The two siRNAs are covalently linked via, e.g., a disulfide linker. 
     Accordingly one aspect of the invention is a dual targeting siRNA agent having a first dsRNA targeting a PCSK9 gene and a second dsRNA targeting a second gene, wherein the first dsRNA and the second dsRNA are linked with a covalent linker. The second gene is can be, e.g., XBP-1, PCSK9, PCSK5, ApoC3, SCAP, or MIG12. In one embodiment, the second gene is XBP-1. Each dsRNA is 30 nucleotides or less in length. In general, each strand of each dsRNA is 19-23 bases in length. 
     In one embodiment, the dual targeting siRNA agent comprising a first dsRNA AD-10792 targeting a PCSK9 gene and a second dsRNA AD-18038 targeting an XBP-1 gene, wherein AD-10792 sense strand and AD-18038 sense strand are covalently linked with a disulfide linker. 
     The first dsRNA of the dual targeting siRNA agent targets a PCSK9 gene. In one aspect, the first dsRNA includes at least 15 contiguous nucleotides of an antisense strand of one of Tables 1, 2, or 4-8, or includes an antisense strand of one of Tables 1, 2, or 4-8, or includes a sense strand and an antisense strand of one of Tables 1, 2, or 4-8. The first dsRNA can be AD-9680 or AD-10792. 
     In some embodiments, the second dsRNA target XBP-1. In one aspect, the second dsRNA includes at least 15 contiguous nucleotides of an antisense strand of one of Tables 3 or 9-13, or includes an antisense strand of one of Tables 3 or 9-13, or includes a sense strand and an antisense strand of one of Tables 3 or 9-13. For example, the second dsRNA can be AD-18038. 
     Either the first and second dsRNA can include at least one modified nucleotide, e.g., a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. In some embodiments, the first and second dsRNAs include “endo-light” modification with 2′-O-methyl modified nucleotides and nucleotides comprising a 5′-phosphorothioate group. 
     The first and second dsRNAs are linked with a covalent linker. In some embodiments, the linker is a disulfide linker. Various combinations of strands can be linked, e.g., the first and second dsRNA sense strands are covalently linked or, e.g., the first and second dsRNA antisense strands are covalently linked. In some embodiments, any of the dual targeting siRNA agents of the invention include a ligand. 
     Also included in the invention are isolated cells having and vectors encoding the dual targeting siRNA agent described herein. 
     In one aspect, administration of the dual targeting siRNA agent to a cell inhibits expression of the PCSK9 gene and the second gene at a level equivalent to inhibition of expression of both genes using administration of each siRNA individually. In another aspect, administration of the dual targeting siRNA agent to a subject results in a greater reduction of total serum cholesterol that that obtained by administration of each siRNA alone. 
     The invention also includes a pharmaceutical composition comprising the dual targeting siRNA agents described herein and a pharmaceutical carrier. In one embodiment, the pharmaceutical carrier is a lipid formulation, e.g., a lipid formulation including cationic lipid DLinDMA or cationic lipid XTC. Examples of lipid formulations described in (but not limited to) Table A, below. The lipid formulation can be XTC/DSPC/Cholesterol/PEG-DMG at % mol ratios of 50/10/38.5/1.5. 
     Another aspect of the invention includes methods of using the dual targeting siRNA agents described herein. In one embodiment, the invention is a method of inhibiting expression of the PCSK9 gene and a second gene in a cell, the method comprising (a) introducing into the cell the any of the dual targeting siRNA agents and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the PCSK9 gene and the second gene, thereby inhibiting expression of the PCSK9 gene and the second gene in the cell. 
     In another embodiment, the invention includes methods of treating a disorder mediated by PCSK9 expression with the step of administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical compositions described herein. In one aspect, the disorder is hyperlipidemia. In still another embodiment, the invention includes methods of reducing total serum cholesterol in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical compositions described herein. 
     The details of various embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a graph showing the effect on PCSK9 mRNA levels in primary mouse hepatocytes following treatment with a dual targeting siRNA, AD-23426. AD-23426 was as effective at reducing mRNA expression as each single gene target siRNA. AD-10792: PCSK9 siRNA. AD-18038: XBP-1 siRNA. Lipo2000: control transfection agent only FIG. 1Bis a graph showing the effect on XBP-1 mRNA levels in primary mouse hepatocytes following treatment with a dual targeting siRNA, AD-23426. AD-23426 was as effective at reducing mRNA expression as each single gene target siRNA. AD-10792: PCSK9 siRNA. AD-18038: XBP-1 siRNA. Lipo2000: control transfection agent only. 
         FIG. 2  is a graph showing the effect on PCSK9 and XBP-1 mRNA levels in mice following treatment with a dual targeting siRNA, AD-23426. LNP09 (lipid) formulated siRNA was administered to mice as described. AD-23426 was as effective at reducing mRNA expression as each single gene target siRNA. AD-10792: PCSK9 siRNA. AD-18038: XBP-1 siRNA. 
         FIG. 3  is a graph showing the effect on serum cholesterol levels in mice following treatment with a dual targeting siRNA, AD-23426. LNP09 (lipid) formulated siRNA was administered to mice as described. AD-23426 was more effective at reducing serum cholesterol compared to each single gene target siRNA. AD-10792: PCSK9 siRNA. AD-18038: XBP-1 siRNA. 
         FIG. 4A  is a graph showing the effect on IFN-α, in human PBMC following treatment with a dual targeting siRNA, AD-23426.  FIG. 4B  is a graph showing the effect on TNF-α in human PBMC following treatment with a dual targeting siRNA, AD-23426. DOTAP and LNP09 (lipid) formulated siRNAs was administered huPBMC as described below. AD-23426 did not induce IFN-α or TNF-α. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention provides a solution to the problem of treating diseases that can be modulated by the down regulation of the PCSK9 gene, such as hyperlipidemia, by using dual targeting siRNA to silence the PCSK9 gene. 
     The invention provides compositions and methods for inhibiting the expression of the PCSK9 gene in a subject using two siRNA, e.g., a dual targeting siRNA. The invention also provides compositions and methods for treating pathological conditions and diseases, such as hyperlipidemia, that can be modulated by down regulating the expression of the PCSK9 gene. 
     The dual targeting siRNA agents target a PCSK9 gene and at least one other gene. The other gene can be another region of the PCSK9 gene, or can be another gene, e.g., XBP-1. 
     The dual targeting siRNA agents have the advantage of lower toxicity, lower off-target effects, and lower effective concentration compared to individual siRNAs. 
     The use of the dual targeting siRNA dsRNAs enables the targeted degradation of an mRNA that is involved in the regulation of the LDL receptor and circulating cholesterol levels. Using cell-based and animal assays it was demonstrated that inhibiting both a PCSK9 gene and an XBP-1 gene using a dual targeting siRNA is at least as effective at inhibiting their corresponding targets as the use of single siRNAs. It was also demonstrated that administration of a dual targeting siRNA results in a synergistic lowering of total serum cholesterol. Thus, reduction of total serum cholesterol is enhanced with a dual targeting siRNA compared to a single target siRNA. 
     Definitions 
     For convenience, the meaning of certain terms and phrases used in the specification, examples, and appended claims, are provided below. If there is an apparent discrepancy between the usage of a term in other parts of this specification and its definition provided in this section, the definition in this section shall prevail. 
     “G,” “C,” “A,” “T” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine and uracil as a base, respectively. “T” and “dT” are used interchangeably herein and refer to a deoxyribonucleotide wherein the nucleobase is thymine, e.g., deoxyribothymine. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of dsRNA featured in the invention by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the invention. 
     The term “PCSK9” refers to the proprotein convertase subtilisin kexin 9 gene or protein (also known as FH3, HCHOLA3, NARC-1, NARC1). Examples of mRNA sequences to PCSK9 include but are not limited to the following: human: NM_174936; mouse: NM_153565, and rat: NM_199253. Additional examples of PCSK9 mRNA sequences are readily available using, e.g., GenBank. 
     The term “XBP-1” refers to -Box Protein 1, which is also known as Tax-responsive element-binding protein 5, TREB5, and XBP2. XBP-1 sequence can be found as NCBI GeneID:7494 and RefSeq ID number: NM_005080 (human) and NM_013842 (mouse). A dsRNA featured in the invention can target a specific XBP-1 isoform, e.g., the spliced form (XBP-1S) or the unspliced form (XBP-1U), or a dsRNA featured in the invention can target both isoforms by binding to a common region of the mRNA transcript. 
     The term “PCSK5” refers to the Proprotein convertase subtilisin/kexin type 5 gene, mRNA or protein belonging to the subtilisin-like proprotein convertase family. 
     The term “ApoC3” refers to the Apolipoprotein C-III protein gene, mRNA or protein, and is a very low density lipoprotein (VLDL). 
     The term “SCAP” refers to the SREBP cleavage-activating protein gene, mRNA or protein. SCAP is a regulatory protein that is required for the proteolytic cleavage of the sterol regulatory element binding protein (SREBP). Example of siRNA targeting SCAP are described in U.S. patent application Ser. No. 11/857,120, filed on Sep. 18, 2007, published as US 20090093426. This application and the siRNA sequences described therein are incorporated by reference for all purposes. 
     The term “MIG12” is a gene also known as TMSB10 and TB10 refers to the thymosin beta 10 gene. Example of siRNA targeting MIG12 are described International patent application no. PCT/US10/25444, filed on Feb. 25, 2010, published as WO/20XX/XXXXXX This application and the siRNA sequences described therein are incorporated by reference for all purposes. 
     As used herein, the term “iRNA” refers to an agent that contains RNA and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. The term iRNA includes siRNA. 
     As described in more detail below, the term “siRNA” and “siRNA agent” refers to a dsRNA that mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. 
     A “double-stranded RNA” or “dsRNA,” as used herein, refers to an RNA molecule or complex of molecules having a hybridized duplex region that comprises two anti-parallel and substantially complementary nucleic acid strands, which will be referred to as having “sense” and “antisense” orientations with respect to a target RNA. 
     The term “dual targeting siRNA agent” refers to a composition of two siRNAs, e.g., two dsRNAs. One dsRNA includes an antisense strand with a first region of complementarity to a first target gene, e.g., PCSK9. The second dsRNA include an antisense strand with a second region of complementarity to a second target gene. In some embodiments, the first and second target genes are identical, e.g., both are PCSK9 and each dsRNA targets a different region of PCSK9. In other embodiments, the first and second target genes are different, e.g., the first dsRNA targets PCSK9 and the second dsRNA targets a different gene, e.g., XBP-1. 
     “Covalent linker” refers to a molecule for covalently joining two molecules, e.g., two dsRNAs. As described in more detail below, the term includes, e.g., a nucleic acid linker, a peptide linker, and the like and includes disulfide linkers. 
     The term “target gene” refers to a gene of interest, e.g., PCSK9 or a second gene, e.g., XBP-1, targeted by an siRNA of the invention for inhibition of expression. 
     As described in more detail below, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a target gene, including mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence will be at least long enough to serve as a substrate for iRNA-directed cleavage at or near that portion. For example, the target sequence will generally be from 9-36 nucleotides in length, e.g., 15-30 nucleotides in length, including all sub-ranges therebetween. 
     As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. 
     As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. 
     Complementary sequences within an iRNA, e.g., within a dsRNA as described herein, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 5, 4, 1 or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as “fully complementary” for the purposes described herein. 
     “Complementary” sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs includes, but are not limited to, G:U Wobble or Hoogstein base pairing. 
     The terms “complementary,” “fully complementary” and “substantially complementary” herein may be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of an iRNA agent and a target sequence, as will be understood from the context of their use. 
     As used herein, a polynucleotide that is “substantially complementary to at least part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of the target gene (e.g., an mRNA encoding PCSK9 or a second gene, e.g., XBP-1). For example, a polynucleotide is complementary to at least a part of a PCSK9 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding PCSK9. 
     The skilled artisan will recognize that the term “RNA molecule” or “ribonucleic acid molecule” encompasses not only RNA molecules as expressed or found in nature, but also analogs and derivatives of RNA comprising one or more ribonucleotide/ribonucleoside analogs or derivatives as described herein or as known in the art. Strictly speaking, a “ribonucleoside” includes a nucleoside base and a ribose sugar, and a “ribonucleotide” is a ribonucleoside with one, two or three phosphate moieties. However, the terms “ribonucleoside” and “ribonucleotide” can be considered to be equivalent as used herein. The RNA can be modified in the nucleobase structure or in the ribose-phosphate backbone structure, e.g., as described herein below. However, the molecules comprising ribonucleoside analogs or derivatives must retain the ability to form a duplex. As non-limiting examples, an RNA molecule can also include at least one modified ribonucleoside including but not limited to a 2′-O-methyl modified nucleotide, a nucleoside comprising a 5′ phosphorothioate group, a terminal nucleoside linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a locked nucleoside, an abasic nucleoside, a 2′-deoxy-2′-fluoro modified nucleoside, a 2′-amino-modified nucleoside, 2′-alkyl-modified nucleoside, morpholino nucleoside, a phosphoramidate or a non-natural base comprising nucleoside, or any combination thereof. Alternatively, an RNA molecule can comprise at least two modified ribonucleosides, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20 or more, up to the entire length of the dsRNA molecule. The modifications need not be the same for each of such a plurality of modified ribonucleosides in an RNA molecule. In one embodiment, modified RNAs contemplated for use in methods and compositions described herein are peptide nucleic acids (PNAs) that have the ability to form the required duplex structure and that permit or mediate the specific degradation of a target RNA via a RISC pathway. 
     In one aspect, a modified ribonucleoside includes a deoxyribonucleoside. In such an instance, an iRNA agent can comprise one or more deoxynucleosides, including, for example, a deoxynucleoside overhang(s), or one or more deoxynucleosides within the double stranded portion of a dsRNA. However, it is self evident that under no circumstances is a double stranded DNA molecule encompassed by the term “iRNA.” 
     As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of an iRNA, e.g., a dsRNA. For example, when a 3′-end of one strand of a dsRNA extends beyond the 5′-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) may be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′ end, 3′ end or both ends of either an antisense or sense strand of a dsRNA. One or more of the nucleotides in the overhang can be replaced with a nucleoside thiophosphate. 
     The terms “blunt” or “blunt ended” as used herein in reference to a dsRNA mean that there are no unpaired nucleotides or nucleotide analogs at a given terminal end of a dsRNA, i.e., no nucleotide overhang. One or both ends of a dsRNA can be blunt. Where both ends of a dsRNA are blunt, the dsRNA is said to be blunt ended. To be clear, a “blunt ended” dsRNA is a dsRNA that is blunt at both ends, i.e., no nucleotide overhang at either end of the molecule. Most often such a molecule will be double-stranded over its entire length. 
     The term “antisense strand” or “guide strand” refers to the strand of an iRNA, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches may be in the internal or terminal regions of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5′ and/or 3′ terminus. 
     The term “sense strand” or “passenger strand” as used herein, refers to the strand of an iRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. 
     As used herein, the term “SNALP” refers to a stable nucleic acid-lipid particle. A SNALP represents a vesicle of lipids coating a reduced aqueous interior comprising a nucleic acid such as an iRNA or a plasmid from which an iRNA is transcribed. SNALPs are described, e.g., in U.S. Patent Application Publication Nos. 20060240093, 20070135372, and in International Application No. WO 2009082817. These applications are incorporated herein by reference in their entirety. 
     “Introducing into a cell,” when referring to an iRNA, means facilitating or effecting uptake or absorption into the cell, as is understood by those skilled in the art. Absorption or uptake of an iRNA can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. The meaning of this term is not limited to cells in vitro; an iRNA may also be “introduced into a cell,” wherein the cell is part of a living organism. In such an instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery, iRNA can be injected into a tissue site or administered systemically. In vivo delivery can also be by a beta-glucan delivery system, such as those described in U.S. Pat. Nos. 5,032,401 and 5,607,677, and U.S. Publication No. 2005/0281781, which are hereby incorporated by reference in their entirety. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein below or known in the art. 
     As used herein, the term “modulate the expression of,” refers to at an least partial “inhibition” or partial “activation” of target gene expression in a cell treated with an iRNA composition as described herein compared to the expression of the target gene in an untreated cell. 
     The terms “activate,” “enhance,” “up-regulate the expression of,” “increase the expression of,” and the like, in so far as they refer to a target gene, herein refer to the at least partial activation of the expression of a target gene, as manifested by an increase in the amount of target mRNA, which may be isolated from or detected in a first cell or group of cells in which a target gene is transcribed and which has or have been treated such that the expression of a target gene is increased, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). 
     In one embodiment, expression of a target gene is activated by at least about 10%, 15%,   25%, 30%, 35%, 40%, 45%, or 50% by administration of an iRNA as described herein. In some embodiments, a target gene is activated by at least about 60%, 70%, or 80% by administration of an iRNA featured in the invention. In some embodiments, expression of a target  gene  is activated by at least about 85%, 90%, or 95% or more by administration of an iRNA as described herein. In some embodiments, the target gene expression is increased by at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000 fold or more in cells treated with an iRNA as described herein compared to the expression in an untreated cell. Activation of expression by small dsRNAs is described, for example, in Li et al., 2006  Proc. Natl. Acad. Sci. U.S.A.  103:17337-42, and in US20070111963 and US2005226848, each of which is incorporated herein by reference. 
     The terms “silence,” “inhibit the expression of,” “down-regulate the expression of,” “suppress the expression of,” and the like, in so far as they refer to a target gene, herein refer to the at least partial suppression of the expression of a target gene, as manifested by a reduction of the amount of target mRNA which may be isolated from or detected in a first cell or group of cells in which a target gene is transcribed and which has or have been treated such that the expression of target gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition is usually expressed in terms of 
     
       
         
           
             
               
                 
                   
                     ( 
                     
                       mRNA 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       in 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       control 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       cells 
                     
                     ) 
                   
                   - 
                   
                     ( 
                     
                       mRNA 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       in 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       treated 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       cells 
                     
                     ) 
                   
                 
                 
                   ( 
                   
                     mRNA 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     in 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     control 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     cells 
                   
                   ) 
                 
               
               · 
               100 
             
             ⁢ 
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     Alternatively, the degree of inhibition may be given in terms of a reduction of a parameter that is functionally linked to target gene expression, e.g., the amount of protein encoded by a target gene, or the number of cells displaying a certain phenotype, e.g., lack of or decreased cytokine production. In principle, target gene silencing may be determined in any cell expressing target, either constitutively or by genomic engineering, and by any appropriate assay. However, when a reference is needed in order to determine whether a given iRNA inhibits the expression of the target gene by a certain degree and therefore is encompassed by the instant invention, the assays provided in the Examples below shall serve as such reference. 
     For example, in certain instances, expression of a target gene is suppressed by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% by administration of an iRNA featured in the invention. In some embodiments, a target gene is suppressed by at least about 60%, 65%, 70%, 75%, or 80% by administration of an iRNA featured in the invention. In some embodiments, a target gene is suppressed by at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more by administration of an iRNA as described herein. 
     As used herein in the context of target gene expression, the terms “treat,” “treatment,” and the like, refer to relief from or alleviation of pathological processes mediated by target expression. In the context of the present invention insofar as it relates to any of the other conditions recited herein below (other than pathological processes mediated by target expression), the terms “treat,” “treatment,” and the like mean to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression or anticipated progression of such condition. 
     By “lower” in the context of a disease marker or symptom is meant a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without such disorder. 
     As used herein, the phrase “therapeutically effective amount” ” refers to an amount that provides a therapeutic benefit in the treatment or management of pathological processes mediated by target gene expression, e.g., PCSK9 and/or a second gene, e.g., XBP-1, or an overt symptom of pathological processes mediated target gene expression. The phrase “prophylactically effective amount” refer to an amount that provides a therapeutic benefit in the prevention of pathological processes mediated by target gene expression or an overt symptom of pathological processes mediated by target gene expression. The specific amount that is therapeutically effective can be readily determined by an ordinary medical practitioner, and may vary depending on factors known in the art, such as, for example, the type of pathological processes mediated by target gene expression, the patient&#39;s history and age, the stage of pathological processes mediated by target gene expression, and the administration of other agents that inhibit pathological processes mediated by target gene expression. 
     As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of an iRNA and a pharmaceutically acceptable carrier. As used herein, “pharmacologically effective amount,” “therapeutically effective amount” or simply “effective amount” refers to that amount of an iRNA effective to produce the intended pharmacological or therapeutic result. For example, if a given clinical treatment is considered effective when there is at least a 10% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to effect at least a 10% reduction in that parameter. 
     The term “pharmaceutically carrier” refers to a carrier for administration of a therapeutic agent, e.g., a dual targeting siRNA agent. Carriers are described in more detail below, and include lipid formulations, e.g., LNP09 and SNALP formulations. 
     Double-Stranded Ribonucleic Acid (dsRNA) 
     Described herein are dual targeting siRNA agents, e.g., siRNAs that inhibit the expression of a PCSK9 gene and a second gene. The dual targeting siRNA agent includes two siRNA covalently linked via, e.g., a disulfide linker. The first siRNA targets a first region of a PCSK9 gene. The second siRNA targets a second gene, e.g., XBP-1, or, e.g., targets a second region of the PCSK9 gene. 
     The dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g., by use of an automated DNA synthesizer, such as are commercially available from, for example, Applied Biosystems, Inc. Further descriptions of synthesis are found below and in the examples. 
     Each siRNA is a dsRNA. A dsRNA includes two RNA strands that are sufficiently complementary to hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of a target gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. 
     Where the duplex region is formed from two strands of a single molecule, the molecule can have a duplex region separated by a single stranded chain of nucleotides (herein referred to as a “hairpin loop”) between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure. The hairpin loop can comprise at least one unpaired nucleotide; in some embodiments the hairpin loop can comprise at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. 
     Where the two substantially complementary strands of a dsRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. Where the two strands are connected covalently by means other than a hairpin loop, the connecting structure is referred to as a “linker.” 
     Generally, the duplex structure of the siRNA, e.g., dsRNA, is between 15 and 30 inclusive, more generally between 18 and 25 inclusive, yet more generally between 19 and 24 inclusive, and most generally between 19 and 21 base pairs in length, inclusive. Considering a duplex between 9 and 36 base pairs, the duplex can be any length in this range, for example, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 and any sub-range therein between, including, but not limited to 15-30 base pairs, 15-26 base pairs, 15-23 base pairs, 15-22 base pairs, 15-21 base pairs, 15-20 base pairs, 15-19 base pairs, 15-18 base pairs, 15-17 base pairs, 18-30 base pairs, 18-26 base pairs, 18-23 base pairs, 18-22 base pairs, 18-21 base pairs, 18-20 base pairs, 19-30 base pairs, 19-26 base pairs, 19-23 base pairs, 19-22 base pairs, 19-21 base pairs, 19-20 base pairs, 20-30 base pairs, 20-26 base pairs, 20-25 base pairs, 20-24 base pairs, 20-23 base pairs, 20-22 base pairs, 20-21 base pairs, 21-30 base pairs, 21-26 base pairs, 21-25 base pairs, 21-24 base pairs, 21-23 base pairs, or 21-22 base pairs. 
     The two siRNAs in the dual targeting siRNA agent can have duplex lengths that are identical or that differ. 
     The region of complementarity to the target sequence in an siRNA is between 15 and 30 inclusive, more generally between 18 and 25 inclusive, yet more generally between 19 and 24 inclusive, and most generally between 19 and 21 nucleotides in length, inclusive. In some embodiments, the dsRNA is between 15 and 20 nucleotides in length, inclusive, and in other embodiments, the dsRNA is between 25 and 30 nucleotides in length, inclusive. The region of complementarity can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. As non-limiting examples, the target sequence can be from 15-30 nucleotides, 15-26 nucleotides, 15-23 nucleotides, 15-22 nucleotides, 15-21 nucleotides, 15-20 nucleotides, 15-19 nucleotides, 15-18 nucleotides, 15-17 nucleotides, 18-30 nucleotides, 18-26 nucleotides, 18-23 nucleotides, 18-22 nucleotides, 18-21 nucleotides, 18-20 nucleotides, 19-30 nucleotides, 19-26 nucleotides, 19-23 nucleotides, 19-22 nucleotides, 19-21 nucleotides, 19-20 nucleotides, 20-30 nucleotides, 20-26 nucleotides, 20-25 nucleotides, 20-24 nucleotides, 20-23 nucleotides, 20-22 nucleotides, 20-21 nucleotides, 21-30 nucleotides, 21-26 nucleotides, 21-25 nucleotides, 21-24 nucleotides, 21-23 nucleotides, or 21-22 nucleotides. In some embodiments the target sequence is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. 
     The two siRNAs in the dual targeting siRNA agent can have regions of complementarity that are identical in length or that differ in length. 
     Any of the dsRNA, e.g., siRNA as described herein may include one or more single-stranded nucleotide overhangs. In one embodiment, at least one end of a dsRNA has a single-stranded nucleotide overhang of 1 to 4, or 1 or 2 or 3 or 4 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. Generally, the single-stranded overhang is located at the 3′-terminal end of the antisense strand or, alternatively, at the 3′-terminal end of the sense strand. The dsRNA can also have a blunt end, generally located at the 5′-end of the antisense strand. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. The two siRNAs in the dual targeting siRNA agent can have different or identical overhangs as described by location, length, and nucleotide. 
     The dual targeting siRNA agent includes at least a first siRNA targeting a first region of a PCSK9 gene. In one embodiment, a PCSK9 gene is a human PCSK9 gene. In another embodiment the PCSK9 gene is a mouse or a rat PCSK9 gene. Exemplary siRNA targeting PCSK9 are described in U.S. patent application Ser. No. 11/746,864 filed on May 10, 2007 (now U.S. Pat. No. 7,605,251) and International Patent Application No. PCT/US2007/068655 filed May 10, 2007 (published as WO 2007/134161). Additional disclosure can be found in U.S. patent application Ser. No. 12/478,452 filed Jun. 4, 2009 (published as US 2010/0010066) and International Patent Application No. PCT/US2009/032743 filed Jan. 30, 2009 (published as WO 2009/134487). The sequences of the target, sense, and antisense strands are incorporated by reference for all purposes. 
     Tables 1, 2, and 4-8 disclose sequences of the target, sense strands, and antisense strands of PCSK9 targeting siRNA. 
     In one embodiment the first siRNA is AD-9680. The dsRNA AD-9680 targets the human PCSK 9 gene at nucleotides 3530-3548 of a human PCSK9 gene (accession number NM_174936). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 AD-9680 siRNA sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Table 1: AD-9680 
                 Sequence 5′ to 3′ 
                 NO: 
               
               
                   
               
               
                 Target sequence 
                 UUCUAGACCUGUUUUGCUU 
                 4142 
               
               
                   
               
               
                 Sense strand 
                 UUCUAGACCUGUUUUGCUU 
                 4143 
               
               
                   
               
               
                 Sense strand, 
                 uucuAGAccuGuuuuGcuuTsT 
                 4144 
               
               
                 modified 
                   
                   
               
               
                   
               
               
                 Antisense strand 
                 AAGCAAAACAGGUCUAGAA 
                 4145 
               
               
                   
               
               
                 Antisense strand, 
                 AAGcAAAAcAGGUCuAGAATsT 
                 4146 
               
               
                 modified 
               
               
                   
               
            
           
         
       
     
     In another embodiment, the first siRNA is AD-10792. The dsRNA AD-10792 targets the PCSK9 gene at nucleotides 1091-1109 of a human PCSK9 gene (accession number NM 174936). AD-10792 is also complementary to rodent PCSK9. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 AD-10792 siRNA sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Table 2: AD-10792 
                 Sequence 5′ to 3′ 
                 NO: 
               
               
                   
               
               
                 Target sequence 
                 GCCUGGAGUUUAUUCGGAA 
                 4147 
               
               
                   
               
               
                 Sense strand 
                 GCCUGGAGUUUAUUCGGAA 
                 4148 
               
               
                   
               
               
                 Sense strand, 
                 GccuGGAGuuuAuucGGAATsT 
                 4149 
               
               
                 modified 
                   
                   
               
               
                   
               
               
                 Antisense strand 
                 UUCCGAAUAAACUCCAGGC 
                 4150 
               
               
                   
               
               
                 Antisense strand, 
                 UUCCGAAuAAACUCcAGGCTsT 
                 4151 
               
               
                 modified 
               
               
                   
               
            
           
         
       
     
     The second siRNA of the dual targeting siRNA agent targets a second gene. In one embodiment, the second gene is PCSK9, and the second siRNA target a region of PCSK9 that is different from the region targeted by the first siRNA. 
     Alternatively, the second siRNA targets a different second gene. Examples include genes that interact with PCSK9 and/or are involved with lipid metabolism or cholesterol metabolism. For example, the second target gene can be XBP-1, PCSK5, ApoC3, SCAP, MIG12, HMG CoA Reductase, or IDOL (Inducible Degrader of the LDLR) and the like. In one embodiment, the second gene is a human gene. In another embodiment the second gene is a mouse or a rat gene. 
     In one embodiment, the second siRNA targets the XBP-1 gene. Exemplary siRNA targeting XBP-1 can be found in U.S. patent application Ser. No. 12/425,811 filed Apr. 17, 2009 (published as US 2009-0275638). The sequences of the target, sense, and antisense strands are incorporated by reference for all purposes. 
     Tables 3 and 9-13 disclose sequences of the target, sense strands, and antisense strands of XBP-1 targeting siRNA. 
     In one embodiment the first siRNA is AD-18038. The dsRNA AD-18038 targets the human XBP-1 gene at nucleotides 896-914 of a human XBP-1 gene (accession number NM_001004210). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 AD-18038 siRNA sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Table 3: AD-18038 
                 Sequence 5′ to 3′ 
                 NO: 
               
               
                   
               
               
                 Target sequence 
                 CACCCUGAAUUCAUUGUCU 
                 4153 
               
               
                   
               
               
                 Sense strand 
                 CACCCUGAAUUCAUUGUCU 
                 4154 
               
               
                   
               
               
                 Sense strand, 
                 cAcccuGAAuucAuuGucudTsdT 
                 4155 
               
               
                 modified 
                   
                   
               
               
                   
               
               
                 Antisense strand 
                 AGACAAUGAAUUCAGGGUG 
                 4156 
               
               
                   
               
               
                 Antisense strand, 
                 AGAcAAUGAAUUcAGGGUGdTsdT 
                 4157 
               
               
                 modified 
               
               
                   
               
            
           
         
       
     
     Additional dsRNA 
     A dsRNAs having a partial sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from one of the sequences in Tables 1-13, and differing in their ability to inhibit the expression of a target gene by not more than 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated according to the invention. 
     In addition, the RNAs provided in Tables 1-13 identify a site in the target gene transcript that is susceptible to RISC-mediated cleavage. As such, the present invention further features iRNAs that target within one of such sequences. As used herein, an iRNA is said to target within a particular site of an RNA transcript if the iRNA promotes cleavage of the transcript anywhere within that particular site. Such an iRNA will generally include at least 15 contiguous nucleotides from one of the sequences provided herein coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a target gene. 
     While a target sequence is generally 15-30 nucleotides in length, there is wide variation in the suitability of particular sequences in this range for directing cleavage of any given target RNA. Various software packages and the guidelines set out herein provide guidance for the identification of optimal target sequences for any given gene target, but an empirical approach can also be taken in which a “window” or “mask” of a given size (as a non-limiting example, 21 nucleotides) is literally or figuratively (including, e.g., in silico) placed on the target RNA sequence to identify sequences in the size range that may serve as target sequences. By moving the sequence “window” progressively one nucleotide upstream or downstream of an initial target sequence location, the next potential target sequence can be identified, until the complete set of possible sequences is identified for any given target size selected. This process, coupled with systematic synthesis and testing of the identified sequences (using assays as described herein or as known in the art) to identify those sequences that perform optimally can identify those RNA sequences that, when targeted with an iRNA agent, mediate the best inhibition of target gene expression. Thus, while the sequences identified, for example, above represent effective target sequences, it is contemplated that further optimization of inhibition efficiency can be achieved by progressively “walking the window” one nucleotide upstream or downstream of the given sequences to identify sequences with equal or better inhibition characteristics. 
     Further, it is contemplated that for any sequence identified, e.g., in Tables 1-13, further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those and sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point. Again, coupling this approach to generating new candidate targets with testing for effectiveness of iRNAs based on those target sequences in an inhibition assay as known in the art or as described herein can lead to further improvements in the efficiency of inhibition. Further still, such optimized sequences can be adjusted by, e.g., the introduction of modified nucleotides as described herein or as known in the art, addition or changes in overhang, or other modifications as known in the art and/or discussed herein to further optimize the molecule (e.g., increasing serum stability or circulating half-life, increasing thermal stability, enhancing transmembrane delivery, targeting to a particular location or cell type, increasing interaction with silencing pathway enzymes, increasing release from endosomes, etc.) as an expression inhibitor. 
     An iRNA as described in Tables 1-13 can contain one or more mismatches to the target sequence. In one embodiment, an iRNA as described in Tables 1-13 contains no more than 3 mismatches. If the antisense strand of the iRNA contains mismatches to a target sequence, it is preferable that the area of mismatch not be located in the center of the region of complementarity. If the antisense strand of the iRNA contains mismatches to the target sequence, it is preferable that the mismatch be restricted to be within the last 5 nucleotides from either the 5′ or 3′ end of the region of complementarity. For example, for a 23 nucleotide iRNA agent RNA strand which is complementary to a region of a PCSK9 gene, the RNA strand generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used to determine whether an iRNA containing a mismatch to a target sequence is effective in inhibiting the expression of a PCSK9 gene. Consideration of the efficacy of iRNAs with mismatches in inhibiting expression of a PCSK9 gene is important, especially if the particular region of complementarity in a PCSK9 gene is known to have polymorphic sequence variation within the population. 
     Covalent Linkage 
     The dual targeting siRNA agents of the invention include two siRNAs joined via a covalent linker. Covalent linkers are well-known to one of skill in the art and include, e.g., a nucleic acid linker, a peptide linker, and the like. 
     The covalent linker joins the two siRNAs. The covalent linker can join two sense strands, two antisense strands, one sense and one antisense strand, two sense strands and one antisense strand, two antisense strands and one sense strand, or two sense and two antisense strands. 
     The covalent linker can include RNA and/or DNA and/or a peptide. The linker can be single stranded, double stranded, partially single strands, or partially double stranded. In some embodiments the linker includes a disulfide bond. The linker can be cleavable or non-cleavable. 
     The covalent linker can be, e.g., dTsdTuu=(5′-2′deoxythymidy1-3′-thiophosphate-5′-2′deoxythymidy 1-3′-phosphate-5′-uridy 1-3′-phosphate-5′-uridy 1-3′-phosphate); rUsrU (a thiophosphate linker: 5′-uridy1-3′-thiophosphate-5′-uridy1-3′-phosphate); an rUrU linker; dTsdTaa (aadTsdT, 5′-2′deoxythymidy1-3′-thiophosphate-5′-2′deoxythymidy1-3′-phosphate-5′-adeny1-3′-phosphate-5′-adeny1-3′-phosphate); dTsdT (5′-2′deoxythymidy1-3′-thiophosphate-5′-2′ deoxythymidy1-3′-phosphate); dTsdTuu=uudTsdT=5′-2′deoxythymidy1-3′-thiophosphate-5′-2′deoxythymidy 1-3′-phosphate-5′-uridy1-3′-phosphate-5′-uridy1-3′-phosphate. 
     The covalent linker can be a polyRNA, such as poly(5′-adenyl-3′-phosphate—AAAAAAAA) or poly(5′-cytidyl-3′-phosphate-5′-uridyl-3′-phosphate—CUCUCUCU)), e.g., X n  single stranded poly RNA linker wherein n is an integer from 2-50 inclusive, preferable 4-15 inclusive, most preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can also be present in said polyRNA linker. The covalent linker can be a polyDNA, such as poly(5′-2′deoxythymidy1-3′-phosphate—TTTTTTTT), e.g., wherein n is an integer from 2-50 inclusive, preferable 4-15 inclusive, most preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can also be present in said polyDNA linker. a single stranded polyDNA linker wherein n is an integer from 2-50 inclusive, preferable 4-15 inclusive, most preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can also be present in said polyDNA linker. 
     The covalent linker can include a disulfide bond, optionally a bis-hexyl-disulfide linker. In one embodiment, the disulfide linker is 
     
       
         
         
             
             
         
       
     
     The covalent linker can include a peptide bond, e.g., include amino acids. In one embodiment, the covalent linker is a 1-10 amino acid long linker, preferably comprising 4-5 amino acids, optionally X-Gly-Phe-Gly-Y wherein X and Y represent any amino acid. 
     The covalent linker can include HEG, a hexaethylenglycol linker. 
     Modifications 
     In yet another embodiment, at least one of the siRNA of the dual targeting siRNA agent is chemically modified to enhance stability or other beneficial characteristics. The nucleic acids featured in the invention may be synthesized and/or modified by methods well established in the art, such as those described in “Current protocols in nucleic acid chemistry,” Beaucage, S. L. et al. (Edrs.), John Wiley &amp; Sons, Inc., New York, N.Y., USA, which is hereby incorporated herein by reference. Modifications include, for example, (a) end modifications, e.g., 5′ end modifications (phosphorylation, conjugation, inverted linkages, etc.) 3′ end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), (b) base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases, (c) sugar modifications (e.g., at the 2′ position or 4′ position) or replacement of the sugar, as well as (d) backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of RNA compounds useful in this invention include, but are not limited to RNAs containing modified backbones or no natural internucleoside linkages. RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In particular embodiments, the modified RNA will have a phosphorus atom in its internucleoside backbone. 
     Modified RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those) having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Various salts, mixed salts and free acid forms are also included. 
     Representative U.S. patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; 6,028,188; 6,124,445; 6,160,109; 6,169,170; 6,172,209; 6,239,265; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and U.S. Pat. No. RE39464, each of which is herein incorporated by reference 
     Modified RNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH 2  component parts. 
     Representative U.S. patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and, 5,677,439, each of which is herein incorporated by reference. 
     In other RNA mimetics suitable or contemplated for use in iRNAs, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found, for example, in Nielsen et al.,  Science,  1991, 254, 1497-1500. 
     Some embodiments featured in the invention include RNAs with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—O—CH 2 —[known as a methylene (methylimino) or MMI backbone], —CH 2 —O—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—N(CH 3 )—CH 2 — and —N(CH 3 )—CH 2 —CH 2 —[wherein the native phosphodiester backbone is represented as —O—P—O—CH 2 —] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. In some embodiments, the RNAs featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. 
     Modified RNAs may also contain one or more substituted sugar moieties. The iRNAs, e.g., dsRNAs, featured herein can include one of the following at the 2′ position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1  to C 10  alkyl or C 2  to C 10  alkenyl and alkynyl. Exemplary suitable modifications include O[(CH 2 ) n O] m CH 3 , O(CH 2 ). n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 , where n and m are from 1 to about 10. In other embodiments, dsRNAs include one of the following at the 2′ position: C 1  to C 10  lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an iRNA, or a group for improving the pharmacodynamic properties of an iRNA, and other substituents having similar properties. In some embodiments, the modification includes a 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples herein below, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e., 2′-O—CH 2 —O—CH 2 —N(CH 2 ) 2 , also described in examples herein below. 
     Other modifications include 2′-methoxy (2′-OCH 3 ), 2′-aminopropoxy (2′-OCH 2 CH 2 CH 2 NH 2 ) and 2′-fluoro (2′-F). Similar modifications may also be made at other positions on the RNA of an iRNA, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked dsRNAs and the 5′ position of 5′ terminal nucleotide. iRNAs may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference. 
     An iRNA may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley &amp; Sons, 1990, these disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S., Chapter 15, dsRNA Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., Ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds featured in the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications. 
     Representative U.S. patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos. 4,845,205; 5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,681,941; 6,015,886; 6,147,200; 6,166,197; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, also herein incorporated by reference. 
     The RNA of an iRNA can also be modified to include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2′ and 4′ carbons. This structure effectively “locks” the ribose in the 3′-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., (2005)  Nucleic Acids Research  33(1):439-447; Mook, O R. et al., (2007) Mol Canc Ther  6(3):833-843; Grunweller, A. et al., (2003)  Nucleic Acids Research  31(12):3185-3193). 
     Representative U.S. Patents that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,670,461; 6,794,499; 6,998,484; 7,053,207; 7,084,125; and 7,399,845, each of which is herein incorporated by reference in its entirety. 
     Potentially stabilizing modifications to the ends of RNA molecules can include N-(acetylaminocaproyl)-4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (Hyp-C6), N-(acetyl-4-hydroxyprolinol (Hyp-NHAc), thymidine-2′-O-deoxythymidine (ether), N-(aminocaproyl)-4-hydroxyprolinol (Hyp-C6-amino), 2′-docosanoyl-uridine-3′-phosphate, inverted base dT(idT) and others. Disclosure of this modification can be found in U.S. Provisional Patent Application No. 61/223,665 (“the &#39;665 application”), filed Jul. 7, 2009, entitled “Oligonucleotide End Caps” and International patent application no. PCT/US10/41214, filed Jul. 7, 2010. 
     Ligands 
     Another modification of the RNA of an iRNA featured in the invention involves chemically linking to the RNA one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides &amp; Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937). 
     In one embodiment, a ligand alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated. In preferred embodiments a ligand provides an 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. 
     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 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-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, 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 kidney 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, 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 (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, bomeol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(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, 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 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-κB. 
     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&#39;s cytoskeleton, e.g., by disrupting the cell&#39;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. 
     In one ligand, 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 ligand allows for distribution of the conjugate to a target tissue, e.g., a non-kidney target tissue of the body. For example, the target tissue can be the liver, including 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 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 kidney and therefore less likely to be cleared from the body. A lipid or lipid-based ligand that binds to HSA less strongly can be used to target the conjugate to the kidney. 
     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. 
     In another preferred embodiment, the lipid based ligand binds HSA weakly or not at all, such that the conjugate will be preferably distributed to the kidney. Other moieties that target to kidney cells can also be used in place of or in addition to the lipid based ligand. 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 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 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 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. 
     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 peptide. In another alternative, the 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:4158). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO:4159)) containing a hydrophobic MTS can also be a targeting 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:4160)) and the  Drosophila  Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO:4161)) have been found to be capable of functioning as delivery peptides. A peptide or peptidomimetic can be 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 a dsRNA 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 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 peptide can facilitate targeting of an dsRNA 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). Preferably, the RGD peptide will facilitate targeting of an iRNA agent to the kidney. 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 a iRNA agent to a tumor cell expressing αvß 3  (Haubner et al.,  Jour. Nucl. Med.,  42:326-336, 2001). 
     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-permeating peptide can be, for example, an α-helical linear peptide (e.g., LL-37 or Ceropin P1), a disulfide bond-containing peptide (e.g., α-defensin, β-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 the fusion peptide domain of HIV-1 gp41 and the NLS of SV40 large T antigen (Simeoni et al., Nucl. Acids Res. 31:2717-2724, 2003). 
     Representative U.S. patents that teach the preparation of RNA conjugates include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941; 6,294,664; 6,320,017; 6,576,752; 6,783,931; 6,900,297; 7,037,646; each of which is herein incorporated by reference. 
     Chimeras 
     It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an iRNA. The present invention also includes iRNA compounds that are chimeric compounds. “Chimeric” iRNA compounds or “chimeras,” in the context of this invention, are iRNA compounds, preferably dsRNAs, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of a dsRNA compound. These iRNAs typically contain at least one region wherein the RNA is modified so as to confer upon the iRNA increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the iRNA may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of iRNA inhibition of gene expression. Consequently, comparable results can often be obtained with shorter iRNAs when chimeric dsRNAs are used, compared to phosphorothioate deoxy dsRNAs hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art. 
     Non-Ligand Groups 
     In certain instances, the RNA of an iRNA can be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to iRNAs in order to enhance the activity, cellular distribution or cellular uptake of the iRNA, and procedures for performing such conjugations are available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (Kubo, T. et al.. Biochem. Biophys. Res. Comm., 2007, 365(1):54-61; Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86:6553), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4:1053), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3:2765), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10:111; Kabanov et al., FEBS Lett., 1990, 259:327; Svinarchuk et al., Biochimie, 1993, 75:49), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2d-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651; Shea et al., Nucl. Acids Res., 1990, 18:3777), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides &amp; Nucleotides, 1995, 14:969), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923). Representative United States patents that teach the preparation of such RNA conjugates have been listed above. Typical conjugation protocols involve the synthesis of an RNAs bearing an aminolinker at one or more positions of the sequence. The amino group is then reacted with the molecule being conjugated using appropriate coupling or activating reagents. The conjugation reaction may be performed either with the RNA still bound to the solid support or following cleavage of the RNA, in solution phase. Purification of the RNA conjugate by HPLC typically affords the pure conjugate. 
     Delivery of iRNA 
     The delivery of an iRNA to a subject in need thereof can be achieved in a number of different ways. In vivo delivery can be performed directly by administering a composition comprising an iRNA, e.g. a dsRNA, to a subject. Alternatively, delivery can be performed indirectly by administering one or more vectors that encode and direct the expression of the iRNA. These alternatives are discussed further below. 
     Direct Delivery 
     In general, any method of delivering a nucleic acid molecule can be adapted for use with an iRNA (see e.g., Akhtar S. and Julian RL. (1992) Trends Cell. Biol. 2(5):139-144 and WO94/02595, which are incorporated herein by reference in their entireties). However, there are three factors that are important to consider in order to successfully deliver an iRNA molecule in vivo: (a) biological stability of the delivered molecule, (2) preventing non-specific effects, and (3) accumulation of the delivered molecule in the target tissue. The non-specific effects of an iRNA can be minimized by local administration, for example by direct injection or implantation into a tissue (as a non-limiting example, a tumor) or topically administering the preparation. Local administration to a treatment site maximizes local concentration of the agent, limits the exposure of the agent to systemic tissues that may otherwise be harmed by the agent or that may degrade the agent, and permits a lower total dose of the iRNA molecule to be administered. Several studies have shown successful knockdown of gene products when an iRNA is administered locally. For example, intraocular delivery of a VEGF dsRNA by intravitreal injection in cynomolgus monkeys (Tolentino, M J., et al (2004) Retina 24:132-138) and subretinal injections in mice (Reich, S J., et al (2003) Mol. Vis. 9:210-216) were both shown to prevent neovascularization in an experimental model of age-related macular degeneration. In addition, direct intratumoral injection of a dsRNA in mice reduces tumor volume (Pille, J., et al (2005) Mol. Ther. 11:267-274) and can prolong survival of tumor-bearing mice (Kim, W J., et al (2006) Mol. Ther. 14:343-350; Li, S., et al (2007) Mol. Ther. 15:515-523). RNA interference has also shown success with local delivery to the CNS by direct injection (Dom, G., et al. (2004) Nucleic Acids 32:e49; Tan, P H., et al (2005) Gene Ther. 12:59-66; Makimura, H., et al (2002) BMC Neurosci. 3:18; Shishkina, G T., et al (2004) Neuroscience 129:521-528; Thakker, E R., et al (2004) Proc. Natl. Acad. Sci. U.S.A. 101:17270-17275; Akaneya, Y., et al (2005) J. Neurophysiol. 93:594-602) and to the lungs by intranasal administration (Howard, K A., et al (2006) Mol. Ther. 14:476-484; Zhang, X., et al (2004) J. Biol. Chem. 279:10677-10684; Bitko, V., et al (2005) Nat. Med. 11:50-55). For administering an iRNA systemically for the treatment of a disease, the RNA can be modified or alternatively delivered using a drug delivery system; both methods act to prevent the rapid degradation of the dsRNA by endo- and exo-nucleases in vivo. Modification of the RNA or the pharmaceutical carrier can also permit targeting of the iRNA composition to the target tissue and avoid undesirable off-target effects. iRNA molecules can be modified by chemical conjugation to lipophilic groups such as cholesterol to enhance cellular uptake and prevent degradation. For example, an iRNA directed against ApoB conjugated to a lipophilic cholesterol moiety was injected systemically into mice and resulted in knockdown of apoB mRNA in both the liver and jejunum (Soutschek, J., et al (2004) Nature 432:173-178). Conjugation of an iRNA to an aptamer has been shown to inhibit tumor growth and mediate tumor regression in a mouse model of prostate cancer (McNamara, J O., et al (2006) Nat. Biotechnol. 24:1005-1015). In an alternative embodiment, the iRNA can be delivered using drug delivery systems such as a nanoparticle, a dendrimer, a polymer, liposomes, or a cationic delivery system. Positively charged cationic delivery systems facilitate binding of an iRNA molecule (negatively charged) and also enhance interactions at the negatively charged cell membrane to permit efficient uptake of an iRNA by the cell. Cationic lipids, dendrimers, or polymers can either be bound to an iRNA, or induced to form a vesicle or micelle (see e.g., Kim SH., et al (2008) Journal of Controlled Release 129(2):107-116) that encases an iRNA. The formation of vesicles or micelles further prevents degradation of the iRNA when administered systemically. Methods for making and administering cationic-iRNA complexes are well within the abilities of one skilled in the art (see e.g., Sorensen, D R., et al (2003) J. Mol. Biol 327:761-766; Verma, U N., et al (2003) Clin. Cancer Res. 9:1291-1300; Arnold, A S et al (2007) J. Hypertens. 25:197-205, which are incorporated herein by reference in their entirety). Some non-limiting examples of drug delivery systems useful for systemic delivery of iRNAs include DOTAP (Sorensen, D R., et al (2003), supra; Verma, U N., et al (2003), supra), Oligofectamine, “solid nucleic acid lipid particles” (Zimmermann, T S., et al (2006) Nature 441:111-114), cardiolipin (Chien, P Y., et al (2005) Cancer Gene Ther. 12:321-328; Pal, A., et al (2005) Int J. Oncol. 26:1087-1091), polyethyleneimine (Bonnet M E., et al (2008) Pharm. Res. August 16 Epub ahead of print; Aigner, A. (2006) J. Biomed. Biotechnol. 71659), Arg-Gly-Asp (RGD) peptides (Liu, S. (2006) Mol. Pharm. 3:472-487), and polyamidoamines (Tomalia, D A., et al (2007) Biochem. Soc. Trans. 35:61-67; Yoo, H., et al (1999) Pharm. Res. 16:1799-1804). In some embodiments, an iRNA forms a complex with cyclodextrin for systemic administration. Methods for administration and pharmaceutical compositions of iRNAs and cyclodextrins can be found U.S. Pat. No. 7,427,605, which is herein incorporated by reference in its entirety. 
     Vector Encoded dsRNAs 
     In another aspect, the dsRNAs of the invention can be expressed from transcription units inserted into DNA or RNA vectors (see, e.g., Couture, A, et al.,  TIG . (1996), 12:5-10; Skillem, A., et al., International PCT Publication No. WO 00/22113, Conrad, International PCT Publication No. WO 00/22114, and Conrad, U.S. Pat. No. 6,054,299). Expression can be transient (on the order of hours to weeks) or sustained (weeks to months or longer), depending upon the specific construct used and the target tissue or cell type. These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be an integrating or non-integrating vector. The transgene can also be constructed to permit it to be inherited as an extrachromosomal plasmid (Gassmann, et al.,  Proc. Natl. Acad. Sci. USA  (1995) 92:1292). 
     The individual strand or strands of an iRNA can be transcribed from a promoter on an expression vector. Where two separate strands are to be expressed to generate, for example, a dsRNA, two separate expression vectors can be co-introduced (e.g., by transfection or infection) into a target cell. Alternatively each individual strand of a dsRNA can be transcribed by promoters both of which are located on the same expression plasmid. In one embodiment, a dsRNA is expressed as an inverted repeat joined by a linker polynucleotide sequence such that the dsRNA has a stem and loop structure. 
     iRNA expression vectors are generally DNA plasmids or viral vectors. Expression vectors compatible with eukaryotic cells, preferably those compatible with vertebrate cells, can be used to produce recombinant constructs for the expression of an iRNA as described herein. Eukaryotic cell expression vectors are well known in the art and are available from a number of commercial sources. Typically, such vectors are provided containing convenient restriction sites for insertion of the desired nucleic acid segment. Delivery of iRNA expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that allows for introduction into a desired target cell. 
     iRNA expression plasmids can be transfected into target cells as a complex with cationic lipid carriers (e.g., Oligofectamine) or non-cationic lipid-based carriers (e.g., Transit-TKO™). Multiple lipid transfections for iRNA-mediated knockdowns targeting different regions of a target RNA over a period of a week or more are also contemplated by the invention. Successful introduction of vectors into host cells can be monitored using various known methods. For example, transient transfection can be signaled with a reporter, such as a fluorescent marker, such as Green Fluorescent Protein (GFP). Stable transfection of cells ex vivo can be ensured using markers that provide the transfected cell with resistance to specific environmental factors (e.g., antibiotics and drugs), such as hygromycin B resistance. 
     Viral vector systems which can be utilized with the methods and compositions described herein include, but are not limited to, (a) adenovirus vectors; (b) retrovirus vectors, including but not limited to lentiviral vectors, moloney murine leukemia virus, etc.; (c) adeno-associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picomavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors or avipox, e.g. canary pox or fowl pox; and (j) a helper-dependent or gutless adenovirus. Replication-defective viruses can also be advantageous. Different vectors will or will not become incorporated into the cells&#39; genome. The constructs can include viral sequences for transfection, if desired. Alternatively, the construct may be incorporated into vectors capable of episomal replication, e.g. EPV and EBV vectors. Constructs for the recombinant expression of an iRNA will generally require regulatory elements, e.g., promoters, enhancers, etc., to ensure the expression of the iRNA in target cells. Other aspects to consider for vectors and constructs are further described below. 
     Vectors useful for the delivery of an iRNA will include regulatory elements (promoter, enhancer, etc.) sufficient for expression of the iRNA in the desired target cell or tissue. The regulatory elements can be chosen to provide either constitutive or regulated/inducible expression. 
     Expression of the iRNA can be precisely regulated, for example, by using an inducible regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones (Docherty et al., 1994, FASEB J. 8:20-24). Such inducible expression systems, suitable for the control of dsRNA expression in cells or in mammals include, for example, regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-beta-D1-thiogalactopyranoside (IPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the iRNA transgene. 
     In a specific embodiment, viral vectors that contain nucleic acid sequences encoding an iRNA can be used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding an iRNA are cloned into one or more vectors, which facilitates delivery of the nucleic acid into a patient. More detail about retroviral vectors can be found, for example, in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest. 93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993). Lentiviral vectors contemplated for use include, for example, the HIV based vectors described in U.S. Pat. Nos. 6,143,520; 5,665,557; and 5,981,276, which are herein incorporated by reference. 
     Adenoviruses are also contemplated for use in delivery of iRNAs. Adenoviruses are especially attractive vehicles, e.g., for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992); Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). A suitable AV vector for expressing an iRNA featured in the invention, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia H et al. (2002),  Nat. Biotech.  20: 1006-1010. 
     Use of Adeno-associated virus (AAV) vectors is also contemplated (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146). In one embodiment, the iRNA can be expressed as two separate, complementary single-stranded RNA molecules from a recombinant AAV vector having, for example, either the U6 or H1 RNA promoters, or the cytomegalovirus (CMV) promoter. Suitable AAV vectors for expressing the dsRNA featured in the invention, methods for constructing the recombinant AV vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher K J et al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989), J. Virol. 63: 3822-3826; U.S. Pat. Nos. 5,252,479; 5,139,941; International Patent Application No. WO 94/13788; and International Patent Application No. WO 93/24641, the entire disclosures of which are herein incorporated by reference. 
     Another preferred viral vector is a pox virus such as a vaccinia virus, for example an attenuated vaccinia such as Modified Virus Ankara (MVA) or NYVAC, an avipox such as fowl pox or canary pox. 
     The tropism of viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate. For example, lentiviral vectors can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors can be made to target different cells by engineering the vectors to express different capsid protein serotypes; see, e.g., Rabinowitz J E et al. (2002), J Virol 76:791-801, the entire disclosure of which is herein incorporated by reference. 
     The pharmaceutical preparation of a vector can include the vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. 
     Pharmaceutical Compositions Containing iRNA 
     In one embodiment, the invention provides pharmaceutical compositions containing a dual targeting siRNA agent, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the siRNA is useful for treating a disease or disorder associated with the expression or activity of a target gene, such as pathological processes mediated by PCSK9 expression. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV) delivery. Another example is compositions that are formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion. 
     The pharmaceutical compositions featured herein are administered in dosages sufficient to inhibit expression of the target genes. In general, a suitable dose of siRNA will be in the range of 0.01 to 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39 mg/kg, 40 mg/kg, 41 mg/kg, 42 mg/kg, 43 mg/kg, 44 mg/kg, 45 mg/kg, 46 mg/kg, 47 mg/kg, 48 mg/kg, 49 mg/kg, or 50 mg/kg per single dose. 
     The pharmaceutical composition may be administered once daily, or the iRNA may be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the iRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the iRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. 
     The effect of a single dose of siRNA on PCSK9 levels can be long lasting, such that subsequent doses are administered at not more than 3, 4, or 5 day intervals, or at not more than 1, 2, 3, or 4 week intervals. 
     The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the individual iRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein. 
     Advances in mouse genetics have generated a number of mouse models for the study of various human diseases, such as pathological processes mediated by PCSK9 expression. Such models can be used for in vivo testing of iRNA, as well as for determining a therapeutically effective dose. A suitable mouse model is, for example, a mouse containing a transgene expressing human PCSK9. 
     The present invention also includes pharmaceutical compositions and formulations that include the iRNA compounds featured in the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (e.g., by a transdermal patch), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal, e.g., via an implanted device; or intracranial, e.g., by intraparenchymal, intrathecal or intraventricular, administration. 
     The iRNA can be delivered in a manner to target a particular tissue, such as the liver (e.g., the hepatocytes of the liver). 
     Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional 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. Suitable topical formulations include those in which the iRNAs featured in the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Suitable lipids and liposomes include neutral (e.g., dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g., dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g., dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). iRNAs featured in the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, iRNAs may be complexed to lipids, in particular to cationic lipids. Suitable fatty acids and esters include but are not limited to arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcamitine, an acylcholine, or a C1-20 alkyl ester (e.g., isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. Topical formulations are described in detail in U.S. Pat. No. 6,747,014, which is incorporated herein by reference. 
     Liposomal Formulations 
     There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. 
     Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo. 
     In order to traverse intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores. 
     Further advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., 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. 
     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 liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act. 
     Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that 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 a wide variety of drugs, both hydrophilic and hydrophobic, into the skin. 
     Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis 
     Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al., Biochem. Biophys. Res. Commun., 1987, 147, 980-985). 
     Liposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is 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, 1992, 19, 269-274). 
     One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. 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 as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol. 
     Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g., as a solution or as an emulsion) were ineffective (Weiner et al., Journal of Drug Targeting, 1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al., Antiviral Research, 1992, 18, 259-265). 
     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 dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin (Hu et al. S.T.P.Pharma. Sci., 1994, 4, 6, 466). 
     Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53, 3765). 
     Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. (Ann. N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside G M1 , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G M1  or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al). 
     Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C 1215G , that contains a PEG moiety. Illum et al. (FEBS Lett., 1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. (FEBS Lett., 1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. (Biochimica et Biophysica Acta, 1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. EP 0 445 131 B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073 (Zalipsky et al.) Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al). U.S. Pat. No. 5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces. 
     A number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include a dsRNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising dsRNAs targeted to the raf gene. 
     Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g., they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin. 
     Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most 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 (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285). 
     If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic 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, 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. 
     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 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. 
     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, N.Y., 1988, p. 285). 
     Nucleic Acid Lipid Particles 
     In one embodiment, a dual targeting siRNA agent featured in the invention is fully encapsulated in the lipid formulation, e.g., to form a nucleic acid-lipid particle, e.g., a SPLP, pSPLP, or SNALP. As used herein, the term “SNALP” refers to a stable nucleic acid-lipid particle, including SPLP. As used herein, the term “SPLP” refers to a nucleic acid-lipid particle comprising plasmid DNA encapsulated within a lipid vesicle. Nucleic acid-lipid particles, e.g., SNALPs, typically contain a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the particle (e.g., a PEG-lipid conjugate). SNALPs and SPLPs are extremely useful for systemic applications, as they exhibit extended circulation lifetimes following intravenous (i.v.) injection and accumulate at distal sites (e.g., sites physically separated from the administration site). SPLPs include “pSPLP”, which include an encapsulated condensing agent-nucleic acid complex as set forth in PCT Publication No. WO 00/03683. 
     The particles of the present invention typically have a mean diameter of about 50 nm to about 150 nm, more typically about 60 nm to about 130 nm, more typically about 70 nm to about 110 nm, most typically about 70 nm to about 90 nm, and are substantially nontoxic. For example, the mean diameter of the particles can be about 50 nm, 55 nm, 60 nn, 65 nn, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 140 nm, 145 nm, or 150 nm. 
     In addition, the nucleic acids when present in the nucleic acid-lipid particles of the present invention are resistant in aqueous solution to degradation with a nuclease. Nucleic acid-lipid particles and their method of preparation are disclosed in, e.g., U.S. Pat. Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; 6,815,432; and PCT Publication No. WO 96/40964. 
     In one embodiment, the lipid to drug ratio (mass/mass ratio) (e.g., lipid to dsRNA ratio) will be in the range of from about 1:1 to about 50:1, from about 1:1 to about 25:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. The lipid to dsRNA ratio can be about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 113:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, or 50:1. 
     The nucleic acid lipid particles include a cationic lipid. The cationic lipid may be, for example, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or analogs thereof, 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (XTC), (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1,1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol (Tech G1, e.g., C12-200), or a mixture thereof. The cationic lipid may comprise from about 10 mol % to about 70 mol % or about 40 mol % of the total lipid present in the particle. The cationic lipid may comprise 10 mol %, 15 mol %, 20 mol %, 25 mol %, 30 mol %, 35 mol %, 40 mol %, 45 mol %, 50 mol %, 55 mol %, 60 mol %, 65 mol %, 70 mol %, 75 mol %, 80 mol %, 85 mol %, 90 mol %, or 95 mol % of the total lipid present in the particle. The cationic lipid may comprise 57.1 mol % or 57.5 mol % of the total lipid present in the particle. 
     In one embodiment, the compound 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (XTC) can be used to prepare lipid-siRNA nanoparticles. Synthesis of 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane is described in U.S. provisional patent application No. 61/107,998 filed on Oct. 23, 2008, which is herein incorporated by reference. 
     In one embodiment, the lipid-siRNA particle includes 40% 2, 2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane: 10% DSPC: 40% Cholesterol: 10% PEG-C-DOMG (mole percent) with a particle size of 63.0±20 nm and a 0.027 siRNA/Lipid Ratio. 
     The nucleic acid lipid particle generally includes a non-cationic lipid. The non-cationic lipid may be an anionic lipid or a neutral lipid including, but not limited to, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), cholesterol, or a mixture thereof. 
     The non-cationic lipid may be from about 5 mol % to about 90 mol %, about 10 mol %, or about 58 mol % if cholesterol is included, of the total lipid present in the particle. The non-cationic lipid may be about 5 mol %, 6 mol %, 7 mol %, 7.5 mol %, 7.7 mol %, 8 mol %. 9 mol %, 10 mol %, 11 mol %, 12 mol %, 13 mol %, 14 mol %, 15 mol %, 16 mol %, 17 mol %, 18 mol %, 19 mol %, 20 mol %, 25 mol %, 30 mol %, 35 mol %, 40 mol %, 45 mol %, 50 mol %, 55 mol %, 60 mol %, 65 mol %, 70 mol %, 75 mol %, 80 mol %, 85 mol %, 90 mol %, or 95 mol %. 
     The nucleic acid lipid particle generally includes a conjugated lipid. The conjugated lipid that inhibits aggregation of particles may be, for example, a polyethyleneglycol (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof. The PEG-DAA conjugate may be, for example, a PEG-dilauryloxypropyl (Ci 2 ), a PEG-dimyristyloxypropyl (Ci 4 ), a PEG-dipalmityloxypropyl (Ci 6 ), or a PEG-distearyloxypropyl (C] 8 ). The conjugated lipid can be PEG-DMG (PEG-didimyristoyl glycerol (C14-PEG, or PEG-C14) (PEG with avg mol wt of 2000); PEG-DSG (PEG-distyryl glycerol (C18-PEG, or PEG-C18) (PEG with avg mol wt of 2000); or PEG-cDMA: PEG-carbamoyl-1,2-dimyristyloxypropylamine (PEG with avg mol wt of 2000). 
     The conjugated lipid that prevents aggregation of particles may be from 0 mol % to about 20 mol % or about 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0 17.0, 18, 19.0 or 20.0 mol % of the total lipid present in the particle. 
     In some embodiments, the nucleic acid-lipid particle further includes cholesterol at, e.g., about 10 mol % to about 60 mol % or about 48 mol % of the total lipid present in the particle. For example, the nucleic acid-lipid particle further includes cholesterol at about 5 mol %, 10 mol %, 15 mol %, 20 mol %, 25 mol %, 30 mol %, 35 mol %, 40 mol %, 45 mol %, 50 mol %, 55 mol %, or 60 mol %. The nucleic acid-lipid particle can include cholesterol at about 31.5 mol %, 34.4 mol %, 35 mol %, 38.5 mol %, or 40 mol % of the total lipid present in the particle. 
     LNP01 
     In one embodiment, the lipidoid ND98.4HCl (MW 1487) (see U.S. patent application Ser. No. 12/056,230, filed Mar. 26, 2008, which is herein incorporated by reference), Cholesterol (Sigma-Aldrich), and PEG-Ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-dsRNA nanoparticles (i.e., LNP01 particles). Stock solutions of each in ethanol can be prepared as follows: ND98, 133 mg/ml; Cholesterol, 25 mg/ml, PEG-Ceramide C16, 100 mg/ml. The ND98, Cholesterol, and PEG-Ceramide C16 stock solutions can then be combined in a, e.g., 42:48:10 molar ratio. The combined lipid solution can be mixed with aqueous dsRNA (e.g., in sodium acetate pH 5) such that the final ethanol concentration is about 35-45% and the final sodium acetate concentration is about 100-300 mM. Lipid-dsRNA nanoparticles typically form spontaneously upon mixing. Depending on the desired particle size distribution, the resultant nanoparticle mixture can be extruded through a polycarbonate membrane (e.g., 100 nm cut-off) using, for example, a thermobarrel extruder, such as Lipex Extruder (Northern Lipids, Inc). In some cases, the extrusion step can be omitted. Ethanol removal and simultaneous buffer exchange can be accomplished by, for example, dialysis or tangential flow filtration. Buffer can be exchanged with, for example, phosphate buffered saline (PBS) at about pH 7, e.g., about pH 6.9, about pH 7.0, about pH 7.1, about pH 7.2, about pH 7.3, or about pH 7.4. 
     
       
         
         
             
             
         
       
     
     LNP01 formulations are described, e.g., in International Application Publication No. WO 2008/042973, which is hereby incorporated by reference. 
     Exemplary Nucleic Acid Lipid Particles 
     Additional exemplary lipid-dsRNA formulations arm as follows: 
     
       
         
           
               
               
               
             
               
                 TABLE A 
               
               
                   
               
               
                   
                   
                 cationic lipid/non-cationic 
               
               
                   
                   
                 lipid/cholesterol/PEG-lipid conjugate 
               
               
                   
                 Cationic 
                 Mol % ratios 
               
               
                   
                 Lipid 
                 Lipid:siRNA ratio 
               
               
                   
               
             
            
               
                 SNALP 
                 DLinDMA 
                 DLinDMA/DPPC/Cholesterol/PEG-cDMA 
               
               
                   
                   
                 (57.1/7.1/34.4/1.4) 
               
               
                   
                   
                 lipid:siRNA ~ 7:1 
               
               
                 S-XTC 
                 XTC 
                 XTC/DPPC/Cholesterol/PEG-cDMA 
               
               
                   
                   
                 57.1/7.1/34.4/1.4 
               
               
                   
                   
                 lipid:siRNA ~ 7:1 
               
               
                 LNP05 
                 XTC 
                 XTC/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA ~ 6:1 
               
               
                 LNP06 
                 XTC 
                 XTC/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA ~ 11:1 
               
               
                 LNP07 
                 XTC 
                 XTC/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 60/7.5/31/1.5, 
               
               
                   
                   
                 lipid:siRNA ~ 6:1 
               
               
                 LNP08 
                 XTC 
                 XTC/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 60/7.5/31/1.5, 
               
               
                   
                   
                 lipid:siRNA ~ 11:1 
               
               
                 LNP09 
                 XTC 
                 XTC/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP10 
                 ALN100 
                 ALN100/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP11 
                 MC3 
                 MC-3/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP12 
                 C12-200 
                 C12-200/DSPC/Cholesterol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP13 
                 XTC 
                 XTC/DSPC/Chol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 33:1 
               
               
                 LNP14 
                 MC3 
                 MC3/DSPC/Chol/PEG-DMG 
               
               
                   
                   
                 40/15/40/5 
               
               
                   
                   
                 Lipid:siRNA: 11:1 
               
               
                 LNP15 
                 MC3 
                 MC3/DSPC/Chol/PEG-DSG/GalNAc-PEG-DSG 
               
               
                   
                   
                 50/10/35/4.5/0.5 
               
               
                   
                   
                 Lipid:siRNA: 11:1 
               
               
                 LNP16 
                 MC3 
                 MC3/DSPC/Chol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 7:1 
               
               
                 LNP17 
                 MC3 
                 MC3/DSPC/Chol/PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                 LNP18 
                 MC3 
                 MC3/DSPC/Chol/PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 12:1 
               
               
                 LNP19 
                 MC3 
                 MC3/DSPC/Chol/PEG-DMG 
               
               
                   
                   
                 50/10/35/5 
               
               
                   
                   
                 Lipid:siRNA: 8:1 
               
               
                 LNP20 
                 MC3 
                 MC3/DSPC/Chol/PEG-DPG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                 LNP21 
                 C12-200 
                 C12-200/DSPC/Chol/PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 7:1 
               
               
                 LNP22 
                 XTC 
                 XTC/DSPC/Chol/PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                   
               
            
           
         
       
     
     SNALP (1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA)) comprising formulations are described in International Publication No. WO2009/127060, filed Apr. 15, 2009, which is hereby incorporated by reference. 
     XTC comprising formulations are described, e.g., in U.S. Provisional Ser. No. 61/239,686, filed Sep. 3, 2009, and International patent application no. PCT/US10/22614, filed Jan. 29, 2010, which are hereby incorporated by reference. 
     MC3 comprising formulations are described, e.g., in U.S. Provisional Ser. No. 61/244,834, filed Sep. 22, 2009, and U.S. Provisional Ser. No. 61/185,800, filed Jun. 10, 2009, which are hereby incorporated by reference. 
     ALN100, i.e., ALNY-100 comprising formulations are described, e.g., International patent application number PCT/US09/63933, filed on Nov. 10, 2009, which is hereby incorporated by reference. 
     C12-200, i.e., Tech G1 comprising formulations are described in U.S. Provisional Ser. No. 61/175,770, filed May 5, 2009, which is hereby incorporated by reference. 
     Synthesis of Cationic Lipids. 
     Any of the compounds, e.g., cationic lipids and the like, used in the nucleic acid-lipid particles of the invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. All substituents are as defined below unless indicated otherwise. 
     “Alkyl” means a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. 
     “Alkenyl” means an alkyl, as defined above, containing at least one double bond between adjacent carbon atoms. Alkenyls include both cis and trans isomers. Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. 
     “Alkynyl” means any alkyl or alkenyl, as defined above, which additionally contains at least one triple bond between adjacent carbons. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like. 
     “Acyl” means any alkyl, alkenyl, or alkynyl wherein the carbon at the point of attachment is substituted with an oxo group, as defined below. For example, —C(═O)alkyl, —C(═O)alkenyl, and —C(═O)alkynyl are acyl groups. 
     “Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined below. Heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperizynyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. 
     The terms “optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted acyl”, and “optionally substituted heterocycle” means that, when substituted, at least one hydrogen atom is replaced with a substituent. In the case of an oxo substituent (═O) two hydrogen atoms are replaced. In this regard, substituents include oxo, halogen, heterocycle, —CN, —ORx, —NRxRy, —NRxC(═O)Ry, —NRxSO2Ry, —C(═O)Rx, —C(═O)ORx, —C(═O)NRxRy, —SOnRx and —SOnNRxRy, wherein n is 0, 1 or 2, Rx and Ry are the same or different and independently hydrogen, alkyl or heterocycle, and each of said alkyl and heterocycle substituents may be further substituted with one or more of oxo, halogen, —OH, —CN, alkyl, —ORx, heterocycle, —NRxRy, —NRxC(═O)Ry, —NRxSO2Ry, —C(═O)Rx, —C(═O)ORx, —C(═O)NRxRy, —SOnRx and —SOnNRxRy. 
     “Halogen” means fluoro, chloro, bromo and iodo. 
     In some embodiments, the methods of the invention may require the use of protecting groups. Protecting group methodology is well known to those skilled in the art (see, for example, Protective Groups in Organic Synthesis, Green, T. W. et al., Wiley-Interscience, New York City, 1999). Briefly, protecting groups within the context of this invention are any group that reduces or eliminates unwanted reactivity of a functional group. A protecting group can be added to a functional group to mask its reactivity during certain reactions and then removed to reveal the original functional group. In some embodiments an “alcohol protecting group” is used. An “alcohol protecting group” is any group which decreases or eliminates unwanted reactivity of an alcohol functional group. Protecting groups can be added and removed using techniques well known in the art. 
     Synthesis of Formula A 
     In one embodiments, nucleic acid-lipid particles of the invention are formulated using a cationic lipid of formula A; XTC is a cationic lipid of formula A: 
     
       
         
         
             
             
         
       
     
     where R1 and R2 are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R3 and R4 are independently lower alkyl or R3 and R4 can be taken together to form an optionally substituted heterocyclic ring. 
     In general, the lipid of formula A above may be made by the following Reaction Schemes 1 or 2, wherein all substituents are as defined above unless indicated otherwise. 
     
       
         
         
             
             
         
       
     
     Lipid A, where R 1  and R 2  are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R 3  and R 4  are independently lower alkyl or R 3  and R 4  can be taken together to form an optionally substituted heterocyclic ring, can be prepared according to Scheme 1. Ketone 1 and bromide 2 can be purchased or prepared according to methods known to those of ordinary skill in the art. Reaction of 1 and 2 yields ketal 3. Treatment of ketal 3 with amine 4 yields lipids of formula A. The lipids of formula A can be converted to the corresponding ammonium salt with an organic salt of formula 5, where X is anion counter ion selected from halogen, hydroxide, phosphate, sulfate, or the like. 
     
       
         
         
             
             
         
       
     
     Alternatively, the ketone 1 starting material can be prepared according to Scheme 2. Grignard reagent 6 and cyanide 7 can be purchased or prepared according to methods known to those of ordinary skill in the art. Reaction of 6 and 7 yields ketone 1. Conversion of ketone 1 to the corresponding lipids of formula A is as described in Scheme 1. 
     Synthesis of MC3 
     Preparation of DLin-M-C3-DMA (i.e., (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate) was as follows. A solution of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-ol (0.53 g), 4-N,N-dimethylaminobutyric acid hydrochloride (0.51 g), 4-N,N-dimethylaminopyridine (0.61 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.53 g) in dichloromethane (5 mL) was stirred at room temperature overnight. The solution was washed with dilute hydrochloric acid followed by dilute aqueous sodium bicarbonate. The organic fractions were dried over anhydrous magnesium sulphate, filtered and the solvent removed on a rotovap. The residue was passed down a silica gel column (20 g) using a 1-5% methanol/dichloromethane elution gradient. Fractions containing the purified product were combined and the solvent removed, yielding a colorless oil (0.54 g). 
     Synthesis of ALNY-100 
     Synthesis of ketal 519 [ALNY-100] was performed using the following scheme 3: 
     
       
         
         
             
             
         
       
     
     Synthesis of 515: 
     To a stirred suspension of LiAlH4 (3.74 g, 0.09852 mol) in 200 ml anhydrous THF in a two neck RBF (1 L), was added a solution of 514 (10 g, 0.04926 mol) in 70 mL of THF slowly at 0 0C under nitrogen atmosphere. After complete addition, reaction mixture was warmed to room temperature and then heated to reflux for 4 h. Progress of the reaction was monitored by TLC. After completion of reaction (by TLC) the mixture was cooled to 0 0C and quenched with careful addition of saturated Na2SO4 solution. Reaction mixture was stirred for 4 h at room temperature and filtered off. Residue was washed well with THF. The filtrate and washings were mixed and diluted with 400 mL dioxane and 26 mL conc. HCl and stirred for 20 minutes at room temperature. The volatilities were stripped off under vacuum to furnish the hydrochloride salt of 515 as a white solid. Yield: 7.12 g 1H-NMR (DMSO, 400 MHz): δ=9.34 (broad, 2H), 5.68 (s, 2H), 3.74 (m, 1H), 2.66-2.60 (m, 2H), 2.50-2.45 (m, 5H). 
     Synthesis of 516: 
     To a stirred solution of compound 515 in 100 mL dry DCM in a 250 mL two neck RBF, was added NEt3 (37.2 mL, 0.2669 mol) and cooled to 0 0C under nitrogen atmosphere. After a slow addition of N-(benzyloxy-carbonyloxy)-succinimide (20 g, 0.08007 mol) in 50 mL dry DCM, reaction mixture was allowed to warm to room temperature. After completion of the reaction (2-3 h by TLC) mixture was washed successively with 1N HCl solution (1×100 mL) and saturated NaHCO 3 solution (1×50 mL). The organic layer was then dried over anhyd. Na2SO4 and the solvent was evaporated to give crude material which was purified by silica gel column chromatography to get 516 as sticky mass. Yield: 11 g (89%). 1H-NMR (CDCl3, 400 MHz): δ=7.36-7.27 (m, 5H), 5.69 (s, 2H), 5.12 (s, 2H), 4.96 (br., 1H) 2.74 (s, 3H), 2.60 (m, 2H), 2.30-2.25 (m, 2H). LC-MS [M+H] −232.3 (96.94%). 
     Synthesis of 517A and 517B: 
     The cyclopentene 516 (5 g, 0.02164 mol) was dissolved in a solution of 220 mL acetone and water (10:1) in a single neck 500 mL RBF and to it was added N-methyl morpholine-N-oxide (7.6 g, 0.06492 mol) followed by 4.2 mL of 7.6% solution of OsO4 (0.275 g, 0.00108 mol) in tert-butanol at room temperature. After completion of the reaction (˜3 h), the mixture was quenched with addition of solid Na2SO3 and resulting mixture was stirred for 1.5 h at room temperature. Reaction mixture was diluted with DCM (300 mL) and washed with water (2×100 mL) followed by saturated NaHCO 3  (1×50 mL) solution, water (1×30 mL) and finally with brine (lx 50 mL). Organic phase was dried over an. Na2SO4 and solvent was removed in vacuum. Silica gel column chromatographic purification of the crude material was afforded a mixture of diastereomers, which were separated by prep HPLC. Yield: −6 g crude 
     517A—Peak-1 (white solid), 5.13 g (96%). 1H-NMR (DMSO, 400 MHz): δ=7.39-7.31 (m, 5H), 5.04 (s, 2H), 4.78-4.73 (m, 1H), 4.48-4.47 (d, 2H), 3.94-3.93 (m, 2H), 2.71 (s, 3H), 1.72-1.67 (m, 4H). LC-MS—[M+H]-266.3, [M+NH4+]-283.5 present, HPLC-97.86%. Stereochemistry confirmed by X-ray. 
     Synthesis of 518: 
     Using a procedure analogous to that described for the synthesis of compound 505, compound 518 (1.2 g, 41%) was obtained as a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ=7.35-7.33 (m, 4H), 7.30-7.27 (m, 1H), 5.37-5.27 (m, 8H), 5.12 (s, 2H), 4.75 (m, 1H), 4.58-4.57 (m, 2H), 2.78-2.74 (m, 7H), 2.06-2.00 (m, 8H), 1.96-1.91 (m, 2H), 1.62 (m, 4H), 1.48 (m, 2H), 1.37-1.25 (br m, 36H), 0.87 (m, 6H). HPLC-98.65%. 
     General Procedure for the Synthesis of Compound 519: 
     A solution of compound 518 (1 eq) in hexane (15 mL) was added in a drop-wise fashion to an ice-cold solution of LAH in THF (1 M, 2 eq). After complete addition, the mixture was heated at 40° C. over 0.5 h then cooled again on an ice bath. The mixture was carefully hydrolyzed with saturated aqueous Na2SO4 then filtered through celite and reduced to an oil. Column chromatography provided the pure 519 (1.3 g, 68%) which was obtained as a colorless oil. 13C NMR □=130.2, 130.1 (×2), 127.9 (×3), 112.3, 79.3, 64.4, 44.7, 38.3, 35.4, 31.5, 29.9 (×2), 29.7, 29.6 (×2), 29.5 (×3), 29.3 (×2), 27.2 (×3), 25.6, 24.5, 23.3, 226, 14.1; Electrospray MS (+ve): Molecular weight for C44H80NO2 (M+H)+ Calc. 654.6, Found 654.6. 
     General Synthesis of Nucleic Add Lipid Particles 
     Formulations prepared by either the standard or extrusion-free method can be characterized in similar manners. For example, formulations are typically characterized by visual inspection. They should be whitish translucent solutions free from aggregates or sediment. Particle size and particle size distribution of lipid-nanoparticles can be measured by light scattering using, for example, a Malvern Zetasizer Nano ZS (Malvern, USA). Particles should be about 20-300 nm, such as 40-100 nm in size. The particle size distribution should be unimodal. The total dsRNA concentration in the formulation, as well as the entrapped fraction, is estimated using a dye exclusion assay. A sample of the formulated dsRNA can be incubated with an RNA-binding dye, such as Ribogreen (Molecular Probes) in the presence or absence of a formulation disrupting surfactant, e.g., 0.5% Triton-X100. The total dsRNA in the formulation can be determined by the signal from the sample containing the surfactant, relative to a standard curve. The entrapped fraction is determined by subtracting the “free” dsRNA content (as measured by the signal in the absence of surfactant) from the total dsRNA content. Percent entrapped dsRNA is typically &gt;85%. For SNALP formulation, the particle size is at least 30 nm, at least 40 nm, at least 50 nm, at least 60 nm, at least 70 nm, at least 80 nm, at least 90 nm, at least 100 nm, at least 110 nm, and at least 120 nm. The suitable range is typically about at least 50 nm to about at least 110 nm, about at least 60 nm to about at least 100 nm, or about at least 80 nm to about at least 90 nm. 
     Other Formulations 
     Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. In some embodiments, oral formulations are those in which dsRNAs featured in the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcamitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g., sodium). In some embodiments, combinations of penetration enhancers are used, for example, fatty acids/salts in combination with bile acids/salts. One exemplary combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. DsRNAs featured in the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. DsRNA complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Suitable complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyomithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylaminomethylethylene P(TDAE), polyaminostyrene (e.g., p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for dsRNAs and their preparation are described in detail in U.S. Pat. No. 6,887,906, US Publn. No. 20030027780, and U.S. Pat. No. 6,747,014, each of which is incorporated herein by reference. 
     Compositions and formulations for parenteral, intraparenchymal (into the brain), intrathecal, intraventricular or intrahepatic administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. 
     Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. Particularly preferred are formulations that target the liver when treating hepatic disorders such as hepatic carcinoma. 
     The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. 
     The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. 
     Additional Formulations 
     Emulsions 
     The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in Remington&#39;s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion. 
     Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y. Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285). 
     Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate. 
     A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase. 
     Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin. 
     The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions. 
     In one embodiment of the present invention, the compositions of iRNAs and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington&#39;s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271). 
     The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, LV., Popovich NG., and Ansel HC., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously. 
     Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DAO750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil. 
     Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or iRNAs. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of iRNAs and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of iRNAs and nucleic acids. 
     Microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the iRNAs and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these classes has been discussed above. 
     Penetration Enhancers 
     In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly iRNAs, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. 
     Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of the above mentioned classes of penetration enhancers are described below in greater detail. 
     Surfactants: In connection with the present invention, surfactants (or “surface-active agents”) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of iRNAs through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92); and perfluorochemical emulsions, such as FC-43. Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252). 
     Fatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcamitines, acylcholines, C1-20 alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (see e.g., Touitou, E., et al. Enhancement in Drug Delivery, CRC Press, Danvers, Mass., 2006; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654). 
     Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Brunton, Chapter 38 in: Goodman &amp; Gilman&#39;s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term “bile salts” includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. Suitable bile salts include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington&#39;s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al., J. Pharm. Exp. Ther., 1992, 263, 25; Yamashita et al., J. Pharm. Sci., 1990, 79, 579-583). 
     Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of iRNAs through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Suitable chelating agents include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enaminesxsee e.g., Katdare, A. et al., Excipient development for pharmaceutical, biotechnology, and drug delivery, CRC Press, Danvers, Mass., 2006; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al., J. Control Rel., 1990, 14, 43-51). 
     Non-chelating non-surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of iRNAs through the alimentary mucosa (see e.g., Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626). 
     Agents that enhance uptake of iRNAs at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97/30731), are also known to enhance the cellular uptake of dsRNAs. Examples of commercially available transfection reagents include, for example Lipofectamine™ (Invitrogen; Carlsbad, Calif.), Lipofectamine 2000™ (Invitrogen; Carlsbad, Calif.), 293Fectin™ (Invitrogen; Carlsbad, Calif.), Cellfectin™ (Invitrogen; Carlsbad, Calif.), DMRIE-CT™ (Invitrogen; Carlsbad, Calif.), FreeStyle™ MAX (Invitrogen; Carlsbad, Calif.), Lipofectamine™ 2000 CD (Invitrogen; Carlsbad, Calif.), Lipofectamine™ (Invitrogen; Carlsbad, Calif.), RNAiMAX (Invitrogen; Carlsbad, Calif.), Oligofectamine™ (Invitrogen; Carlsbad, Calif.), Optifect™ (Invitrogen; Carlsbad, Calif.), X-tremeGENE Q2 Transfection Reagent (Roche; Grenzacherstrasse, Switzerland), DOTAP Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), DOSPER Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), or Fugene (Grenzacherstrasse, Switzerland), Transfectam® Reagent (Promega; Madison, Wis.), TransFast™ Transfection Reagent (Promega; Madison, Wis.), Tfx™-20 Reagent (Promega; Madison, Wis.), Tfx™-50 Reagent (Promega; Madison, Wis.), DreamFect™ (OZ Biosciences; Marseille, France), EcoTransfect (OZ Biosciences; Marseille, France), TransPass a  D1 Transfection Reagent (New England Biolabs; Ipswich, Mass., USA), LyoVec™/LipoGen™ (Invivogen; San Diego, Calif., USA), PerFectin Transfection Reagent (Genlantis; San Diego, Calif., USA), NeuroPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), GenePORTER Transfection reagent (Genlantis; San Diego, Calif., USA), GenePORTER 2 Transfection reagent (Genlantis; San Diego, Calif., USA), Cytofectin Transfection Reagent (Genlantis; San Diego, Calif., USA), BaculoPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), TroganPORTER™ transfection Reagent (Genlantis; San Diego, Calif., USA), RiboFect (Bioline; Taunton, Mass., USA), PlasFect (Bioline; Taunton, Mass., USA), UniFECTOR (B-Bridge International; Mountain View, Calif., USA), SureFECTOR (B-Bridge International; Mountain View, Calif., USA), or HiFect™ (B-Bridge International, Mountain View, Calif., USA), among others. 
     Other agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone. 
     Carriers 
     Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate dsRNA in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al., DsRNA Res. Dev., 1995, 5, 115-121; Takakura et al., DsRNA &amp; Nucl. Acid Drug Dev., 1996, 6, 177-183. 
     Excipients 
     In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc). 
     Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. 
     Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used. 
     Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. 
     Other Components 
     The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. 
     Aqueous suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. 
     In some embodiments, pharmaceutical compositions featured in the invention include (a) one or more iRNA compounds and (b) one or more biologic agents which function by a non-RNAi mechanism. Examples of such biologics include, biologics that target one or more of PD-1, PD-L1, or B7-H1 (CD80) (e.g., monoclonal antibodies against PD-1, PD-L1, or B7-H1), or one or more recombinant cytokines (e.g., IL6, IFN-γ, and TNF). 
     Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. 
     The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured in the invention lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods featured in the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range of the compound or, when appropriate, of the polypeptide product of a target sequence (e.g., achieving a decreased concentration of the polypeptide) that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. 
     In addition to their administration, as discussed above, the dual targeting siRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by PCSK9 expression. In any event, the administering physician can adjust the amount and timing of iRNA administration on the basis of results observed using standard measures of efficacy known in the art or described herein. 
     Method Using Dual Targeting siRNAs 
     In one aspect, the invention provides use of a dual targeting siRNA agent for inhibiting the expression of the PCSK9 gene in a mammal. The method includes administering a composition of the invention to the mammal such that expression of the target PCSK9 gene is decreased. In some embodiments, PCSK9 expression is decreased for an extended duration, e.g., at least one week, two weeks, three weeks, or four weeks or longer. For example, in certain instances, expression of the PCSK9 gene is suppressed by at least about 5%, 10%, 15%,   25%, 30%, 35%, 40%, 45%, or 50% by administration of a dual targeting siRNA agent described herein. In some embodiments, the PCSK9 gene is suppressed by at least about 60%, 70%, or 80% by administration of the dual targeting siRNA agent. In some embodiments, the   is suppressed by at least about 85%, 90%, or 95% by administration of the double-stranded oligonucleotide. 
     The methods and compositions described herein can be used to treat diseases and conditions that can be modulated by down regulating PCSK9 gene expression. For example, the compositions described herein can be used to treat hyperlipidemia and other forms of lipid imbalance such as hypercholesterolemia, hypertriglyceridemia and the pathological conditions associated with these disorders such as heart and circulatory diseases 
     Therefore, the invention also relates to the use of a dual targeting siRNA agent for the treatment of a PCSK9-mediated disorder or disease. For example, a dual targeting siRNA agent is used for treatment of a hyperlipidemia. 
     The effect of the decreased PCSK9 gene preferably results in a decrease in LDLc (low density lipoprotein cholesterol) levels in the blood, and more particularly in the serum, of the mammal. In some embodiments, LDLc levels are decreased by at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 60%, or more, as compared to pretreatment levels. 
     The method includes administering a dual targeting siRNA agent to the subject to be treated. When the organism to be treated is a mammal such as a human, the composition can be administered by any means known in the art including, but not limited to oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, and airway (aerosol) administration. In some embodiments, the compositions are administered by intravenous infusion or injection. 
     The method includes administering a dual targeting siRNA agent, e.g., a dose sufficient to depress levels of PCSK9 mRNA for at least 5, more preferably 7, 10, 14, 21, 25, 30 or 40 days; and optionally, administering a second single dose of dsRNA, wherein the second single dose is administered at least 5, more preferably 7, 10, 14, 21, 25, 30 or 40 days after the first single dose is administered, thereby inhibiting the expression of the PCSK9 gene in a subject. 
     In one embodiment, doses of dual targeting siRNA agent are administered not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administrations can be maintained for one, two, three, or six months, or one year or longer. 
     In another embodiment, administration can be provided when Low Density Lipoprotein cholesterol (LDLc) levels reach or surpass a predetermined minimal level, such as greater than 70 mg/dL, 130 mg/dL, 150 mg/dL, 200 mVdL, 300 mg/dL, or 400 mg/dL. 
        dual targeting siRNA agent                              
     For example, a subject can be administered a therapeutic amount of dual targeting siRNA agent, such as 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg dsRNA. The dual targeting siRNA agent can be administered by intravenous infusion over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, or 25 minute period. The administration is repeated, for example, on a regular basis, such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration biweekly for three months, administration can be repeated once per month, for six months or a year or longer. Administration of the dual targeting siRNA agent can reduce PCSK9 levels, e.g., in a cell, tissue, blood, urine or other compartment of the patient by at least 10%, at least 15%, at least 20%, at least 25%., at least 30%, at least 40%., at least 50%, at least 60%, at least 70%, at least 80% or at least 90% or more. 
     Before administration of a full dose of the iRNA, patients can be administered a smaller dose, such as a 5% infusion reaction, and monitored for adverse effects, such as an allergic reaction, or for elevated lipid levels or blood pressure. In another example, the patient can be monitored for unwanted immunostimulatory effects, such as increased cytokine (e.g., TNF-alpha or INF-alpha) levels. 
     A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and preferably at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given dual targeting siRNA agent drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. 
     Additional Agents 
     In further embodiments, administration of a dual targeting siRNA agent is administered in combination an additional therapeutic agent. The dual targeting siRNA agent and an additional therapeutic agent can be administered in combination in the same composition, e.g., parenterally, or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. 
     Examples of additional therapeutic agents include those known to treat an agent known to treat a lipid disorders, such as hypercholesterolemia, atherosclerosis or dyslipidemia. For example, a dual targeting siRNA agent featured in the invention can be administered with, e.g., an HMG-CoA reductase inhibitor (e.g., a statin), a fibrate, a bile acid sequestrant, niacin, an antiplatelet agent, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist (e.g., losartan potassium, such as Merck &amp; Co.&#39;s Cozaar®), an acylCoA cholesterol acetyltransferase (ACAT) inhibitor, a cholesterol absorption inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a microsomal triglyceride transfer protein (MTTP) inhibitor, a cholesterol modulator, a bile acid modulator, a peroxisome proliferation activated receptor (PPAR) agonist, a gene-based therapy, a composite vascular protectant (e.g., AGI-1067, from Atherogenics), a glycoprotein IIb/IIIa inhibitor, aspirin or an aspirin-like compound, an IBAT inhibitor (e.g., S-8921, from Shionogi), a squalene synthase inhibitor, or a monocyte chemoattractant protein (MCP)-I inhibitor. Exemplary HMG-CoA reductase inhibitors include atorvastatin (Pfizer&#39;s Lipitor®/Tahor/Sortis/Torvast/Cardyl), pravastatin (Bristol-Myers Squibb&#39;s Pravachol, Sankyo&#39;s Mevalotin/Sanaprav), simvastatin (Merck&#39;s Zocor®/Sinvacor, Boehringer Ingelheim&#39;s Denan, Banyu&#39;s Lipovas), lovastatin (Merck&#39;s Mevacor/Mevinacor, Bexal&#39;s Lovastatina, Cepa; Schwarz Pharma&#39;s Liposcler), fluvastatin (Novartis&#39; Lescol®/Locol/Lochol, Fujisawa&#39;s Cranoc, Solvay&#39;s Digaril), cerivastatin (Bayer&#39;s Lipobay/GlaxoSmithKline&#39;s Baycol), rosuvastatin (AstraZeneca&#39;s Crestor®), and pitivastatin (itavastatin/risivastatin) (Nissan Chemical, Kowa Kogyo, Sankyo, and Novartis). Exemplary fibrates include, e.g., bezafibrate (e.g., Roche&#39;s Befizal®/Cedur®/Bezalip®, Kissei&#39;s Bezatol), clofibrate (e.g., Wyeth&#39;s Atromid-S®), fenofibrate (e.g., Fournier&#39;s Lipidil/Lipantil, Abbott&#39;s Tricor®, Takeda&#39;s Lipantil, generics), gemfibrozil (e.g., Pfizer&#39;s Lopid/Lipur) and ciprofibrate (Sanofi-Synthelabo&#39;s Modalim®). Exemplary bile acid sequestrants include, e.g., cholestyramine (Bristol-Myers Squibb&#39;s Questran® and Questran Light™), colestipol (e.g., Pharmacia&#39;s Colestid), and colesevelam (Genzyme/Sankyo&#39;s WelChol™). Exemplary niacin therapies include, e.g., immediate release formulations, such as Aventis&#39; Nicobid, Upsher-Smith&#39;s Niacor, Aventis&#39; Nicolar, and Sanwakagaku&#39;s Perycit. Niacin extended release formulations include, e.g., Kos Pharmaceuticals&#39; Niaspan and Upsher-Smith&#39;s SIo-Niacin. Exemplary antiplatelet agents include, e.g., aspirin (e.g., Bayer&#39;s aspirin), clopidogrel (Sanof{dot over (ι)}-Synthelabo/Bristol-Myers Squibb&#39;s Plavix), and ticlopidine (e.g., Sanof{dot over (ι)}-Synthelabo&#39;s Ticlid and Daiichi&#39;s Panaldine). Other aspirin-like compounds useful in combination with a dsRNA targeting PCSK9 include, e.g., Asacard (slow-release aspirin, by Pharmacia) and Pamicogrel (Kanebo/Angelini Ricerche/CEPA). Exemplary angiotensin-converting enzyme inhibitors include, e.g., ramipril (e.g., Aventis&#39; Altace) and enalapril (e.g., Merck &amp; Co.&#39;s Vasotec). Exemplary acyl CoA cholesterol acetyltransferase (ACAT) inhibitors include, e.g., avasimibe (Pfizer), eflucimibe (BioM{acute over (ε)}rieux Pierre Fabre/Eli Lilly), CS-505 (Sankyo and Kyoto), and SMP-797 (Sumito). Exemplary cholesterol absorption inhibitors include, e.g., ezetimibe (Merck/Schering-Plough Pharmaceuticals Zetia®) and Pamaqueside (Pfizer). Exemplary CETP inhibitors include, e.g., Torcetrapib (also called CP-529414, Pfizer), JTT-705 (Japan Tobacco), and CETi-I (Avant Immunotherapeutics). Exemplary microsomal triglyceride transfer protein (MTTP) inhibitors include, e.g., implitapide (Bayer), R-103757 (Janssen), and CP-346086 (Pfizer). Other exemplary cholesterol modulators include, e.g., NO-1886 (Otsuka/TAP Pharmaceutical), CI-1027 (Pfizer), and WAY-135433 (Wyeth-Ayerst). Exemplary bile acid modulators include, e.g., HBS-107 (Hisamitsu/Banyu), Btg-511 (British Technology Group), BARI-1453 (Aventis), S-8921 (Shionogi), SD-5613 (Pfizer), and AZD-7806 (AstraZeneca). Exemplary peroxisome proliferation activated receptor (PPAR) agonists include, e.g., tesaglitazar (AZ-242) (AstraZeneca), Netoglitazone (MCC-555) (Mitsubishi/Johnson &amp; Johnson), GW-409544 (Ligand Pharmaceuticals/GlaxoSmithKline), GW-501516 (Ligand Pharmaceuticals/GlaxoSmithKline), LY-929 (Ligand Pharmaceuticals and Eli Lilly), LY-465608 (Ligand Pharmaceuticals and Eli Lilly), LY-518674 (Ligand Pharmaceuticals and Eli Lilly), and MK-767 (Merck and Kyorin). Exemplary gene-based therapies include, e.g., AdGWEGF121.10 (GenVec), ApoAl (UCB Pharma/Groupe Fournier), EG-004 (Trinam) (Ark Therapeutics), and ATP-binding cassette transporter-Al (ABCAl) (CV Therapeutics/Incyte, Aventis, Xenon). Exemplary Glycoprotein Ilb/IIIa inhibitors include, e.g., roxifiban (also called DMP754, Bristol-Myers Squibb), Gantofiban (Merck KGaA/Yamanouchi), and Cromafiban (Millennium Pharmaceuticals). Exemplary squalene synthase inhibitors include, e.g., BMS-1884941 (Bristol-Myers Squibb), CP-210172 (Pfizer), CP-295697 (Pfizer), CP-294838 (Pfizer), and TAK-475 (Takeda). An exemplary MCP-I inhibitor is, e.g., RS-504393 (Roche Bioscience). The anti-atherosclerotic agent BO-653 (Chugai Pharmaceuticals), and the nicotinic acid derivative Nyclin (Yamanouchi Pharmaceuticals) are also appropriate for administering in combination with a dsRNA featured in the invention. Exemplary combination therapies suitable for administration with a dsRNA targeting PCSK9 include, e.g., advicor (Niacin/lovastatin from Kos Pharmaceuticals), amlodipine/atorvastatin (Pfizer), and ezetimibe/simvastatin (e.g., Vytorin® 10/10, 10/20, 10/40, and 10/80 tablets by Merck/Schering-Plough Pharmaceuticals). Agents for treating hypercholesterolemia, and suitable for administration in combination with a dsRNA targeting PCSK9 include, e.g., lovastatin, niacin Altoprev® Extended-Release Tablets (Andrx Labs), lovastatin Caduet® Tablets (Pfizer), amlodipine besylate, atorvastatin calcium Crestor® Tablets (AstraZeneca), rosuvastatin calcium Lescol® Capsules (Novartis), fluvastatin sodium Lescol® (Reliant, Novartis), fluvastatin sodium Lipitor® Tablets (Parke-Davis), atorvastatin calcium Lofibra® Capsules (Gate), Niaspan Extended-Release Tablets (Kos), niacin Pravachol Tablets (Bristol-Myers Squibb), pravastatin sodium TriCor® Tablets (Abbott), fenofibrate Vytorin® 10/10 Tablets (Merck/Schering-Plough Pharmaceuticals), ezetimibe, simvastatin WelChol™ Tablets (Sankyo), colesevelam hydrochloride Zetia® Tablets (Schering), ezetimibe Zetia® Tablets (Merck/Schering-Plough Pharmaceuticals), and ezetimibe Zocor® Tablets (Merck). 
     In one embodiment, a dual targeting siRNA agent is administered in combination with an ezetimibe/simvastatin combination (e.g., Vytorin® (Merck/Schering-Plough Pharmaceuticals)). 
     In one embodiment, the dual targeting siRNA agent is administered to the patient, and then the additional therapeutic agent is administered to the patient (or vice versa). In another embodiment, the dual targeting siRNA agent and the additional therapeutic agent are administered at the same time. 
     In another aspect, the invention features, a method of instructing an end user, e.g., a caregiver or a subject, on how to administer a dual targeting siRNA agent described herein. The method includes, optionally, providing the end user with one or more doses of the dual targeting siRNA agent, and instructing the end user to administer the dual targeting siRNA agent on a regimen described herein, thereby instructing the end user. 
     Identification of Patients 
     In one aspect, the invention provides a method of treating a patient by selecting a patient on the basis that the patient is in need of LDL lowering, LDL lowering without lowering of HDL, ApoB lowering, or total cholesterol lowering. The method includes administering to the patient a dual targeting siRNA agent in an amount sufficient to lower the patient&#39;s LDL levels or ApoB levels, e.g., without substantially lowering HDL levels. 
     Genetic predisposition plays a role in the development of target gene associated diseases, e.g., hyperlipidemia. Therefore, a patient in need of a dual targeting siRNA agent can be identified by taking a family history, or, for example, screening for one or more genetic markers or variants. A healthcare provider, such as a doctor, nurse, or family member, can take a family history before prescribing or administering a dual targeting siRNA agent. For example, a DNA test may also be performed on the patient to identify a mutation in the PCSK9 gene, before a PCSK9 dsRNA is administered to the patient. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the iRNAs and methods featured in the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein am incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples am illustrative only and not intended to be limiting. 
     EXAMPLES 
     Example 1. iRNA Synthesis 
     Source of Reagents 
     Where the source of a reagent is not specifically given herein, such reagent may be obtained from any supplier of reagents for molecular biology at a quality/purity standard for application in molecular biology. 
     Oligonucleotide Synthesis. 
     All oligonucleotides are synthesized on an AKTAoligopilot synthesizer. Commercially available controlled pore glass solid support (dT-CPG, 500{acute over (Å)}, Prime Synthesis) and RNA phosphoramidites with standard protecting groups, 5′-O-dimethoxytrityl N6-benzoyl-2′-t-butyldimethylsilyl-adenosine-3′-O—N,N′-diisopropyl-2-cyanoethylphosphoramidite, 5′-O-dimethoxytrityl-N4-acetyl-2′-t-butyldimethylsilyl-cytidine-3′-O—N,N′-diisopropyl-2-cyanoethylphosphoramidite, 5′-O-dimethoxytrityl-N2-isobutryl-2′-t-butyldimethylsilyl-guanosine-3′-O—N,N′-diisopropyl-2-cyanoethylphosphoramidite, and 5′-O-dimethoxytrityl-2′-t-butyldimethylsilyl-uridine-3′-O—N,N′-diisopropyl-2-cyanoethylphosphoramidite (Pierce Nucleic Acids Technologies) were used for the oligonucleotide synthesis. The 2′-F phosphoramidites, 5′-O-dimethoxytrityl-N4-acetyl-2′-fluro-cytidine-3′-O—N,N′-diisopropyl-2-cyanoethyl-phosphoramidite and 5′-O-dimethoxytrityl-2′-fluro-uridine-3′-O—N,N′-diisopropyl-2-cyanoethyl-phosphoramidite are purchased from (Promega). All phosphoramidites are used at a concentration of 0.2M in acetonitrile (CH 3 CN) except for guanosine which is used at 0.2M concentration in 10% THF/ANC (v/v). Coupling/recycling time of 16 minutes is used. The activator is 5-ethyl thiotetrazole (0.75M, American International Chemicals); for the PO-oxidation iodine/water/pyridine is used and for the PS-oxidation PADS (2%) in 2,6-lutidine/ACN (1:1 v/v) is used. 
     3′-ligand conjugated strands are synthesized using solid support containing the corresponding ligand. For example, the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite. Cholesterol is tethered to trans-4-hydroxyprolinol via a 6-aminohexanoate linkage to obtain a hydroxyprolinol-cholesterol moiety. 5′-end Cy-3 and Cy-5.5 (fluorophore) labeled iRNAs are synthesized from the corresponding Quasar-570 (Cy-3) phosphoramidite are purchased from Biosearch Technologies. Conjugation of ligands to 5′-end and or internal position is achieved by using appropriately protected ligand-phosphoramidite building block. An extended 15 min coupling of 0.1 M solution of phosphoramidite in anhydrous CH 3 CN in the presence of 5-(ethylthio)-1H-tetrazole activator to a solid-support-bound oligonucleotide. Oxidation of the internucleotide phosphite to the phosphate is carried out using standard iodine-water as reported (1) or by treatment with tert-butyl hydroperoxide/acetonitrile/water (10:87:3) with 10 min oxidation wait time conjugated oligonucleotide. Phosphorothioate is introduced by the oxidation of phosphite to phosphorothioate by using a sulfur transfer reagent such as DDTT (purchased from AM Chemicals), PADS and or Beaucage reagent. The cholesterol phosphoramidite is synthesized in house and used at a concentration of 0.1 M in dichloromethane. Coupling time for the cholesterol phosphoramidite is 16 minutes. 
     Deprotection I (Nucleobase Deprotection) 
     After completion of synthesis, the support is transferred to a 100 mL glass bottle (VWR). The oligonucleotide is cleaved from the support with simultaneous deprotection of base and phosphate groups with 80 mL of a mixture of ethanolic ammonia [ammonia: ethanol (3:1)] for 6.5 h at 55° C. The bottle is cooled briefly on ice and then the ethanolic ammonia mixture is filtered into a new 250-mL bottle. The CPG is washed with 2×40 mL portions of ethanol/water (1:1 v/v). The volume of the mixture is then reduced to ˜30 mL by roto-vap. The mixture is then frozen on dry ice and dried under vacuum on a speed vac. 
     Deprotection II (Removal of 2′-TBDMS Group) 
     The dried residue is resuspended in 26 mL of triethylamine, triethylamine trihydrofluoride (TEA.3HF) or pyridine-HF and DMSO (3:4:6) and heated at 60° C. for 90 minutes to remove the tert-butyldimethylsilyl (TBDMS) groups at the 2′ position. The reaction is then quenched with 50 mL of 20 mM sodium acetate and the pH is adjusted to 6.5. Oligonucleotide is stored in a freezer until purification. 
     Analysis 
     The oligonucleotides are analyzed by high-performance liquid chromatography (HPLC) prior to purification and selection of buffer and column depends on nature of the sequence and or conjugated ligand. 
     HPLC Purification 
     The ligand-conjugated oligonucleotides are purified by reverse-phase preparative HPLC. The unconjugated oligonucleotides are purified by anion-exchange HPLC on a TSK gel column packed in house. The buffers are 20 mM sodium phosphate (pH 8.5) in 10% CH 3 CN (buffer A) and 20 mM sodium phosphate (pH 8.5) in 10% CH 3 CN, 1M NaBr (buffer B). Fractions containing full-length oligonucleotides are pooled, desalted, and lyophilized. Approximately 0.15 OD of desalted oligonucleotides are diluted in water to 150 μL and then pipetted into special vials for CGE and LC/MS analysis. Compounds are then analyzed by LC-ESMS and CGE. 
     iRNA Preparation 
     For the general preparation of iRNA, equimolar amounts of sense and antisense strand are heated in 1×PBS at 95° C. for 5 min and slowly cooled to room temperature. Integrity of the duplex is confirmed by HPLC analysis. 
     Nucleic acid sequences are represented below using standard nomenclature, and specifically the abbreviations of Table B. 
     
       
         
           
               
             
               
                 TABLE B 
               
             
            
               
                   
               
               
                 Abbreviations of nucleotide monomers used in nucleic acid sequence  
               
               
                 representation. It will be understood that these monomers, when present  
               
               
                 in an oligonucleotide, are mutually linked by 5′-3′-phosphodiester bonds. 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Nucleotide (s) 
               
               
                   
               
               
                 A 
                 adenosine 
               
               
                 C 
                 cytidine 
               
               
                 G 
                 guanosine 
               
               
                 U 
                 uridine 
               
               
                 N 
                 any nucleotide (G, A, C, T or U) 
               
               
                 a 
                 2′-O-methyladenosine 
               
               
                 c 
                 2′-O-methylcytidine 
               
               
                 g 
                 2′-O-methylguanosine 
               
               
                 u 
                 2′-O-methyluridine 
               
               
                 dT , T 
                 2′-deoxythymidine 
               
               
                 s 
                 phosphorothioate linkage 
               
               
                   
               
            
           
         
       
     
     Example 2. PCSK9 siRNA Design, Synthesis, and Screening 
     A description of the design, synthesis, and assays using PCSK9 siRNA can be found in detail in U.S. patent application Ser. No. 11/746,864 filed on May 10, 2007 (now U.S. Pat. No. 7,605,251) and International Patent Application No. PCT/US2007/068655 filed May 10, 2007 (published as WO 2007/134161) and in U.S. patent application Ser. No. 12/478,452 filed Jun. 4, 2009 (published as US 2010/0010066) and International Patent Application No. PCT/US2009/032743 filed Jan. 30, 2009 (published as WO 2009/134487). All are incorporated by reference in their entirety for all purposes. 
     The sequences of siRNA targeting a PCSK9 gene are described in Table 1 and Table 2 above, and Tables 4-8 below. 
     Example 3. XBP-1 siRNA Design, Synthesis, and Screening 
     A description of the design, synthesis, and assays using XBP-1 siRNA can be found in detail in U.S. patent application Ser. No. 12/425,811 filed on Apr. 17, 2009 and published as US 2009-0275638. This application is incorporated by reference in its entirety for all purposes. The sequences of siRNA targeting a XBP-1 gene are described in Table 3 above, and Tables 9-13 below. 
     Example 4. A Dual Targeting siRNA Agent 
     A dual targeting siRNA agent was synthesized. The sense and antisense strands for AD-10792 (target gene is PCSK9, see Table 2)) and AD-18038 (target gene is XBP-1, see Table 3) were synthesized. The two sense strands were covalently bound using a disulfide linker “Q51” with the structure shown below. 
     
       
         
         
             
             
         
       
     
     The resulting dual sense strand was hybridized to the corresponding antisense strands to create a 42 mer dual targeting siRNA agent “AD-23426” (SEQ ID NOS 4162-4165, respectively, in order of appearance): 
     
       
         
           
               
            
               
                 GccuGGAGuuuAuucGGAAdTsdTQ51cAcccuGAAuucAuuGucudTsdT 
               
               
                   
               
               
                 dTsdTCGGAcCUCAAAuAAGCCUU dTsdTGUGGGAcUUAAGUAAcAGA 
               
            
           
         
       
     
     Example 5. Inhibition of PCSK9 and Xbp-1 mRNA Levels by the PCSK9-Xbp1 Dual Targeting siRNA in Primary Mouse Hepatocytes 
     Primary mouse hepatocytes were transfected with dual targeting AD-23426 or individual siRNAs (AD-10792 and AD-18038) in lipofectamine 2000 (Invitrogen protocol). 48 hours after transfection cells were harvested and lysed. PCSK9, Xbp-1 and GAPDH transcripts were measured via bDNA in cell lysates prepared according to manufacturer&#39;s protocol. PCSK9 to GAPDH or Xbp-1 to GAPDH ratios were normalized to control (luciferase) and graphed. 
     As shown in  FIG. 1 , the dual targeting siRNA was at least as effective at inhibiting their corresponding target gene as the single siRNAs. 
     Example 6. Inhibition of PCSK9 and Xbp-1 mRNA Levels and Reduction of Total Serum Cholesterol by the PCSK9-Xbp1 Dual Targeting siRNA in Mice 
     The dual targeting AD-23426 was formulated in an LNP09 formulation: XTC/DSPC/Cholesterol/PEG-DMG in a % mol ratio of 50/10/38.5/1.5 with a lipid:siRNA ratio of about 10:1. The LNP09-AD-23426 was administered by tail vein injection into C57B6 mice at 6.0 mg/kg, 2.0 mg/kg and 0.6 mg/kg. LNP09 formulated single siRNAs (AD-10792 and AD-18038) were administered each at 3.0 mg/kg, 1.0 mg/kg and 0.3 mg/kg. Livers and plasma were harvested 72 hours post-injection (5 animals per group). 
     PCSK9, Xbp-1 and GAPDH transcript levels were measured via bDNA in livers prepared according to the manufacturer&#39;s protocol. PCSK9 to GAPDH or Xbp-1 to GAPDH ratios were normalized to control (luciferase) and graphed. The results are shown in  FIG. 2 . 
     Total cholesterol was measure in serum according to manufacturer&#39;s instructions using a cholesterol kit from WAKO Tex. 
     The results demonstrate that the dual targeting siRNAs were at least as effective at inhibiting their corresponding target as single siRNAs in vivo. The results also show that the dual targeting construct has an additive effect compared to the single siRNAs at reducing total serum cholesterol. 
     Example 7: No Induction of IFN-α and TNF-α in HuPBMC 
     The effect of a dual targeting siRNA, AD-23426, on IFN-α and TNF-α in human PBMC was investigated. 
     Whole Blood anti-coagulated with Sodium Heparin was obtained from healthy donors at Research Blood Components, Inc (Boston, Mass.). Peripheral blood mononuclear cells (PBMC) were isolated by standard Ficoll-Hypaque density centrifugation. Isolated PBMC were seeded at 1×10 5 cells/well in 96 well plates and cultured in RPMI 1640 GlutaMax Medium (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum and 1% antibiotic/antimycotic (Invitrogen). siRNAs were transfected using DOTAP Transfection Reagent (Roche Applied Science). DOTAP was first diluted in Opti-MEM (Invitrogen) for 5 minutes before mixing with an equal volume of Opti-MEM containing the siRNA. siRNA/transfection reagent complexes were incubated for 15 minutes at room temperature prior to being added to PBMC. siRNAs were transfected at final concentrations of 266 nM, 133 nM or 67 nM using 16 μg/ml, 8 μg/ml or 4 μg/ml DOTAP, respectively. The ratio of siRNA to DOTAP is 16.5 μmol/μg. Transfected PBMC were incubated at 37° C., 5% CO 2  for 24 hrs after which supernatants were harvested and stored at −80° C. until analysis. Quantitative cytokine analysis was done using commercially available Instant ELISA Kits for IFN-α, (BMS216INST) and TNF-α (BMS223INST); both from Bender MedSystems (Vienna, Austria). 
     LNP09 and DOTAP formulated siRNAs were administered. Control siRNAs were AD-1730, AD-1955, AD-6248, AD-18889, AD-5048, and AD-18221. AD-10792: PCSK9 siRNA. AD-18038: XBP-1 siRNA. 
     The results are shown in  FIG. 4 . AD-23426 did not induce production of IFN-α and TNF-α, similar to the result obtained with the single target gene siRNAs. As expected, unmodified siRNAs (AD-5048 and AD-18889) induced production of both IFN-α and TNF-α. These results demonstrate that a dual targeting siRNA does not induce an immune response. 
     Example 8. Reduction of Total Serum Cholesterol with PCSK9-Xbp1 Dual Targeting siRNA Humans 
     A human subject is treated with a pharmaceutical composition, e.g., a nucleic acid-lipid particle having a dual targeting siRNA agent. 
     At time zero, a suitable first dose of the pharmaceutical composition is subcutaneously administered to the subject. The composition is formulated as described herein. After a period of time, the subject&#39;s condition is evaluated, e.g., by measurement of total serum cholesterol. This measurement can be accompanied by a measurement of PCSK9 expression in said subject, and/or the products of the successful siRNA-targeting of PCSK9 mRNA. Other relevant criteria can also be measured. The number and strength of doses are adjusted according to the subject&#39;s needs. 
     After treatment, the subject&#39;s condition is compared to the condition existing prior to the treatment, or relative to the condition of a similarly afflicted but untreated subject. 
     Those skilled in the art are familiar with methods and compositions in addition to those specifically set out in the present disclosure which will allow them to practice this invention to the full scope of the claims hereinafter appended. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Sequences of siRNA targeted to PCSK9 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                 Antisense 
                 SEQ 
                   
               
               
                   
                 Sense strand 
                 ID 
                 strand 
                 ID 
                   
               
               
                 *Target 
                 (5′-3′) 1   
                 NO: 
                 (5′-3′) 1   
                 NO: 
                 Duplex # 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                  2-20 
                 AGCGACGUCGAGGCGCUCATT 
                 1 
                 UGAGCGCCUCGAC 
                 2 
                 AD-15220 
               
               
                   
                   
                   
                 GUCGCUTT 
                   
                   
               
               
                   
               
               
                 15-33 
                 CGCUCAUGGUUGCAGGCGGTT 
                 3 
                 CCGCCUGCAACCA 
                 4 
                 AD-15275 
               
               
                   
                   
                   
                 UGAGCGTT 
                   
                   
               
               
                   
               
               
                 16-34 
                 GCUCAUGGUUGCAGGCGGGTT 
                 5 
                 CCCGCCUGCAACC 
                 6 
                 AD-15301 
               
               
                   
                   
                   
                 AUGAGCTT 
                   
                   
               
               
                   
               
               
                 30-48 
                 GCGGGCGCCGCCGUUCAGUTT 
                 7 
                 ACUGAACGGCGGC 
                 8 
                 AD-15276 
               
               
                   
                   
                   
                 GCCCGCTT 
                   
                   
               
               
                   
               
               
                 31-49 
                 CGGGCGCCGCCGUUCAGUUTT 
                 9 
                 AACUGAACGGCGG 
                 10 
                 AD-15302 
               
               
                   
                   
                   
                 CGCCCGTT 
                   
                   
               
               
                   
               
               
                 32-50 
                 GGGCGCCGCCGUUCAGUUCTT 
                 11 
                 GAACUGAACGGCG 
                 12 
                 AD-15303 
               
               
                   
                   
                   
                 GCGCCCTT 
                   
                   
               
               
                   
               
               
                 40-58 
                 CCGUUCAGUUCAGGGUCUGTT 
                 13 
                 CAGACCCUGAACU 
                 14 
                 AD-15221 
               
               
                   
                   
                   
                 GAACGGTT 
                   
                   
               
               
                   
               
               
                 43-61 
                 UUCAGUUCAGGGUCUGAGCTT 
                 15 
                 GCUCAGACCCUGA 
                 16 
                 AD-15413 
               
               
                   
                   
                   
                 ACUGAATT 
                   
                   
               
               
                   
               
               
                  82-100 
                 GUGAGACUGGCUCGGGCGGTT 
                 17 
                 CCGCCCGAGCCAG 
                 18 
                 AD-15304 
               
               
                   
                   
                   
                 UCUCACTT 
                   
                   
               
               
                   
               
               
                 100-118 
                 GGCCGGGACGCGUCGUUGCTT 
                 19 
                 GCAACGACGCGUC 
                 20 
                 AD-15305 
               
               
                   
                   
                   
                 CCGGCCTT 
                   
                   
               
               
                   
               
               
                 101-119 
                 GCCGGGACGCGUCGUUGCATT 
                 21 
                 UGCAACGACGCGU 
                 22 
                 AD-15306 
               
               
                   
                   
                   
                 CCCGGCTT 
                   
                   
               
               
                   
               
               
                 102-120 
                 CCGGGACGCGUCGUUGCAGTT 
                 23 
                 CUGCAACGACGCG 
                 24 
                 AD-15307 
               
               
                   
                   
                   
                 UCCCGGTT 
                   
                   
               
               
                   
               
               
                 105-123 
                 GGACGCGUCGUUGCAGCAGTT 
                 25 
                 CUGCUGCAACGAC 
                 26 
                 AD-15277 
               
               
                   
                   
                   
                 GCGUCCTT 
                   
                   
               
               
                   
               
               
                 135-153 
                 UCCCAGCCAGGAUUCCGCGTsT 
                 27 
                 CGCGGAAUCCUGG 
                 28 
                 AD-9526 
               
               
                   
                   
                   
                 CUGGGATsT 
                   
                   
               
               
                   
               
               
                 135-153 
                 ucccAGccAGGAuuccGcGTsT 
                 29 
                 CGCGGAAUCCUGG 
                 30 
                 AD-9652 
               
               
                   
                   
                   
                 CUGGGATsT 
                   
                   
               
               
                   
               
               
                 136-154 
                 CCCAGCCAGGAUUCCGCGCTsT 
                 31 
                 GCGCGGAAUCCUG 
                 32 
                 AD-9519 
               
               
                   
                   
                   
                 GCUGGGTsT 
                   
                   
               
               
                   
               
               
                 136-154 
                 cccAGccAGGAuuccGcGcTsT 
                 33 
                 GCGCGGAAUCCUG 
                 34 
                 AD-9645 
               
               
                   
                   
                   
                 GCUGGGTsT 
                   
                   
               
               
                   
               
               
                 138-156 
                 CAGCCAGGAUUCCGCGCGCTsT 
                 35 
                 GCGCGCGGAAUCC 
                 36 
                 AD-9523 
               
               
                   
                   
                   
                 UGGCUGTsT 
                   
                   
               
               
                   
               
               
                 138-156 
                 cAGccAGGAuuccGcGcGcTsT 
                 37 
                 GCGCGCGGAAUCC 
                 38 
                 AD-9649 
               
               
                   
                   
                   
                 UGGCUGTsT 
                   
                   
               
               
                   
               
               
                 185-203 
                 AGCUCCUGCACAGUCCUCCTsT 
                 39 
                 GGAGGACUGUGCA 
                 40 
                 AD-9569 
               
               
                   
                   
                   
                 GGAGCUTsT 
                   
                   
               
               
                   
               
               
                 185-203 
                 AGcuccuGcAcAGuccuccTsT 
                 41 
                 GGAGGACUGUGcA 
                 42 
                 AD-9695 
               
               
                   
                   
                   
                 GGAGCUTsT 
                   
                   
               
               
                   
               
               
                 205-223 
                 CACCGCAAGGCUCAAGGCGTT 
                 43 
                 CGCCUUGAGCCUU 
                 44 
                 AD-15222 
               
               
                   
                   
                   
                 GCGGUGTT 
                   
                   
               
               
                   
               
               
                 208-226 
                 CGCAAGGCUCAAGGCGCCGTT 
                 45 
                 CGGCGCCUUGAGC 
                 46 
                 AD-15278 
               
               
                   
                   
                   
                 CUUGCGTT 
                   
                   
               
               
                   
               
               
                 210-228 
                 CAAGGCUCAAGGCGCCGCCTT 
                 47 
                 GGCGGCGCCUUGA 
                 48 
                 AD-15178 
               
               
                   
                   
                   
                 GCCUUGTT 
                   
                   
               
               
                   
               
               
                 232-250 
                 GUGGACCGCGCACGGCCUCTT 
                 49 
                 GAGGCCGUGCGCG 
                 50 
                 AD-15308 
               
               
                   
                   
                   
                 GUCCACTT 
                   
                   
               
               
                   
               
               
                 233-251 
                 UGGACCGCGCACGGCCUCUTT 
                 51 
                 AGAGGCCGUGCGC 
                 52 
                 AD-15223 
               
               
                   
                   
                   
                 GGUCCATT 
                   
                   
               
               
                   
               
               
                 234-252 
                 GGACCGCGCACGGCCUCUATT 
                 53 
                 UAGAGGCCGUGCG 
                 54 
                 AD-15309 
               
               
                   
                   
                   
                 CGGUCCTT 
                   
                   
               
               
                   
               
               
                 235-253 
                 GACCGCGCACGGCCUCUAGTT 
                 55 
                 CUAGAGGCCGUGC 
                 56 
                 AD-15279 
               
               
                   
                   
                   
                 GCGGUCTT 
                   
                   
               
               
                   
               
               
                 236-254 
                 ACCGCGCACGGCCUCUAGGTT 
                 57 
                 CCUAGAGGCCGUG 
                 58 
                 AD-15194 
               
               
                   
                   
                   
                 CGCGGUTT 
                   
                   
               
               
                   
               
               
                 237-255 
                 CCGCGCACGGCCUCUAGGUTT 
                 59 
                 ACCUAGAGGCCGU 
                 60 
                 AD-15310 
               
               
                   
                   
                   
                 GCGCGGTT 
                   
                   
               
               
                   
               
               
                 238-256 
                 CGCGCACGGCCUCUAGGUCTT 
                 61 
                 GACCUAGAGGCCG 
                 62 
                 AD-15311 
               
               
                   
                   
                   
                 UGCGCGTT 
                   
                   
               
               
                   
               
               
                 239-257 
                 GCGCACGGCCUCUAGGUCUTT 
                 63 
                 AGACCUAGAGGCC 
                 64 
                 AD-15392 
               
               
                   
                   
                   
                 GUGCGCTT 
                   
                   
               
               
                   
               
               
                 240-258 
                 CGCACGGCCUCUAGGUCUCTT 
                 65 
                 GAGACCUAGAGGC 
                 66 
                 AD-15312 
               
               
                   
                   
                   
                 CGUGCGTT 
                   
                   
               
               
                   
               
               
                 248-266 
                 CUCUAGGUCUCCUCGCCAGTT 
                 67 
                 CUGGCGAGGAGAC 
                 68 
                 AD-15313 
               
               
                   
                   
                   
                 CUAGAGTT 
                   
                   
               
               
                   
               
               
                 249-267 
                 UCUAGGUCUCCUCGCCAGGTT 
                 69 
                 CCUGGCGAGGAGA 
                 70 
                 AD-15280 
               
               
                   
                   
                   
                 CCUAGATT 
                   
                   
               
               
                   
               
               
                 250-268 
                 CUAGGUCUCCUCGCCAGGATT 
                 71 
                 UCCUGGCGAGGAG 
                 72 
                 AD-15267 
               
               
                   
                   
                   
                 ACCUAGTT 
                   
                   
               
               
                   
               
               
                 252-270 
                 AGGUCUCCUCGCCAGGACATT 
                 73 
                 UGUCCUGGCGAGG 
                 74 
                 AD-15314 
               
               
                   
                   
                   
                 AGACCUTT 
                   
                   
               
               
                   
               
               
                 258-276 
                 CCUCGCCAGGACAGCAACCTT 
                 75 
                 GGUUGCUGUCCUG 
                 76 
                 AD-15315 
               
               
                   
                   
                   
                 GCGAGGTT 
                   
                   
               
               
                   
               
               
                 300-318 
                 CGUCAGCUCCAGGCGGUCCTsT 
                 77 
                 GGACCGCCUGGAG 
                 78 
                 AD-9624 
               
               
                   
                   
                   
                 CUGACGTsT 
                   
                   
               
               
                   
               
               
                 300-318 
                 cGucAGcuccAGGcGGuccTsT 
                 79 
                 GGACCGCCUGGAG 
                 80 
                 AD-9750 
               
               
                   
                   
                   
                 CUGACGTsT 
                   
                   
               
               
                   
               
               
                 301-319 
                 GUCAGCUCCAGGCGGUCCUTsT 
                 81 
                 AGGACCGCCUGGA 
                 82 
                 AD-9623 
               
               
                   
                   
                   
                 GCUGACTsT 
                   
                   
               
               
                   
               
               
                 301-319 
                 GucAGcuccAGGcGGuccuTsT 
                 83 
                 AGGACCGCCUGGA 
                 84 
                 AD-9749 
               
               
                   
                   
                   
                 GCUGACTsT 
                   
                   
               
               
                   
               
               
                 370-388 
                 GGCGCCCGUGCGCAGGAGGTT 
                 85 
                 CCUCCUGCGCACG 
                 86 
                 AD-15384 
               
               
                   
                   
                   
                 GGCGCCTT 
                   
                   
               
               
                   
               
               
                 408-426 
                 GGAGCUGGUGCUAGCCUUGTsT 
                 87 
                 CAAGGCUAGCACC 
                 88 
                 AD-9607 
               
               
                   
                   
                   
                 AGCUCCTsT 
                   
                   
               
               
                   
               
               
                 408-426 
                 GGAGcuGGuGcuAGccuuGTsT 
                 89 
                 cAAGGCuAGcACc 
                 90 
                 AD-9733 
               
               
                   
                   
                   
                 AGCUCCTsT 
                   
                   
               
               
                   
               
               
                 411-429 
                 GCUGGUGCUAGCCUUGCGUTsT 
                 91 
                 ACGCAAGGCUAGC 
                 92 
                 AD-9524 
               
               
                   
                   
                   
                 ACCAGCTsT 
                   
                   
               
               
                   
               
               
                 411-429 
                 GcuGGuGcuAGccuuGcGuTsT 
                 93 
                 ACGcAAGGCuAGc 
                 94 
                 AD-9650 
               
               
                   
                   
                   
                 ACcAGCTsT 
                   
                   
               
               
                   
               
               
                 412-430 
                 CUGGUGCUAGCCUUGCGUUTsT 
                 95 
                 AACGCAAGGCUAG 
                 96 
                 AD-9520 
               
               
                   
                   
                   
                 CACCAGTsT 
                   
                   
               
               
                   
               
               
                 412-430 
                 CUGGUGCUAGCCUUGCGUUTsT 
                 97 
                 AACGCAAGGCUAG 
                 98 
                 AD-9520 
               
               
                   
                   
                   
                 CACCAGTsT 
                   
                   
               
               
                   
               
               
                 412-430 
                 cuGGuGcuAGccuuGcGuuTsT 
                 99 
                 AACGcAAGGCuAG 
                 100 
                 AD-9646 
               
               
                   
                   
                   
                 cACcAGTsT 
                   
                   
               
               
                   
               
               
                 416-434 
                 UGCUAGCCUUGCGUUCCGATsT 
                 101 
                 UCGGAACGCAAGG 
                 102 
                 AD-9608 
               
               
                   
                   
                   
                 CUAGCATsT 
                   
                   
               
               
                   
               
               
                 416-434 
                 uGcuAGccuuGcGuuccGATsT 
                 103 
                 UCGGAACGcAAGG 
                 104 
                 AD-9734 
               
               
                   
                   
                   
                 CuAGcATsT 
                   
                   
               
               
                   
               
               
                 419-437 
                 UAGCCUUGCGUUCCGAGGATsT 
                 105 
                 UCCUCGGAACGCA 
                 106 
                 AD-9546 
               
               
                   
                   
                   
                 AGGCUATsT 
                   
                   
               
               
                   
               
               
                 419-437 
                 uAGccuuGcGuuccGAGGATsT 
                 107 
                 UCCUCGGAACGcA 
                 108 
                 AD-9672 
               
               
                   
                   
                   
                 AGGCuATsT 
                   
                   
               
               
                   
               
               
                 439-457 
                 GACGGCCUGGCCGAAGCACTT 
                 109 
                 GUGCUUCGGCCAG 
                 110 
                 AD-15385 
               
               
                   
                   
                   
                 GCCGUCTT 
                   
                   
               
               
                   
               
               
                 447-465 
                 GGCCGAAGCACCCGAGCACTT 
                 111 
                 GUGCUCGGGUGCU 
                 112 
                 AD-15393 
               
               
                   
                   
                   
                 UCGGCCTT 
                   
                   
               
               
                   
               
               
                 448-466 
                 GCCGAAGCACCCGAGCACGTT 
                 113 
                 CGUGCUCGGGUGC 
                 114 
                 AD-15316 
               
               
                   
                   
                   
                 UUCGGCTT 
                   
                   
               
               
                   
               
               
                 449-467 
                 CCGAAGCACCCGAGCACGGTT 
                 115 
                 CCGUGCUCGGGUG 
                 116 
                 AD-15317 
               
               
                   
                   
                   
                 CUUCGGTT 
                   
                   
               
               
                   
               
               
                 458-476 
                 CCGAGCACGGAACCACAGCTT 
                 117 
                 GCUGUGGUUCCGU 
                 118 
                 AD-15318 
               
               
                   
                   
                   
                 GCUCGGTT 
                   
                   
               
               
                   
               
               
                 484-502 
                 CACCGCUGCGCCAAGGAUCTT 
                 119 
                 GAUCCUUGGCGCA 
                 120 
                 AD-15195 
               
               
                   
                   
                   
                 GCGGUGTT 
                   
                   
               
               
                   
               
               
                 486-504 
                 CCGCUGCGCCAAGGAUCCGTT 
                 121 
                 CGGAUCCUUGGCG 
                 122 
                 AD-15224 
               
               
                   
                   
                   
                 CAGCGGTT 
                   
                   
               
               
                   
               
               
                 487-505 
                 CGCUGCGCCAAGGAUCCGUTT 
                 123 
                 ACGGAUCCUUGGC 
                 124 
                 AD-15188 
               
               
                   
                   
                   
                 GCAGCGTT 
                   
                   
               
               
                   
               
               
                 489-507 
                 CUGCGCCAAGGAUCCGUGGTT 
                 125 
                 CCACGGAUCCUUG 
                 126 
                 AD-15225 
               
               
                   
                   
                   
                 GCGCAGTT 
                   
                   
               
               
                   
               
               
                 500-518 
                 AUCCGUGGAGGUUGCCUGGTT 
                 127 
                 CCAGGCAACCUCC 
                 128 
                 AD-15281 
               
               
                   
                   
                   
                 ACGGAUTT 
                   
                   
               
               
                   
               
               
                 509-527 
                 GGUUGCCUGGCACCUACGUTT 
                 129 
                 ACGUAGGUGCCAG 
                 130 
                 AD-15282 
               
               
                   
                   
                   
                 GCAACCTT 
                   
                   
               
               
                   
               
               
                 542-560 
                 AGGAGACCCACCUCUCGCATT 
                 131 
                 UGCGAGAGGUGGG 
                 132 
                 AD-15319 
               
               
                   
                   
                   
                 UCUCCUTT 
                   
                   
               
               
                   
               
               
                 543-561 
                 GGAGACCCACCUCUCGCAGTT 
                 133 
                 CUGCGAGAGGUGG 
                 134 
                 AD-15226 
               
               
                   
                   
                   
                 GUCUCCTT 
                   
                   
               
               
                   
               
               
                 544-562 
                 GAGACCCACCUCUCGCAGUTT 
                 135 
                 ACUGCGAGAGGUG 
                 136 
                 AD-15271 
               
               
                   
                   
                   
                 GGUCUCTT 
                   
                   
               
               
                   
               
               
                 549-567 
                 CCACCUCUCGCAGUCAGAGTT 
                 137 
                 CUCUGACUGCGAG 
                 138 
                 AD-15283 
               
               
                   
                   
                   
                 AGGUGGTT 
                   
                   
               
               
                   
               
               
                 552-570 
                 CCUCUCGCAGUCAGAGCGCTT 
                 139 
                 GCGCUCUGACUGC 
                 140 
                 AD-15284 
               
               
                   
                   
                   
                 GAGAGGTT 
                   
                   
               
               
                   
               
               
                 553-571 
                 CUCUCGCAGUCAGAGCGCATT 
                 141 
                 UGCGCUCUGACUG 
                 142 
                 AD-15189 
               
               
                   
                   
                   
                 CGAGAGTT 
                   
                   
               
               
                   
               
               
                 554-572 
                 UCUCGCAGUCAGAGCGCACTT 
                 143 
                 GUGCGCUCUGACU 
                 144 
                 AD-15227 
               
               
                   
                   
                   
                 GCGAGATT 
                   
                   
               
               
                   
               
               
                 555-573 
                 CUCGCAGUCAGAGCGCACUTsT 
                 145 
                 AGUGCGCUCUGAC 
                 146 
                 AD-9547 
               
               
                   
                   
                   
                 UGCGAGTsT 
                   
                   
               
               
                   
               
               
                 555-573 
                 cucGcAGucAGAGcGcAcuTsT 
                 147 
                 AGUGCGCUCUGAC 
                 148 
                 AD-9673 
               
               
                   
                   
                   
                 UGCGAGTsT 
                   
                   
               
               
                   
               
               
                 558-576 
                 GCAGUCAGAGCGCACUGCCTsT 
                 149 
                 GGCAGUGCGCUCU 
                 150 
                 AD-9548 
               
               
                   
                   
                   
                 GACUGCTsT 
                   
                   
               
               
                   
               
               
                 558-576 
                 GcAGucAGAGcGcAcuGccTsT 
                 151 
                 GGcAGUGCGCUCU 
                 152 
                 AD-9674 
               
               
                   
                   
                   
                 GACUGCTsT 
                   
                   
               
               
                   
               
               
                 606-624 
                 GGGAUACCUCACCAAGAUCTsT 
                 153 
                 GAUCUUGGUGAGG 
                 154 
                 AD-9529 
               
               
                   
                   
                   
                 UAUCCCTsT 
                   
                   
               
               
                   
               
               
                 606-624 
                 GGGAuAccucAccAAGAucTsT 
                 155 
                 GAUCUUGGUGAGG 
                 156 
                 AD-9655 
               
               
                   
                   
                   
                 uAUCCCTsT 
                   
                   
               
               
                   
               
               
                 659-677 
                 UGGUGAAGAUGAGUGGCGATsT 
                 157 
                 UCGCCACUCAUCU 
                 158 
                 AD-9605 
               
               
                   
                   
                   
                 UCACCATsT 
                   
                   
               
               
                   
               
               
                 659-677 
                 uGGuGAAGAuGAGuGGcGATsT 
                 159 
                 UCGCcACUcAUCU 
                 160 
                 AD-9731 
               
               
                   
                   
                   
                 UcACcATsT 
                   
                   
               
               
                   
               
               
                 663-681 
                 GAAGAUGAGUGGCGACCUGTsT 
                 161 
                 CAGGUCGCCACUC 
                 162 
                 AD-9596 
               
               
                   
                   
                   
                 AUCUUCTsT 
                   
                   
               
               
                   
               
               
                 663-681 
                 GAAGAuGAGuGGcGAccuGTsT 
                 163 
                 cAGGUCGCcACUc 
                 164 
                 AD-9722 
               
               
                   
                   
                   
                 AUCUUCTsT 
                   
                   
               
               
                   
               
               
                 704-722 
                 CCCAUGUCGACUACAUCGATsT 
                 165 
                 UCGAUGUAGUCGA 
                 166 
                 AD-9583 
               
               
                   
                   
                   
                 CAUGGGTsT 
                   
                   
               
               
                   
               
               
                 704-722 
                 cccAuGucGAcuAcAucGATsT 
                 167 
                 UCGAUGuAGUCGA 
                 168 
                 AD-9709 
               
               
                   
                   
                   
                 cAUGGGTsT 
                   
                   
               
               
                   
               
               
                 718-736 
                 AUCGAGGAGGACUCCUCUGTsT 
                 169 
                 CAGAGGAGUCCUC 
                 170 
                 AD-9579 
               
               
                   
                   
                   
                 CUCGAUTsT 
                   
                   
               
               
                   
               
               
                 718-736 
                 AucGAGGAGGAcuccucuGTsT 
                 171 
                 cAGAGGAGUCCUC 
                 172 
                 AD-9705 
               
               
                   
                   
                   
                 CUCGAUTsT 
                   
                   
               
               
                   
               
               
                 758-776 
                 GGAACCUGGAGCGGAUUACTT 
                 173 
                 GUAAUCCGCUCCA 
                 174 
                 AD-15394 
               
               
                   
                   
                   
                 GGUUCCTT 
                   
                   
               
               
                   
               
               
                 759-777 
                 GAACCUGGAGCGGAUUACCTT 
                 175 
                 GGUAAUCCGCUCC 
                 176 
                 AD-15196 
               
               
                   
                   
                   
                 AGGUUCTT 
                   
                   
               
               
                   
               
               
                 760-778 
                 AACCUGGAGCGGAUUACCCTT 
                 177 
                 GGGUAAUCCGCUC 
                 178 
                 AD-15197 
               
               
                   
                   
                   
                 CAGGUUTT 
                   
                   
               
               
                   
               
               
                 777-795 
                 CCCUCCACGGUACCGGGCGTT 
                 179 
                 CGCCCGGUACCGU 
                 180 
                 AD-15198 
               
               
                   
                   
                   
                 GGAGGGTT 
                   
                   
               
               
                   
               
               
                 782-800 
                 CACGGUACCGGGCGGAUGATsT 
                 181 
                 UCAUCCGCCCGGU 
                 182 
                 AD-9609 
               
               
                   
                   
                   
                 ACCGUGTsT 
                   
                   
               
               
                   
               
               
                 782-800 
                 cAcGGuAccGGGcGGAuGATsT 
                 183 
                 UcAUCCGCCCGGu 
                 184 
                 AD-9735 
               
               
                   
                   
                   
                 ACCGUGTsT 
                   
                   
               
               
                   
               
               
                 783-801 
                 ACGGUACCGGGCGGAUGAATsT 
                 185 
                 UUCAUCCGCCCGG 
                 186 
                 AD-9537 
               
               
                   
                   
                   
                 UACCGUTsT 
                   
                   
               
               
                   
               
               
                 783-801 
                 AcGGuAccGGGcGGAuGAATsT 
                 187 
                 UUcAUCCGCCCGG 
                 188 
                 AD-9663 
               
               
                   
                   
                   
                 uACCGUTsT 
                   
                   
               
               
                   
               
               
                 784-802 
                 CGGUACCGGGCGGAUGAAUTsT 
                 189 
                 AUUCAUCCGCCCG 
                 190 
                 AD-9528 
               
               
                   
                   
                   
                 GUACCGTsT 
                   
                   
               
               
                   
               
               
                 784-802 
                 cGGuAccGGGcGGAuGAAuTsT 
                 191 
                 AUUcAUCCGCCCG 
                 192 
                 AD-9654 
               
               
                   
                   
                   
                 GuACCGTsT 
                   
                   
               
               
                   
               
               
                 785-803 
                 GGUACCGGGCGGAUGAAUATsT 
                 193 
                 UAUUCAUCCGCCC 
                 194 
                 AD-9515 
               
               
                   
                   
                   
                 GGUACCTsT 
                   
                   
               
               
                   
               
               
                 785-803 
                 GGuAccGGGcGGAuGAAuATsT 
                 195 
                 uAUUcAUCCGCCC 
                 196 
                 AD-9641 
               
               
                   
                   
                   
                 GGuACCTsT 
                   
                   
               
               
                   
               
               
                 786-804 
                 GUACCGGGCGGAUGAAUACTsT 
                 197 
                 GUAUUCAUCCGCC 
                 198 
                 AD-9514 
               
               
                   
                   
                   
                 CGGUACTsT 
                   
                   
               
               
                   
               
               
                 786-804 
                 GuAccGGGcGGAuGAAuAcTsT 
                 199 
                 GuAUUcAUCCGCC 
                 200 
                 AD-9640 
               
               
                   
                   
                   
                 CGGuACTsT 
                   
                   
               
               
                   
               
               
                 788-806 
                 ACCGGGCGGAUGAAUACCATsT 
                 201 
                 UGGUAUUCAUCCG 
                 202 
                 AD-9530 
               
               
                   
                   
                   
                 CCCGGUTsT 
                   
                   
               
               
                   
               
               
                 788-806 
                 AccGGGcGGAuGAAuAccATsT 
                 203 
                 UGGuAUUcAUCCG 
                 204 
                 AD-9656 
               
               
                   
                   
                   
                 CCCGGUTsT 
                   
                   
               
               
                   
               
               
                 789-807 
                 CCGGGCGGAUGAAUACCAGTsT 
                 205 
                 CUGGUAUUCAUCC 
                 206 
                 AD-9538 
               
               
                   
                   
                   
                 GCCCGGTsT 
                   
                   
               
               
                   
               
               
                 789-807 
                 ccGGGcGGAuGAAuAccAGTsT 
                 207 
                 CUGGuAUUcAUCC 
                 208 
                 AD-9664 
               
               
                   
                   
                   
                 GCCCGGTsT 
                   
                   
               
               
                   
               
               
                 825-843 
                 CCUGGUGGAGGUGUAUCUCTsT 
                 209 
                 GAGAUACACCUCC 
                 210 
                 AD-9598 
               
               
                   
                   
                   
                 ACCAGGTsT 
                   
                   
               
               
                   
               
               
                 825-843 
                 ccuGGuGGAGGuGuAucucTsT 
                 211 
                 GAGAuAcACCUCc 
                 212 
                 AD-9724 
               
               
                   
                   
                   
                 ACcAGGTsT 
                   
                   
               
               
                   
               
               
                 826-844 
                 CUGGUGGAGGUGUAUCUCCTsT 
                 213 
                 GGAGAUACACCUC 
                 214 
                 AD-9625 
               
               
                   
                   
                   
                 CACCAGTsT 
                   
                   
               
               
                   
               
               
                 826-844 
                 cuGGuGGAGGuGuAucuccTsT 
                 215 
                 GGAGAuAcACCUC 
                 216 
                 AD-9751 
               
               
                   
                   
                   
                 cACcAGTsT 
                   
                   
               
               
                   
               
               
                 827-845 
                 UGGUGGAGGUGUAUCUCCUTsT 
                 217 
                 AGGAGAUACACCU 
                 218 
                 AD-9556 
               
               
                   
                   
                   
                 CCACCATsT 
                   
                   
               
               
                   
               
               
                 827-845 
                 uGGuGGAGGuGuAucuccuTsT 
                 219 
                 AGGAGAuAcACCU 
                 220 
                 AD-9682 
               
               
                   
                   
                   
                 CcACcATsT 
                   
                   
               
               
                   
               
               
                 828-846 
                 GGUGGAGGUGUAUCUCCUATsT 
                 221 
                 UAGGAGAUACACC 
                 222 
                 AD-9539 
               
               
                   
                   
                   
                 UCCACCTsT 
                   
                   
               
               
                   
               
               
                 828-846 
                 GGuGGAGGuGuAucuccuATsT 
                 223 
                 uAGGAGAuAcACC 
                 224 
                 AD-9665 
               
               
                   
                   
                   
                 UCcACCTsT 
                   
                   
               
               
                   
               
               
                 831-849 
                 GGAGGUGUAUCUCCUAGACTsT 
                 225 
                 GUCUAGGAGAUAC 
                 226 
                 AD-9517 
               
               
                   
                   
                   
                 ACCUCCTsT 
                   
                   
               
               
                   
               
               
                 831-849 
                 GGAGGuGuAucuccuAGAcTsT 
                 227 
                 GUCuAGGAGAuAc 
                 228 
                 AD-9643 
               
               
                   
                   
                   
                 ACCUCCTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AGGUGUAUCUCCUAGACACTsT 
                 229 
                 GUGUCUAGGAGAU 
                 230 
                 AD-9610 
               
               
                   
                   
                   
                 ACACCUTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AGGuGuAucuccuAGAcAcTsT 
                 231 
                 GUGUCuAGGAGAu 
                 232 
                 AD-9736 
               
               
                   
                   
                   
                 AcACCUTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AfgGfuGfuAfuCfuCfcUfaG 
                 233 
                 P*gUfgUfcUfaG 
                 234 
                 AD-14681 
               
               
                   
                 faCfaCfTsT 
                   
                 fgAfgAfuAfcAf 
                   
                   
               
               
                   
               
               
                   
                   
                   
                 cCfuTsT 
                   
                   
               
               
                 833-851 
                 AGGUfGUfAUfCfUfCfCfUfA 
                 235 
                 GUfGUfCfUfAGG 
                 236 
                 AD-14691 
               
               
                   
               
               
                   
                 GACfACfTsT 
                   
                 AGAUfACfACfCf 
                   
                   
               
               
                   
                   
                   
                 UfTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AgGuGuAuCuCcUaGaCaCTsT 
                 237 
                 P*gUfgUfcUfaG 
                 238 
                 AD-14701 
               
               
                   
                   
                   
                 fgAfgAfuAfcAf 
                   
                   
               
               
                   
                   
                   
                 cCfuTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AgGuGuAuCuCcUaGaCaCTsT 
                 239 
                 GUfGUfCfUfAGG 
                 240 
                 AD-14711 
               
               
                   
                   
                   
                 AGAUfACfACfCf 
                   
                   
               
               
                   
                   
                   
                 UfTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AfgGfuGfuAfuCfuCfcUfaG 
                 241 
                 GUGUCuaGGagAU 
                 242 
                 AD-14721 
               
               
                   
                 faCfaCfTsT 
                   
                 ACAccuTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AGGUfGUfAUfCfUfCfCfUfA 
                 243 
                 GUGUCuaGGagAU 
                 244 
                 AD-14731 
               
               
                   
                 GACfACfTsT 
                   
                 ACAccuTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 AgGuGuAuCuCcUaGaCaCTsT 
                 245 
                 GUGUCuaGGagAU 
                 246 
                 AD-14741 
               
               
                   
                   
                   
                 ACAccuTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GfcAfcCfcUfcAfuAfgGfcC 
                 247 
                 P*uCfcAfgGfcC 
                 248 
                 AD-15087 
               
               
                   
                 fuGfgAfTsT 
                   
                 fuAfuGfaGfgGf 
                   
                   
               
               
                   
                   
                   
                 uGfcTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GCfACfCfCfUfCfAUfAGGCf 
                 249 
                 UfCfCfAGGCfCf 
                 250 
                 AD-15097 
               
               
                   
                 CfUfGGATsT 
                   
                 UfAUfGAGGGUfG 
                   
                   
               
               
                   
                   
                   
                 CfTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GcAcCcUcAuAgGcCuGgATsT 
                 251 
                 P*uCfcAfgGfcC 
                 252 
                 AD-15107 
               
               
                   
                   
                   
                 fuAfuGfaGfgGf 
                   
                   
               
               
                   
                   
                   
                 uGfcTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GcAcCcUcAuAgGcCuGgATsT 
                 253 
                 UfCfCfAGGCfCf 
                 254 
                 AD-15117 
               
               
                   
                   
                   
                 UfAUfGAGGGUfG 
                   
                   
               
               
                   
                   
                   
                 CfTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GfcAfcCfcUfcAfuAfgGfcC 
                 255 
                 UCCAGgcCUauGA 
                 256 
                 AD-15127 
               
               
                   
                 fuGfgAfTsT 
                   
                 GGGugcTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GCfACfCfCfUfCfAUfAGGCf 
                 257 
                 UCCAGgcCUauGA 
                 258 
                 AD-15137 
               
               
                   
                 CfUfGGATsT 
                   
                 GGGugcTsT 
                   
                   
               
               
                   
               
               
                 833-851 
                 GcAcCcUcAuAgGcCuGgATsT 
                 259 
                 UCCAGgcCUauGA 
                 260 
                 AD-15147 
               
               
                   
                   
                   
                 GGGugcTsT 
                   
                   
               
               
                   
               
               
                 836-854 
                 UGUAUCUCCUAGACACCAGTsT 
                 261 
                 CUGGUGUCUAGGA 
                 262 
                 AD-9516 
               
               
                   
                   
                   
                 GAUACATsT 
                   
                   
               
               
                   
               
               
                 836-854 
                 uGuAucuccuAGAcAccAGTsT 
                 263 
                 CUGGUGUCuAGGA 
                 264 
                 AD-9642 
               
               
                   
                   
                   
                 GAuAcATsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UCUCCUAGACACCAGCAUATsT 
                 265 
                 UAUGCUGGUGUCU 
                 266 
                 AD-9562 
               
               
                   
                   
                   
                 AGGAGATsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 ucuccuAGAcAccAGcAuATsT 
                 267 
                 uAUGCUGGUGUCu 
                 268 
                 AD-9688 
               
               
                   
                   
                   
                 AGGAGATsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UfcUfcCfuAfgAfcAfcCfaG 
                 269 
                 P*uAfuGfcUfgG 
                 270 
                 AD-14677 
               
               
                   
                 fcAfuAfTsT 
                   
                 fuGfuCfuAfgGf 
                   
                   
               
               
                   
                   
                   
                 aGfaTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UfCfUfCfCfUfAGACfACfCf 
                 271 
                 UfAUfGCfUfGGU 
                 272 
                 AD-14687 
               
               
                   
                 AGCfAUfATsT 
                   
                 fGUfCfUfAGGAG 
                   
                   
               
               
                   
                   
                   
                 ATsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UcUcCuAgAcAcCaGcAuATsT 
                 273 
                 P*uAfuGfcUfgG 
                 274 
                 AD-14697 
               
               
                   
                   
                   
                 fuGfuCfuAfgGf 
                   
                   
               
               
                   
                   
                   
                 aGfaTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UcUcCuAgAcAcCaGcAuATsT 
                 275 
                 UfAUfGCfUfGGU 
                 276 
                 AD-14707 
               
               
                   
                   
                   
                 fGUfCfUfAGGAG 
                   
                   
               
               
                   
                   
                   
                 ATsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UfcUfcCfuAafAfcAfcCfaG 
                 277 
                 UAUGCugGUguCU 
                 278 
                 AD-14717 
               
               
                   
                 fcAfuAfTsT 
                   
                 AGGagaTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UfCfUfCfCfUfAGACfACfCf 
                 279 
                 UAUGCugGUguCU 
                 280 
                 AD-14727 
               
               
                   
                 AGCfAUfATsT 
                   
                 AGGagaTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 UcUcCuAgAcAcCaGcAuATsT 
                 281 
                 UAUGCugGUguCU 
                 282 
                 AD-14737 
               
               
                   
                   
                   
                 AGGagaTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AfgGfcCfuGfgAfgUfuUfaU 
                 283 
                 P*cCfgAfaUfaA 
                 284 
                 AD-15083 
               
               
                   
                 fuCfgGfTsT 
                   
                 faCfuCfcAfgGf 
                   
                   
               
               
                   
                   
                   
                 cCfuTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AGGCfCfUfGGAGUfUfUfAUf 
                 285 
                 CfCfGAAUfAAAC 
                 286 
                 AD-15093 
               
               
                   
                 UfCfGGTsT 
                   
                 fUfCfCfAGGCfC 
                   
                   
               
               
                   
                   
                   
                 fUfTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AgGcCuGgAgUuUaUuCgGTsT 
                 287 
                 P*cCfgAfaUfaA 
                 288 
                 AD-15103 
               
               
                   
                   
                   
                 faCfuCfcAfgGf 
                   
                   
               
               
                   
                   
                   
                 cCfuTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AgGcCuGgAgUuUaUuCgGTsT 
                 289 
                 CfCfGAAUfAAAC 
                 290 
                 AD-15113 
               
               
                   
                   
                   
                 fUfCfCfAGGCfC 
                   
                   
               
               
                   
                   
                   
                 fUfTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AfgGfcCfuGfgAfgUfuUfaU 
                 291 
                 CCGAAuaAAcuCC 
                 292 
                 AD-15123 
               
               
                   
                 fuCfgGfTsT 
                   
                 AGGccuTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AGGCfCfUfGGAGUfUfUfAUf 
                 293 
                 CCGAAuaAAcuCC 
                 294 
                 AD-15133 
               
               
                   
                 UfCfGGTsT 
                   
                 AGGccuTsT 
                   
                   
               
               
                   
               
               
                 840-858 
                 AgGcCuGgAgUuUaUuCgGTsT 
                 295 
                 CCGAAuaAAcuCC 
                 296 
                 AD-15143 
               
               
                   
                   
                   
                 AGGccuTsT 
                   
                   
               
               
                   
               
               
                 841-859 
                 CUCCUAGACACCAGCAUACTsT 
                 297 
                 GUAUGCUGGUGUC 
                 298 
                 AD-9521 
               
               
                   
                   
                   
                 UAGGAGTsT 
                   
                   
               
               
                   
               
               
                 841-859 
                 cuccuAGAcAccAGcAuAcTsT 
                 299 
                 GuAUGCUGGUGUC 
                 300 
                 AD-9647 
               
               
                   
                   
                   
                 uAGGAGTsT 
                   
                   
               
               
                   
               
               
                 842-860 
                 UCCUAGACACCAGCAUACATsT 
                 301 
                 UGUAUGCUGGUGU 
                 302 
                 AD-9611 
               
               
                   
                   
                   
                 CUAGGATsT 
                   
                   
               
               
                   
               
               
                 842-860 
                 uccuAGAcAccAGcAuAcATsT 
                 303 
                 UGuAUGCUGGUGU 
                 304 
                 AD-9737 
               
               
                   
                   
                   
                 CuAGGATsT 
                   
                   
               
               
                   
               
               
                 843-861 
                 CCUAGACACCAGCAUACAGTsT 
                 305 
                 CUGUAUGCUGGUG 
                 306 
                 AD-9592 
               
               
                   
                   
                   
                 UCUAGGTsT 
                   
                   
               
               
                   
               
               
                 843-861 
                 ccuAGAcAccAGcAuAcAGTsT 
                 307 
                 CUGuAUGCUGGUG 
                 308 
                 AD-9718 
               
               
                   
                   
                   
                 UCuAGGTsT 
                   
                   
               
               
                   
               
               
                 847-865 
                 GACACCAGCAUACAGAGUGTsT 
                 309 
                 CACUCUGUAUGCU 
                 310 
                 AD-9561 
               
               
                   
                   
                   
                 GGUGUCTsT 
                   
                   
               
               
                   
               
               
                 847-865 
                 GAcAccAGcAuAcAGAGuGTsT 
                 311 
                 cACUCUGuAUGCU 
                 312 
                 AD-9687 
               
               
                   
                   
                   
                 GGUGUCTsT 
                   
                   
               
               
                   
               
               
                 855-873 
                 CAUACAGAGUGACCACCGGTsT 
                 313 
                 CCGGUGGUCACUC 
                 314 
                 AD-9636 
               
               
                   
                   
                   
                 UGUAUGTsT 
                   
                   
               
               
                   
               
               
                 855-873 
                 cAuAcAGAGuGAccAccGGTsT 
                 315 
                 CCGGUGGUcACUC 
                 316 
                 AD-9762 
               
               
                   
                   
                   
                 UGuAUGTsT 
                   
                   
               
               
                   
               
               
                 860-878 
                 AGAGUGACCACCGGGAAAUTsT 
                 317 
                 AUUUCCCGGUGGU 
                 318 
                 AD-9540 
               
               
                   
                   
                   
                 CACUCUTsT 
                   
                   
               
               
                   
               
               
                 860-878 
                 AGAGuGAccAccGGGAAAuTsT 
                 319 
                 AUUUCCCGGUGGU 
                 320 
                 AD-9666 
               
               
                   
                   
                   
                 cACUCUTsT 
                   
                   
               
               
                   
               
               
                 861-879 
                 GAGUGACCACCGGGAAAUCTsT 
                 321 
                 GAUUUCCCGGUGG 
                 322 
                 AD-9535 
               
               
                   
                   
                   
                 UCACUCTsT 
                   
                   
               
               
                   
               
               
                 861-879 
                 GAGuGAccAccGGGAAAucTsT 
                 323 
                 GAUUUCCCGGUGG 
                 324 
                 AD-9661 
               
               
                   
                   
                   
                 UcACUCTsT 
                   
                   
               
               
                   
               
               
                 863-881 
                 GUGACCACCGGGAAAUCGATsT 
                 325 
                 UCGAUUUCCCGGU 
                 326 
                 AD-9559 
               
               
                   
                   
                   
                 GGUCACTsT 
                   
                   
               
               
                   
               
               
                 863-881 
                 GuGAccAccGGGAAAucGATsT 
                 327 
                 UCGAUUUCCCGGU 
                 328 
                 AD-9685 
               
               
                   
                   
                   
                 GGUcACTsT 
                   
                   
               
               
                   
               
               
                 865-883 
                 GACCACCGGGAAAUCGAGGTsT 
                 329 
                 CCUCGAUUUCCCG 
                 330 
                 AD-9533 
               
               
                   
                   
                   
                 GUGGUCTsT 
                   
                   
               
               
                   
               
               
                 865-883 
                 GAccAccGGGAAAucGAGGTsT 
                 331 
                 CCUCGAUUUCCCG 
                 332 
                 AD-9659 
               
               
                   
                   
                   
                 GUGGUCTsT 
                   
                   
               
               
                   
               
               
                 866-884 
                 ACCACCGGGAAAUCGAGGGTsT 
                 333 
                 CCCUCGAUUUCCC 
                 334 
                 AD-9612 
               
               
                   
                   
                   
                 GGUGGUTsT 
                   
                   
               
               
                   
               
               
                 866-884 
                 AccAccGGGAAAucGAGGGTsT 
                 335 
                 CCCUCGAUUUCCC 
                 336 
                 AD-9738 
               
               
                   
                   
                   
                 GGUGGUTsT 
                   
                   
               
               
                   
               
               
                 867-885 
                 CCACCGGGAAAUCGAGGGCTsT 
                 337 
                 GCCCUCGAUUUCC 
                 338 
                 AD-9557 
               
               
                   
                   
                   
                 CGGUGGTsT 
                   
                   
               
               
                   
               
               
                 867-885 
                 ccAccGGGAAAucGAGGGcTsT 
                 339 
                 GCCCUCGAUUUCC 
                 340 
                 AD-9683 
               
               
                   
                   
                   
                 CGGUGGTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AAAUCGAGGGCAGGGUCAUTsT 
                 341 
                 AUGACCCUGCCCU 
                 342 
                 AD-9531 
               
               
                   
                   
                   
                 CGAUUUTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AAAucGAGGGcAGGGucAuTsT 
                 343 
                 AUGACCCUGCCCU 
                 344 
                 AD-9657 
               
               
                   
                   
                   
                 CGAUUUTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AfaAfuCfgAfgGfgCfaGfgG 
                 345 
                 P*aUfgAfcCfcU 
                 346 
                 AD-14673 
               
               
                   
                 fuCfaUfTsT 
                   
                 fgCfcCfuCfgAf 
                   
                   
               
               
                   
                   
                   
                 uUfuTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AAAUfCfGAGGGCfAGGGUfCf 
                 347 
                 AUfGACfCfCfUf 
                 348 
                 AD-14683 
               
               
                   
                 AUfTsT 
                   
                 GCfCfCfUfCfGA 
                   
                   
               
               
                   
                   
                   
                 UfUfUfTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AaAuCgAgGgCaGgGuCaUTsT 
                 349 
                 P*aUfgAfcCfcU 
                 350 
                 AD-14693 
               
               
                   
                   
                   
                 fgCfcCfuCfgAf 
                   
                   
               
               
                   
                   
                   
                 uUfuTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AaAuCgAgGgCaGgGuCaUTsT 
                 351 
                 AUfGACfCfCfUf 
                 352 
                 AD-14703 
               
               
                   
                   
                   
                 GCfCfCfUfCfGA 
                   
                   
               
               
                   
                   
                   
                 UfUfUfTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AfaAfuCfgAfgGfgCfaGfgG 
                 353 
                 AUGACccUGccCU 
                 354 
                 AD-14713 
               
               
                   
                 fuCfaUfTsT 
                   
                 CGAuuuTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AAAUfCfGAGGGCfAGGGUfCf 
                 355 
                 AUGACccUGccCU 
                 356 
                 AD-14723 
               
               
                   
                 AUfTsT 
                   
                 CGAuuuTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 AaAuCgAgGgCaGgGuCaUTsT 
                 357 
                 AUGACccUGccCU 
                 358 
                 AD-14733 
               
               
                   
                   
                   
                 CGAuuuTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CfgGfcAfcCfcUfcAfuAfgG 
                 359 
                 P*cAfgGfcCfuA 
                 360 
                 AD-15079 
               
               
                   
                 fcCfuGfTsT 
                   
                 fuGfaGfgGfuGf 
                   
                   
               
               
                   
                   
                   
                 cCfgTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CfGGCfACfCfCfUfCfAUfAG 
                 361 
                 CfAGGCfCfUfAU 
                 362 
                 AD-15089 
               
               
                   
                 GCfCfUfGTsT 
                   
                 fGAGGGUfGCfCf 
                   
                   
               
               
                   
                   
                   
                 GTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CgGcAcCcUcAuAgGcCuGTsT 
                 363 
                 P*cAfgGfcCfuA 
                 364 
                 AD-15099 
               
               
                   
                   
                   
                 fuGfaGfgGfuGf 
                   
                   
               
               
                   
                   
                   
                 cCfgTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CgGcAcCcUcAuAgGcCuGTsT 
                 365 
                 CfAGGCfCfUfAU 
                 366 
                 AD-15109 
               
               
                   
                   
                   
                 fGAGGGUfGCfCf 
                   
                   
               
               
                   
                   
                   
                 GTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CfgGfcAfcCfcUfcAfuAfgG 
                 367 
                 CAGGCcuAUgaGG 
                 368 
                 AD-15119 
               
               
                   
                 fcCfuGfTsT 
                   
                 GUGccgTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CfGGCfACfCfCfUfCfAUfAG 
                 369 
                 CAGGCcuAUgaGG 
                 370 
                 AD-15129 
               
               
                   
                 GCfCfUfGTsT 
                   
                 GUGccgTsT 
                   
                   
               
               
                   
               
               
                 875-893 
                 CgGcAcCcUcAuAgGcCuGTsT 
                 371 
                 CAGGCcuAUgaGG 
                 372 
                 AD-15139 
               
               
                   
                   
                   
                 GUGccgTsT 
                   
                   
               
               
                   
               
               
                 877-895 
                 AUCGAGGGCAGGGUCAUGGTsT 
                 373 
                 CCAUGACCCUGCC 
                 374 
                 AD-9542 
               
               
                   
                   
                   
                 CUCGAUTsT 
                   
                   
               
               
                   
               
               
                 877-895 
                 AucGAGGGcAGGGucAuGGTsT 
                 375 
                 CcAUGACCCUGCC 
                 376 
                 AD-9668 
               
               
                   
                   
                   
                 CUCGAUTsT 
                   
                   
               
               
                   
               
               
                 878-896 
                 cGAGGGcAGGGucAuGGucTsT 
                 377 
                 GACcAUGACCCUG 
                 378 
                 AD-9739 
               
               
                   
                   
                   
                 CCCUCGTsT 
                   
                   
               
               
                   
               
               
                 880-898 
                 GAGGGCAGGGUCAUGGUCATsT 
                 379 
                 UGACCAUGACCCU 
                 380 
                 AD-9637 
               
               
                   
                   
                   
                 GCCCUCTsT 
                   
                   
               
               
                   
               
               
                 880-898 
                 GAGGGcAGGGucAuGGucATsT 
                 381 
                 UGACcAUGACCCU 
                 382 
                 AD-9763 
               
               
                   
                   
                   
                 GCCCUCTsT 
                   
                   
               
               
                   
               
               
                 882-900 
                 GGGCAGGGUCAUGGUCACCTsT 
                 383 
                 GGUGACCAUGACC 
                 384 
                 AD-9630 
               
               
                   
                   
                   
                 CUGCCCTsT 
                   
                   
               
               
                   
               
               
                 882-900 
                 GGGcAGGGucAuGGucAccTsT 
                 385 
                 GGUGACcAUGACC 
                 386 
                 AD-9756 
               
               
                   
                   
                   
                 CUGCCCTsT 
                   
                   
               
               
                   
               
               
                 885-903 
                 CAGGGUCAUGGUCACCGACTsT 
                 387 
                 GUCGGUGACCAUG 
                 388 
                 AD-9593 
               
               
                   
                   
                   
                 ACCCUGTsT 
                   
                   
               
               
                   
               
               
                 885-903 
                 cAGGGucAuGGucAccGAcTsT 
                 389 
                 GUCGGUGACcAUG 
                 390 
                 AD-9719 
               
               
                   
                   
                   
                 ACCCUGTsT 
                   
                   
               
               
                   
               
               
                 886-904 
                 AGGGUCAUGGUCACCGACUTsT 
                 391 
                 AGUCGGUGACCAU 
                 392 
                 AD-9601 
               
               
                   
                   
                   
                 GACCCUTsT 
                   
                   
               
               
                   
               
               
                 886-904 
                 AGGGucAuGGucAccGAcuTsT 
                 393 
                 AGUCGGUGACcAU 
                 394 
                 AD-9727 
               
               
                   
                   
                   
                 GACCCUTsT 
                   
                   
               
               
                   
               
               
                 892-910 
                 AUGGUCACCGACUUCGAGATsT 
                 395 
                 UCUCGAAGUCGGU 
                 396 
                 AD-9573 
               
               
                   
                   
                   
                 GACCAUTsT 
                   
                   
               
               
                   
               
               
                 892-910 
                 AuGGucAccGAcuucGAGATsT 
                 397 
                 UCUCGAAGUCGGU 
                 398 
                 AD-9699 
               
               
                   
                   
                   
                 GACcAUTsT 
                   
                   
               
               
                   
               
               
                 899-917 
                 CCGACUUCGAGAAUGUGCCTT 
                 399 
                 GGCACAUUCUCGA 
                 400 
                 AD-15228 
               
               
                   
                   
                   
                 AGUCGGTT 
                   
                   
               
               
                   
               
               
                 921-939 
                 GGAGGACGGGACCCGCUUCTT 
                 401 
                 GAAGCGGGUCCCG 
                 402 
                 AD-15395 
               
               
                   
                   
                   
                 UCCUCCTT 
                   
                   
               
               
                   
               
               
                 993- 
                 CAGCGGCCGGGAUGCCGGCTsT 
                 403 
                 GCCGGCAUCCCGG 
                 404 
                 AD-9602 
               
               
                 1011 
                   
                   
                 CCGCUGTsT 
                   
                   
               
               
                   
               
               
                 993- 
                 cAGcGGccGGGAuGccGGcTsT 
                 405 
                 GCCGGcAUCCCGG 
                 406 
                 AD-9728 
               
               
                 1011 
                   
                   
                 CCGCUGTsT 
                   
                   
               
               
                   
               
               
                 1020- 
                 GGGUGCCAGCAUGCGCAGCTT 
                 407 
                 GCUGCGCAUGCUG 
                 408 
                 AD-15386 
               
               
                 1038 
                   
                   
                 GCACCCTT 
                   
                   
               
               
                   
               
               
                 1038- 
                 CCUGCGCGUGCUCAACUGCTsT 
                 409 
                 GCAGUUGAGCACG 
                 410 
                 AD-9580 
               
               
                 1056 
                   
                   
                 CGCAGGTsT 
                   
                   
               
               
                   
               
               
                 1038- 
                 ccuGcGcGuGcucAAcuGcTsT 
                 411 
                 GcAGUUGAGcACG 
                 412 
                 AD-9706 
               
               
                 1056 
                   
                   
                 CGcAGGTsT 
                   
                   
               
               
                   
               
               
                 1040- 
                 UGCGCGUGCUCAACUGCCATsT 
                 413 
                 UGGCAGUUGAGCA 
                 414 
                 AD-9581 
               
               
                 1058 
                   
                   
                 CGCGCATsT 
                   
                   
               
               
                   
               
               
                 1040- 
                 uGcGcGuGcucAAcuGccATsT 
                 415 
                 UGGcAGUUGAGcA 
                 416 
                 AD-9707 
               
               
                 1058 
                   
                   
                 CGCGcATsT 
                   
                   
               
               
                   
               
               
                 1042- 
                 CGCGUGCUCAACUGCCAAGTsT 
                 417 
                 CUUGGCAGUUGAG 
                 418 
                 AD-9543 
               
               
                 1060 
                   
                   
                 CACGCGTsT 
                   
                   
               
               
                   
               
               
                 1042- 
                 cGcGuGcucAAcuGccAAGTsT 
                 419 
                 CUUGGcAGUUGAG 
                 420 
                 AD-9669 
               
               
                 1060 
                   
                   
                 cACGCGTsT 
                   
                   
               
               
                   
               
               
                 1053- 
                 CUGCCAAGGGAAGGGCACGTsT 
                 421 
                 CGUGCCCUUCCCU 
                 422 
                 AD-9574 
               
               
                 1071 
                   
                   
                 UGGCAGTsT 
                   
                   
               
               
                   
               
               
                 1053- 
                 cuGccAAGGGAAGGGcAcGTsT 
                 423 
                 CGUGCCCUUCCCU 
                 424 
                 AD-9700 
               
               
                 1071 
                   
                   
                 UGGcAGTsT 
                   
                   
               
               
                   
               
               
                 1057- 
                 CAAGGGAAGGGCACGGUUATT 
                 425 
                 UAACCGUGCCCUU 
                 426 
                 AD-15320 
               
               
                 1075 
                   
                   
                 CCCUUGTT 
                   
                   
               
               
                   
               
               
                 1058- 
                 AAGGGAAGGGCACGGUUAGTT 
                 427 
                 CUAACCGUGCCCU 
                 428 
                 AD-15321 
               
               
                 1076 
                   
                   
                 UCCCUUTT 
                   
                   
               
               
                   
               
               
                 1059- 
                 AGGGAAGGGCACGGUUAGCTT 
                 429 
                 GCUAACCGUGCCC 
                 430 
                 AD-15199 
               
               
                 1077 
                   
                   
                 UUCCCUTT 
                   
                   
               
               
                   
               
               
                 1060- 
                 GGGAAGGGCACGGUUAGCGTT 
                 431 
                 CGCUAACCGUGCC 
                 432 
                 AD-15167 
               
               
                 1078 
                   
                   
                 CUUCCCTT 
                   
                   
               
               
                   
               
               
                 1061- 
                 GGAAGGGCACGGUUAGCGGTT 
                 433 
                 CCGCUAACCGUGC 
                 434 
                 AD-15164 
               
               
                 1079 
                   
                   
                 CCUUCCTT 
                   
                   
               
               
                   
               
               
                 1062- 
                 GAAGGGCACGGUUAGCGGCTT 
                 435 
                 GCCGCUAACCGUG 
                 436 
                 AD-15166 
               
               
                 1080 
                   
                   
                 CCCUUCTT 
                   
                   
               
               
                   
               
               
                 1063- 
                 AAGGGCACGGUUAGCGGCATT 
                 437 
                 UGCCGCUAACCGU 
                 438 
                 AD-15322 
               
               
                 1081 
                   
                   
                 GCCCUUTT 
                   
                   
               
               
                   
               
               
                 1064- 
                 AGGGCACGGUUAGCGGCACTT 
                 439 
                 GUGCCGCUAACCG 
                 440 
                 AD-15200 
               
               
                 1082 
                   
                   
                 UGCCCUTT 
                   
                   
               
               
                   
               
               
                 1068- 
                 CACGGUUAGCGGCACCCUCTT 
                 441 
                 GAGGGUGCCGCUA 
                 442 
                 AD-15213 
               
               
                 1086 
                   
                   
                 ACCGUGTT 
                   
                   
               
               
                   
               
               
                 1069- 
                 ACGGUUAGCGGCACCCUCATT 
                 443 
                 UGAGGGUGCCGCU 
                 444 
                 AD-15229 
               
               
                 1087 
                   
                   
                 AACCGUTT 
                   
                   
               
               
                   
               
               
                 1072- 
                 GUUAGCGGCACCCUCAUAGTT 
                 445 
                 CUAUGAGGGUGCC 
                 446 
                 AD-15215 
               
               
                 1090 
                   
                   
                 GCUAACTT 
                   
                   
               
               
                   
               
               
                 1073- 
                 UUAGCGGCACCCUCAUAGGTT 
                 447 
                 CCUAUGAGGGUGC 
                 448 
                 AD-15214 
               
               
                 1091 
                   
                   
                 CGCUAATT 
                   
                   
               
               
                   
               
               
                 1076- 
                 GCGGCACCCUCAUAGGCCUTsT 
                 449 
                 AGGCCUAUGAGGG 
                 450 
                 AD-9315 
               
               
                 1094 
                   
                   
                 UGCCGCTsT 
                   
                   
               
               
                   
               
               
                 1079- 
                 GCACCCUCAUAGGCCUGGATsT 
                 451 
                 UCCAGGCCUAUGA 
                 452 
                 AD-9326 
               
               
                 1097 
                   
                   
                 GGGUGCTsT 
                   
                   
               
               
                   
               
               
                 1085- 
                 UCAUAGGCCUGGAGUUUAUTsT 
                 453 
                 AUAAACUCCAGGC 
                 454 
                 AD-9318 
               
               
                 1103 
                   
                   
                 CUAUGATsT 
                   
                   
               
               
                   
               
               
                 1090- 
                 GGCCUGGAGUUUAUUCGGATsT 
                 455 
                 UCCGAAUAAACUC 
                 456 
                 AD-9323 
               
               
                 1108 
                   
                   
                 CAGGCCTsT 
                   
                   
               
               
                   
               
               
                 1091- 
                 GCCUGGAGUUUAUUCGGAATsT 
                 457 
                 UUCCGAAUAAACU 
                 458 
                 AD-9314 
               
               
                 1109 
                   
                   
                 CCAGGCTsT 
                   
                   
               
               
                   
               
               
                 1091- 
                 GccuGGAGuuuAuucGGAATsT 
                 459 
                 UUCCGAAuAAACU 
                 460 
                 AD-10792 
               
               
                 1109 
                   
                   
                 CcAGGCTsT 
                   
                   
               
               
                   
               
               
                 1091- 
                 GccuGGAGuuuAuucGGAATsT 
                 461 
                 UUCCGAAUAACUC 
                 462 
                 AD-10796 
               
               
                 1109 
                   
                   
                 CAGGCTsT 
                   
                   
               
               
                   
               
               
                 1093- 
                 CUGGAGUUUAUUCGGAAAATsT 
                 463 
                 UUUUCCGAAUAAA 
                 464 
                 AD-9638 
               
               
                 1111 
                   
                   
                 CUCCAGTsT 
                   
                   
               
               
                   
               
               
                 1093- 
                 cuGGAGuuuAuucGGAAAATsT 
                 465 
                 UUUUCCGAAuAAA 
                 466 
                 AD-9764 
               
               
                 1111 
                   
                   
                 CUCcAGTsT 
                   
                   
               
               
                   
               
               
                 1095- 
                 GGAGUUUAUUCGGAAAAGCTsT 
                 467 
                 GCUUUUCCGAAUA 
                 468 
                 AD-9525 
               
               
                 1113 
                   
                   
                 AACUCCTsT 
                   
                   
               
               
                   
               
               
                 1095- 
                 GGAGuuuAuucGGAAAAGcTsT 
                 469 
                 GCUUUUCCGAAuA 
                 470 
                 AD-9651 
               
               
                 1113 
                   
                   
                 AACUCCTsT 
                   
                   
               
               
                   
               
               
                 1096- 
                 GAGUUUAUUCGGAAAAGCCTsT 
                 471 
                 GGCUUUUCCGAAU 
                 472 
                 AD-9560 
               
               
                 1114 
                   
                   
                 AAACUCTsT 
                   
                   
               
               
                   
               
               
                 1096- 
                 GAGuuuAuucGGAAAAGccTsT 
                 473 
                 GGCUUUUCCGAAu 
                 474 
                 AD-9686 
               
               
                 1114 
                   
                   
                 AAACUCTsT 
                   
                   
               
               
                   
               
               
                 1100- 
                 UUAUUCGGAAAAGCCAGCUTsT 
                 475 
                 AGCUGGCUUUUCC 
                 476 
                 AD-9536 
               
               
                 1118 
                   
                   
                 GAAUAATsT 
                   
                   
               
               
                   
               
               
                 1100- 
                 uuAuucGGAAAAGccAGcuTsT 
                 477 
                 AGCUGGCUUUUCC 
                 478 
                 AD-9662 
               
               
                 1118 
                   
                   
                 GAAuAATsT 
                   
                   
               
               
                   
               
               
                 1154- 
                 CCCUGGCGGGUGGGUACAGTsT 
                 479 
                 CUGUACCCACCCG 
                 480 
                 AD-9584 
               
               
                 1172 
                   
                   
                 CCAGGGTsT 
                   
                   
               
               
                   
               
               
                 1154- 
                 cccuGGcGGGuGGGuAcAGTsT 
                 481 
                 CUGuACCcACCCG 
                 482 
                 AD-9710 
               
               
                 1172 
                   
                   
                 CcAGGGTsT 
                   
                   
               
               
                   
               
               
                 1155- 
                 CCUGGCGGGUGGGUACAGCTT 
                 483 
                 GCUGUACCCACCC 
                 484 
                 AD-15323 
               
               
                 1173 
                   
                   
                 GCCAGGTT 
                   
                   
               
               
                   
               
               
                 1157- 
                 UGGCGGGUGGGUACAGCCGTsT 
                 485 
                 CGGCUGUACCCAC 
                 486 
                 AD-9551 
               
               
                 1175 
                   
                   
                 CCGCCATsT 
                   
                   
               
               
                   
               
               
                 1157- 
                 uGGcGGGuGGGuAcAGccGTsT 
                 487 
                 CGGCUGuACCcAC 
                 488 
                 AD-9677 
               
               
                 1175 
                   
                   
                 CCGCcATsT 
                   
                   
               
               
                   
               
               
                 1158- 
                 GGCGGGUGGGUACAGCCGCTT 
                 489 
                 GCGGCUGUACCCA 
                 490 
                 AD-15230 
               
               
                 1176 
                   
                   
                 CCCGCCTT 
                   
                   
               
               
                   
               
               
                 1162- 
                 GGUGGGUACAGCCGCGUCCTT 
                 491 
                 GGACGCGGCUGUA 
                 492 
                 AD-15231 
               
               
                 1180 
                   
                   
                 CCCACCTT 
                   
                   
               
               
                   
               
               
                 1164- 
                 UGGGUACAGCCGCGUCCUCTT 
                 493 
                 GAGGACGCGGCUG 
                 494 
                 AD-15285 
               
               
                 1182 
                   
                   
                 UACCCATT 
                   
                   
               
               
                   
               
               
                 1172- 
                 GCCGCGUCCUCAACGCCGCTT 
                 495 
                 GCGGCGUUGAGGA 
                 496 
                 AD-15396 
               
               
                 1190 
                   
                   
                 CGCGGCTT 
                   
                   
               
               
                   
               
               
                 1173- 
                 CCGCGUCCUCAACGCCGCCTT 
                 497 
                 GGCGGCGUUGAGG 
                 498 
                 AD-15397 
               
               
                 1191 
                   
                   
                 ACGCGGTT 
                   
                   
               
               
                   
               
               
                 1216- 
                 GUCGUGCUGGUCACCGCUGTsT 
                 499 
                 CAGCGGUGACCAG 
                 500 
                 AD-9600 
               
               
                 1234 
                   
                   
                 CACGACTsT 
                   
                   
               
               
                   
               
               
                 1216- 
                 GucGuGcuGGucAccGcuGTsT 
                 501 
                 cAGCGGUGACcAG 
                 502 
                 AD-9726 
               
               
                 1234 
                   
                   
                 cACGACTsT 
                   
                   
               
               
                   
               
               
                 1217- 
                 UCGUGCUGGUCACCGCUGCTsT 
                 503 
                 GCAGCGGUGACCA 
                 504 
                 AD-9606 
               
               
                 1235 
                   
                   
                 GCACGATsT 
                   
                   
               
               
                   
               
               
                 1217- 
                 ucGuGcuGGucAccGcuGcTsT 
                 505 
                 GcAGCGGUGACcA 
                 506 
                 AD-9732 
               
               
                 1235 
                   
                   
                 GcACGATsT 
                   
                   
               
               
                   
               
               
                 1223- 
                 UGGUCACCGCUGCCGGCAATsT 
                 507 
                 UUGCCGGCAGCGG 
                 508 
                 AD-9633 
               
               
                 1241 
                   
                   
                 UGACCATsT 
                   
                   
               
               
                   
               
               
                 1223- 
                 uGGucAccGcuGccGGcAATsT 
                 509 
                 UUGCCGGcAGCGG 
                 510 
                 AD-9759 
               
               
                 1241 
                   
                   
                 UGACcATsT 
                   
                   
               
               
                   
               
               
                 1224- 
                 GGUCACCGCUGCCGGCAACTsT 
                 511 
                 GUUGCCGGCAGCG 
                 512 
                 AD-9588 
               
               
                 1242 
                   
                   
                 GUGACCTsT 
                   
                   
               
               
                   
               
               
                 1224- 
                 GGucAccGcuGccGGcAAcTsT 
                 513 
                 GUUGCCGGcAGCG 
                 514 
                 AD-9714 
               
               
                 1242 
                   
                   
                 GUGACCTsT 
                   
                   
               
               
                   
               
               
                 1227- 
                 CACCGCUGCCGGCAACUUCTsT 
                 515 
                 GAAGUUGCCGGCA 
                 516 
                 AD-9589 
               
               
                 1245 
                   
                   
                 GCGGUGTsT 
                   
                   
               
               
                   
               
               
                 1227- 
                 cAccGcuGccGGcAAcuucTsT 
                 517 
                 GAAGUUGCCGGcA 
                 518 
                 AD-9715 
               
               
                 1245 
                   
                   
                 GCGGUGTsT 
                   
                   
               
               
                   
               
               
                 1229- 
                 CCGCUGCCGGCAACUUCCGTsT 
                 519 
                 CGGAAGUUGCCGG 
                 520 
                 AD-9575 
               
               
                 1247 
                   
                   
                 CAGCGGTsT 
                   
                   
               
               
                   
               
               
                 1229- 
                 ccGcuGccGGcAAcuuccGTsT 
                 521 
                 CGGAAGUUGCCGG 
                 522 
                 AD-9701 
               
               
                 1247 
                   
                   
                 cAGCGGTsT 
                   
                   
               
               
                   
               
               
                 1230- 
                 CGCUGCCGGCAACUUCCGGTsT 
                 523 
                 CCGGAAGUUGCCG 
                 524 
                 AD-9563 
               
               
                 1248 
                   
                   
                 GCAGCGTsT 
                   
                   
               
               
                   
               
               
                 1230- 
                 cGcuGccGGcAAcuuccGGTsT 
                 525 
                 CCGGAAGUUGCCG 
                 526 
                 AD-9689 
               
               
                 1248 
                   
                   
                 GcAGCGTsT 
                   
                   
               
               
                   
               
               
                 1231- 
                 GCUGCCGGCAACUUCCGGGTsT 
                 527 
                 CCCGGAAGUUGCC 
                 528 
                 AD-9594 
               
               
                 1249 
                   
                   
                 GGCAGCTsT 
                   
                   
               
               
                   
               
               
                 1231- 
                 GcuGccGGcAAcuuccGGGTsT 
                 529 
                 CCCGGAAGUUGCC 
                 530 
                 AD-9720 
               
               
                 1249 
                   
                   
                 GGcAGCTsT 
                   
                   
               
               
                   
               
               
                 1236- 
                 CGGCAACUUCCGGGACGAUTsT 
                 531 
                 AUCGUCCCGGAAG 
                 532 
                 AD-9585 
               
               
                 1254 
                   
                   
                 UUGCCGTsT 
                   
                   
               
               
                   
               
               
                 1236- 
                 cGGcAAcuuccGGGAcGAuTsT 
                 533 
                 AUCGUCCCGGAAG 
                 534 
                 AD-9711 
               
               
                 1254 
                   
                   
                 UUGCCGTsT 
                   
                   
               
               
                   
               
               
                 1237- 
                 GGCAACUUCCGGGACGAUGTsT 
                 535 
                 CAUCGUCCCGGAA 
                 536 
                 AD-9614 
               
               
                 1255 
                   
                   
                 GUUGCCTsT 
                   
                   
               
               
                   
               
               
                 1237- 
                 GGcAAcuuccGGGAcGAuGTsT 
                 537 
                 cAUCGUCCCGGAA 
                 538 
                 AD-9740 
               
               
                 1255 
                   
                   
                 GUUGCCTsT 
                   
                   
               
               
                   
               
               
                 1243- 
                 UUCCGGGACGAUGCCUGCCTsT 
                 539 
                 GGCAGGCAUCGUC 
                 540 
                 AD-9615 
               
               
                 1261 
                   
                   
                 CCGGAATsT 
                   
                   
               
               
                   
               
               
                 1243- 
                 uuccGGGAcGAuGccuGccTsT 
                 541 
                 GGcAGGcAUCGUC 
                 542 
                 AD-9741 
               
               
                 1261 
                   
                   
                 CCGGAATsT 
                   
                   
               
               
                   
               
               
                 1248- 
                 GGACGAUGCCUGCCUCUACTsT 
                 543 
                 GUAGAGGCAGGCA 
                 544 
                 AD-9534 
               
               
                 1266 
                   
                   
                 UCGUCCTsT 
                   
                   
               
               
                   
               
               
                 1248- 
                 GGACGAUGCCUGCCUCUACTsT 
                 545 
                 GUAGAGGCAGGCA 
                 546 
                 AD-9534 
               
               
                 1266 
                   
                   
                 UCGUCCTsT 
                   
                   
               
               
                   
               
               
                 1248- 
                 GGAcGAuGccuGccucuAcTsT 
                 547 
                 GuAGAGGcAGGcA 
                 548 
                 AD-9660 
               
               
                 1266 
                   
                   
                 UCGUCCTsT 
                   
                   
               
               
                   
               
               
                 1279- 
                 GCUCCCGAGGUCAUCACAGTT 
                 549 
                 CUGUGAUGACCUC 
                 550 
                 AD-15324 
               
               
                 1297 
                   
                   
                 GGGAGCTT 
                   
                   
               
               
                   
               
               
                 1280- 
                 CUCCCGAGGUCAUCACAGUTT 
                 551 
                 ACUGUGAUGACCU 
                 552 
                 AD-15232 
               
               
                 1298 
                   
                   
                 CGGGAGTT 
                   
                   
               
               
                   
               
               
                 1281- 
                 UCCCGAGGUCAUCACAGUUTT 
                 553 
                 AACUGUGAUGACC 
                 554 
                 AD-15233 
               
               
                 1299 
                   
                   
                 UCGGGATT 
                   
                   
               
               
                   
               
               
                 1314- 
                 CCAAGACCAGCCGGUGACCTT 
                 555 
                 GGUCACCGGCUGG 
                 556 
                 AD-15234 
               
               
                 1332 
                   
                   
                 UCUUGGTT 
                   
                   
               
               
                   
               
               
                 1315- 
                 CAAGACCAGCCGGUGACCCTT 
                 557 
                 GGGUCACCGGCUG 
                 558 
                 AD-15286 
               
               
                 1333 
                   
                   
                 GUCUUGTT 
                   
                   
               
               
                   
               
               
                 1348- 
                 ACCAACUUUGGCCGCUGUGTsT 
                 559 
                 CACAGCGGCCAAA 
                 560 
                 AD-9590 
               
               
                 1366 
                   
                   
                 GUUGGUTsT 
                   
                   
               
               
                   
               
               
                 1348- 
                 AccAAcuuuGGccGcuGuGTsT 
                 561 
                 cAcAGCGGCcAAA 
                 562 
                 AD-9716 
               
               
                 1366 
                   
                   
                 GUUGGUTsT 
                   
                   
               
               
                   
               
               
                 1350- 
                 CAACUUUGGCCGCUGUGUGTsT 
                 563 
                 CACACAGCGGCCA 
                 564 
                 AD-9632 
               
               
                 1368 
                   
                   
                 AAGUUGTsT 
                   
                   
               
               
                   
               
               
                 1350- 
                 cAAcuuuGGccGcuGuGuGTsT 
                 565 
                 cAcAcAGCGGCcA 
                 566 
                 AD-9758 
               
               
                 1368 
                   
                   
                 AAGUUGTsT 
                   
                   
               
               
                   
               
               
                 1360- 
                 CGCUGUGUGGACCUCUUUGTsT 
                 567 
                 CAAAGAGGUCCAC 
                 568 
                 AD-9567 
               
               
                 1378 
                   
                   
                 ACAGCGTsT 
                   
                   
               
               
                   
               
               
                 1360- 
                 cGcuGuGuGGAccucuuuGTsT 
                 569 
                 cAAAGAGGUCcAc 
                 570 
                 AD-9693 
               
               
                 1378 
                   
                   
                 AcAGCGTsT 
                   
                   
               
               
                   
               
               
                 1390- 
                 GACAUCAUUGGUGCCUCCATsT 
                 571 
                 UGGAGGCACCAAU 
                 572 
                 AD-9586 
               
               
                 1408 
                   
                   
                 GAUGUCTsT 
                   
                   
               
               
                   
               
               
                 1390- 
                 GAcAucAuuGGuGccuccATsT 
                 573 
                 UGGAGGcACcAAU 
                 574 
                 AD-9712 
               
               
                 1408 
                   
                   
                 GAUGUCTsT 
                   
                   
               
               
                   
               
               
                 1394- 
                 UCAUUGGUGCCUCCAGCGATsT 
                 575 
                 UCGCUGGAGGCAC 
                 576 
                 AD-9564 
               
               
                 1412 
                   
                   
                 CAAUGATsT 
                   
                   
               
               
                   
               
               
                 1394- 
                 ucAuuGGuGccuccAGcGATsT 
                 577 
                 UCGCUGGAGGcAC 
                 578 
                 AD-9690 
               
               
                 1412 
                   
                   
                 cAAUGATsT 
                   
                   
               
               
                   
               
               
                 1417- 
                 AGCACCUGCUUUGUGUCACTsT 
                 579 
                 GUGACACAAAGCA 
                 580 
                 AD-9616 
               
               
                 1435 
                   
                   
                 GGUGCUTsT 
                   
                   
               
               
                   
               
               
                 1417- 
                 AGcAccuGcuuuGuGucAcTsT 
                 581 
                 GUGAcAcAAAGcA 
                 582 
                 AD-9742 
               
               
                 1435 
                   
                   
                 GGUGCUTsT 
                   
                   
               
               
                   
               
               
                 1433- 
                 CACAGAGUGGGACAUCACATT 
                 583 
                 UGUGAUGUCCCAC 
                 584 
                 AD-15398 
               
               
                 1451 
                   
                   
                 UCUGUGTT 
                   
                   
               
               
                   
               
               
                 1486- 
                 AUGCUGUCUGCCGAGCCGGTsT 
                 585 
                 CCGGCUCGGCAGA 
                 586 
                 AD-9617 
               
               
                 1504 
                   
                   
                 CAGCAUTsT 
                   
                   
               
               
                   
               
               
                 1486- 
                 AuGcuGucuGccGAGccGGTsT 
                 587 
                 CCGGCUCGGcAGA 
                 588 
                 AD-9743 
               
               
                 1504 
                   
                   
                 cAGcAUTsT 
                   
                   
               
               
                   
               
               
                 1491- 
                 GUCUGCCGAGCCGGAGCUCTsT 
                 589 
                 GAGCUCCGGCUCG 
                 590 
                 AD-9635 
               
               
                 1509 
                   
                   
                 GCAGACTsT 
                   
                   
               
               
                   
               
               
                 1491- 
                 GucuGccGAGccGGAGcucTsT 
                 591 
                 GAGCUCCGGCUCG 
                 592 
                 AD-9761 
               
               
                 1509 
                   
                   
                 GcAGACTsT 
                   
                   
               
               
                   
               
               
                 1521- 
                 GUUGAGGCAGAGACUGAUCTsT 
                 593 
                 GAUCAGUCUCUGC 
                 594 
                 AD-9568 
               
               
                 1539 
                   
                   
                 CUCAACTsT 
                   
                   
               
               
                   
               
               
                 1521- 
                 GuuGAGGcAGAGAcuGAucTsT 
                 595 
                 GAUcAGUCUCUGC 
                 596 
                 AD-9694 
               
               
                 1539 
                   
                   
                 CUcAACTsT 
                   
                   
               
               
                   
               
               
                 1527- 
                 GCAGAGACUGAUCCACUUCTsT 
                 597 
                 GAAGUGGAUCAGU 
                 598 
                 AD-9576 
               
               
                 1545 
                   
                   
                 CUCUGCTsT 
                   
                   
               
               
                   
               
               
                 1527- 
                 GcAGAGAcuGAuccAcuucTsT 
                 599 
                 GAAGUGGAUcAGU 
                 600 
                 AD-9702 
               
               
                 1545 
                   
                   
                 CUCUGCTsT 
                   
                   
               
               
                   
               
               
                 1529- 
                 AGAGACUGAUCCACUUCUCTsT 
                 601 
                 GAGAAGUGGAUCA 
                 602 
                 AD-9627 
               
               
                 1547 
                   
                   
                 GUCUCUTsT 
                   
                   
               
               
                   
               
               
                 1529- 
                 AGAGAcuGAuccAcuucucTsT 
                 603 
                 GAGAAGUGGAUcA 
                 604 
                 AD-9753 
               
               
                 1547 
                   
                   
                 GUCUCUTsT 
                   
                   
               
               
                   
               
               
                 1543- 
                 UUCUCUGCCAAAGAUGUCATsT 
                 605 
                 UGACAUCUUUGGC 
                 606 
                 AD-9628 
               
               
                 1561 
                   
                   
                 AGAGAATsT 
                   
                   
               
               
                   
               
               
                 1543- 
                 uucucuGccAAAGAuGucATsT 
                 607 
                 UGAcAUCUUUGGc 
                 608 
                 AD-9754 
               
               
                 1561 
                   
                   
                 AGAGAATsT 
                   
                   
               
               
                   
               
               
                 1545- 
                 CUCUGCCAAAGAUGUCAUCTsT 
                 609 
                 GAUGACAUCUUUG 
                 610 
                 AD-9631 
               
               
                 1563 
                   
                   
                 GCAGAGTsT 
                   
                   
               
               
                   
               
               
                 1545- 
                 cucuGccAAAGAuGucAucTsT 
                 611 
                 GAUGAcAUCUUUG 
                 612 
                 AD-9757 
               
               
                 1563 
                   
                   
                 GcAGAGTsT 
                   
                   
               
               
                   
               
               
                 1580- 
                 CUGAGGACCAGCGGGUACUTsT 
                 613 
                 AGUACCCGCUGGU 
                 614 
                 AD-9595 
               
               
                 1598 
                   
                   
                 CCUCAGTsT 
                   
                   
               
               
                   
               
               
                 1580- 
                 cuGAGGAccAGcGGGuAcuTsT 
                 615 
                 AGuACCCGCUGGU 
                 616 
                 AD-9721 
               
               
                 1598 
                   
                   
                 CCUcAGTsT 
                   
                   
               
               
                   
               
               
                 1581- 
                 UGAGGACCAGCGGGUACUGTsT 
                 617 
                 CAGUACCCGCUGG 
                 618 
                 AD-9544 
               
               
                 1599 
                   
                   
                 UCCUCATsT 
                   
                   
               
               
                   
               
               
                 1581- 
                 uGAGGAccAGcGGGuAcuGTsT 
                 619 
                 cAGuACCCGCUGG 
                 620 
                 AD-9670 
               
               
                 1599 
                   
                   
                 UCCUcATsT 
                   
                   
               
               
                   
               
               
                 1666- 
                 ACUGUAUGGUCAGCACACUTT 
                 621 
                 AGUGUGCUGACCA 
                 622 
                 AD-15235 
               
               
                 1684 
                   
                   
                 UACAGUTT 
                   
                   
               
               
                   
               
               
                 1668- 
                 UGUAUGGUCAGCACACUCGTT 
                 623 
                 CGAGUGUGCUGAC 
                 624 
                 AD-15236 
               
               
                 1686 
                   
                   
                 CAUACATT 
                   
                   
               
               
                   
               
               
                 1669- 
                 GUAUGGUCAGCACACUCGGTT 
                 625 
                 CCGAGUGUGCUGA 
                 626 
                 AD-15168 
               
               
                 1687 
                   
                   
                 CCAUACTT 
                   
                   
               
               
                   
               
               
                 1697- 
                 GGAUGGCCACAGCCGUCGCTT 
                 627 
                 GCGACGGCUGUGG 
                 628 
                 AD-15174 
               
               
                 1715 
                   
                   
                 CCAUCCTT 
                   
                   
               
               
                   
               
               
                 1698- 
                 GAUGGCCACAGCCGUCGCCTT 
                 629 
                 GGCGACGGCUGUG 
                 630 
                 AD-15325 
               
               
                 1716 
                   
                   
                 GCCAUCTT 
                   
                   
               
               
                   
               
               
                 1806- 
                 CAAGCUGGUCUGCCGGGCCTT 
                 631 
                 GGCCCGGCAGACC 
                 632 
                 AD-15326 
               
               
                 1824 
                   
                   
                 AGCUUGTT 
                   
                   
               
               
                   
               
               
                 1815- 
                 CUGCCGGGCCCACAACGCUTsT 
                 633 
                 AGCGUUGUGGGCC 
                 634 
                 AD-9570 
               
               
                 1833 
                   
                   
                 CGGCAGTsT 
                   
                   
               
               
                   
               
               
                 1815- 
                 cuGccGGGcccAcAAcGcuTsT 
                 635 
                 AGCGUUGUGGGCC 
                 636 
                 AD-9696 
               
               
                 1833 
                   
                   
                 CGGcAGTsT 
                   
                   
               
               
                   
               
               
                 1816- 
                 UGCCGGGCCCACAACGCUUTsT 
                 637 
                 AAGCGUUGUGGGC 
                 638 
                 AD-9566 
               
               
                 1834 
                   
                   
                 CCGGCATsT 
                   
                   
               
               
                   
               
               
                 1816- 
                 uGccGGGcccAcAAcGcuuTsT 
                 639 
                 AAGCGUUGUGGGC 
                 640 
                 AD-9692 
               
               
                 1834 
                   
                   
                 CCGGcATsT 
                   
                   
               
               
                   
               
               
                 1818- 
                 CCGGGCCCACAACGCUUUUTsT 
                 641 
                 AAAAGCGUUGUGG 
                 642 
                 AD-9532 
               
               
                 1836 
                   
                   
                 GCCCGGTsT 
                   
                   
               
               
                   
               
               
                 1818- 
                 ccGGGcccAcAAcGcuuuuTsT 
                 643 
                 AAAAGCGUUGUGG 
                 644 
                 AD-9658 
               
               
                 1836 
                   
                   
                 GCCCGGTsT 
                   
                   
               
               
                   
               
               
                 1820- 
                 GGGCCCACAACGCUUUUGGTsT 
                 645 
                 CCAAAAGCGUUGU 
                 646 
                 AD-9549 
               
               
                 1838 
                   
                   
                 GGGCCCTsT 
                   
                   
               
               
                   
               
               
                 1820- 
                 GGGcccAcAAcGcuuuuGGTsT 
                 647 
                 CcAAAAGCGUUGU 
                 648 
                 AD-9675 
               
               
                 1838 
                   
                   
                 GGGCCCTsT 
                   
                   
               
               
                   
               
               
                 1840- 
                 GGUGAGGGUGUCUACGCCATsT 
                 649 
                 UGGCGUAGACACC 
                 650 
                 AD-9541 
               
               
                 1858 
                   
                   
                 CUCACCTsT 
                   
                   
               
               
                   
               
               
                 1840- 
                 GGuGAGGGuGucuAcGccATsT 
                 651 
                 UGGCGuAGAcACC 
                 652 
                 AD-9667 
               
               
                 1858 
                   
                   
                 CUcACCTsT 
                   
                   
               
               
                   
               
               
                 1843- 
                 GAGGGUGUCUACGCCAUUGTsT 
                 653 
                 CAAUGGCGUAGAC 
                 654 
                 AD-9550 
               
               
                 1861 
                   
                   
                 ACCCUCTsT 
                   
                   
               
               
                   
               
               
                 1843- 
                 GAGGGuGucuAcGccAuuGTsT 
                 655 
                 cAAUGGCGuAGAc 
                 656 
                 AD-9676 
               
               
                 1861 
                   
                   
                 ACCCUCTsT 
                   
                   
               
               
                   
               
               
                 1861- 
                 GCCAGGUGCUGCCUGCUACTsT 
                 657 
                 GUAGCAGGCAGCA 
                 658 
                 AD-9571 
               
               
                 1879 
                   
                   
                 CCUGGCTsT 
                   
                   
               
               
                   
               
               
                 1861- 
                 GccAGGuGcuGccuGcuAcTsT 
                 659 
                 GuAGcAGGcAGcA 
                 660 
                 AD-9697 
               
               
                 1879 
                   
                   
                 CCUGGCTsT 
                   
                   
               
               
                   
               
               
                 1862- 
                 CCAGGUGCUGCCUGCUACCTsT 
                 661 
                 GGUAGCAGGCAGC 
                 662 
                 AD-9572 
               
               
                 1880 
                   
                   
                 ACCUGGTsT 
                   
                   
               
               
                   
               
               
                 1862- 
                 ccAGGuGcuGccuGcuAccTsT 
                 663 
                 GGuAGcAGGcAGc 
                 664 
                 AD-9698 
               
               
                 1880 
                   
                   
                 ACCUGGTsT 
                   
                   
               
               
                   
               
               
                 2008- 
                 ACCCACAAGCCGCCUGUGCTT 
                 665 
                 GCACAGGCGGCUU 
                 666 
                 AD-15327 
               
               
                 2026 
                   
                   
                 GUGGGUTT 
                   
                   
               
               
                   
               
               
                 2023- 
                 GUGCUGAGGCCACGAGGUCTsT 
                 667 
                 GACCUCGUGGCCU 
                 668 
                 AD-9639 
               
               
                 2041 
                   
                   
                 CAGCACTsT 
                   
                   
               
               
                   
               
               
                 2023- 
                 GuGcuGAGGccAcGAGGucTsT 
                 669 
                 GACCUCGUGGCCU 
                 670 
                 AD-9765 
               
               
                 2041 
                   
                   
                 cAGcACTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UGCUGAGGCCACGAGGUCATsT 
                 671 
                 UGACCUCGUGGCC 
                 672 
                 AD-9518 
               
               
                   
               
               
                 2042 
                   
                   
                 UCAGCATsT 
                   
                   
               
               
                 2024- 
                 UGCUGAGGCCACGAGGUCATsT 
                 673 
                 UGACCUCGUGGCC 
                 674 
                 AD-9518 
               
               
                 2042 
                   
                   
                 UCAGCATsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 uGcuGAGGccAcGAGGucATsT 
                 675 
                 UGACCUCGUGGCC 
                 676 
                 AD-9644 
               
               
                 2042 
                   
                   
                 UcAGcATsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UfgCfuGfaGfgCfcAfcGfaG 
                 677 
                 P*uGfaCfcUfcG 
                 678 
                 AD-14672 
               
               
                 2042 
                 fgUfcAfTsT 
                   
                 fuGfgCfcUfcAf 
                   
                   
               
               
                   
                   
                   
                 gCfaTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UfGCfUfGAGGCfCfACfGAGG 
                 679 
                 UfGACfCfUfCfG 
                 680 
                 AD-14682 
               
               
                 2042 
                 UfCfATsT 
                   
                 UfGGCfCfUfCfA 
                   
                   
               
               
                   
                   
                   
                 GCfATsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UgCuGaGgCcAcGaGgUcATsT 
                 681 
                 P*uGfaCfcUfcG 
                 682 
                 AD-14692 
               
               
                 2042 
                   
                   
                 fuGfgCfcUfcAf 
                   
                   
               
               
                   
                   
                   
                 gCfaTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UgCuGaGgCcAcGaGgUcATsT 
                 683 
                 UfGACfCfUfCfG 
                 684 
                 AD-14702 
               
               
                 2042 
                   
                   
                 UfGGCfCfUfCfA 
                   
                   
               
               
                   
                   
                   
                 GCfATsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UfgCfuGfaGfgCfcAfcGfaG 
                 685 
                 UGACCucGUggCC 
                 686 
                 AD-14712 
               
               
                 2042 
                 fgUfcAfTsT 
                   
                 UCAgcaTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UfGCfUfGAGGCfCfACfGAGG 
                 687 
                 UGACCucGUggCC 
                 688 
                 AD-14722 
               
               
                 2042 
                 UfCfATsT 
                   
                 UCAgcaTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 UgCuGaGgCcAcGaGgUcATsT 
                 689 
                 UGACCucGUggCC 
                 690 
                 AD-14732 
               
               
                 2042 
                   
                   
                 UCAgcaTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GfuGfgUfcAfgCfgGfcCfgG 
                 691 
                 P*cAfuCfcCfgG 
                 692 
                 AD-15078 
               
               
                 2042 
                 fgAfuGfTsT 
                   
                 fcCfgCfuGfaCf 
                   
                   
               
               
                   
                   
                   
                 cAfcTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GUfGGUfCfAGCfGGCfCfGGG 
                 693 
                 CfAUfCfCfCfGG 
                 694 
                 AD-15088 
               
               
                 2042 
                 AUfGTsT 
                   
                 CfCfGCfUfGACf 
                   
                   
               
               
                   
                   
                   
                 CfACfTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GuGgUcAgCgGcCgGgAuGTsT 
                 695 
                 P*cAfuCfcCfgG 
                 696 
                 AD-15098 
               
               
                 2042 
                   
                   
                 fcCfgCfuGfaCf 
                   
                   
               
               
                   
                   
                   
                 cAfcTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GuGgUcAgCgGcCgGgAuGTsT 
                 697 
                 CfAUfCfCfCfGG 
                 698 
                 AD-15108 
               
               
                 2042 
                   
                   
                 CfCfGCfUfGACf 
                   
                   
               
               
                   
                   
                   
                 CfACfTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GfuGfgUfcAfgCfgGfcCfgG 
                 699 
                 CAUCCcgGCcgCU 
                 700 
                 AD-15118 
               
               
                 2042 
                 fgAfuGfTsT 
                   
                 GACcacTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GUfGGUfCfAGCfGGCfCfGGG 
                 701 
                 CAUCCcgGCcgCU 
                 702 
                 AD-15128 
               
               
                 2042 
                 AUfGTsT 
                   
                 GACcacTsT 
                   
                   
               
               
                   
               
               
                 2024- 
                 GuGgUcAgCgGcCgGgAuGTsT 
                 703 
                 CAUCCcgGCcgCU 
                 704 
                 AD-15138 
               
               
                 2042 
                   
                   
                 GACcacTsT 
                   
                   
               
               
                   
               
               
                 2030- 
                 GGCCACGAGGUCAGCCCAATT 
                 705 
                 UUGGGCUGACCUC 
                 706 
                 AD-15237 
               
               
                 2048 
                   
                   
                 GUGGCCTT 
                   
                   
               
               
                   
               
               
                 2035- 
                 CGAGGUCAGCCCAACCAGUTT 
                 707 
                 ACUGGUUGGGCUG 
                 708 
                 AD-15287 
               
               
                 2053 
                   
                   
                 ACCUCGTT 
                   
                   
               
               
                   
               
               
                 2039- 
                 GUCAGCCCAACCAGUGCGUTT 
                 709 
                 ACGCACUGGUUGG 
                 710 
                 AD-15238 
               
               
                 2057 
                   
                   
                 GCUGACTT 
                   
                   
               
               
                   
               
               
                 2041- 
                 CAGCCCAACCAGUGCGUGGTT 
                 711 
                 CCACGCACUGGUU 
                 712 
                 AD-15328 
               
               
                 2059 
                   
                   
                 GGGCUGTT 
                   
                   
               
               
                   
               
               
                 2062- 
                 CACAGGGAGGCCAGCAUCCTT 
                 713 
                 GGAUGCUGGCCUC 
                 714 
                 AD-15399 
               
               
                 2080 
                   
                   
                 CCUGUGTT 
                   
                   
               
               
                   
               
               
                 2072- 
                 CCAGCAUCCACGCUUCCUGTsT 
                 715 
                 CAGGAAGCGUGGA 
                 716 
                 AD-9582 
               
               
                 2090 
                   
                   
                 UGCUGGTsT 
                   
                   
               
               
                   
               
               
                 2072- 
                 ccAGcAuccAcGcuuccuGTsT 
                 717 
                 cAGGAAGCGUGGA 
                 718 
                 AD-9708 
               
               
                 2090 
                   
                   
                 UGCUGGTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AGUCAAGGAGCAUGGAAUCTsT 
                 719 
                 GAUUCCAUGCUCC 
                 720 
                 AD-9545 
               
               
                 2136 
                   
                   
                 UUGACUTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AGucAAGGAGcAuGGAAucTsT 
                 721 
                 GAUUCcAUGCUCC 
                 722 
                 AD-9671 
               
               
                 2136 
                   
                   
                 UUGACUTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AfgUfcAfaGfgAfgCfaUfgG 
                 723 
                 P*gAfuUfcCfaU 
                 724 
                 AD-14674 
               
               
                 2136 
                 faAfuCfTsT 
                   
                 fgCfuCfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 aCfuTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AGUfCfAAGGAGCfAUfGGAAU 
                 725 
                 GAUfUfCfCfAUf 
                 726 
                 AD-14684 
               
               
                 2136 
                 fCfTsT 
                   
                 GCfUfCfCfUfUf 
                   
                   
               
               
                   
                   
                   
                 GACfUfTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AgUcAaGgAgCaUgGaAuCTsT 
                 727 
                 P*gAfuUfcCfaU 
                 728 
                 AD-14694 
               
               
                 2136 
                   
                   
                 fgCfuCfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 aCfuTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AgUcAaGgAgCaUgGaAuCTsT 
                 729 
                 GAUfUfCfCfAUf 
                 730 
                 AD-14704 
               
               
                 2136 
                   
                   
                 GCfUfCfCfUfUf 
                   
                   
               
               
                   
                   
                   
                 GACfUfTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AfgUfcAfaGfgAfgCfaUfgG 
                 731 
                 GAUUCcaUGcuCC 
                 732 
                 AD-14714 
               
               
                 2136 
                 faAfuCfTsT 
                   
                 UUGacuTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AGUfCfAAGGAGCfAUfGGAAU 
                 733 
                 GAUUCcaUGcuCC 
                 734 
                 AD-14724 
               
               
                 2136 
                 fCfTsT 
                   
                 UUGacuTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 AgUcAaGgAgCaUgGaAuCTsT 
                 735 
                 GAUUCcaUGcuCC 
                 736 
                 AD-14734 
               
               
                 2136 
                   
                   
                 UUGacuTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GfcGfgCfaCfcCfuCfaUfaG 
                 737 
                 P*aGfgCfcUfaU 
                 738 
                 AD-15080 
               
               
                 2136 
                 fgCfcUfTsT 
                   
                 fgAfgGfgUfgCf 
                   
                   
               
               
                   
                   
                   
                 cGfcTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GCfGGCfACfCfCfUfCfAUfA 
                 739 
                 AGGCfCfUfAUfG 
                 740 
                 AD-15090 
               
               
                 2136 
                 GGCfCfUfTsT 
                   
                 AGGGUfGCfCfGC 
                   
                   
               
               
                   
                   
                   
                 fTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GcGgCaCcCuCaUaGgCcUTsT 
                 741 
                 P*aGfgCfcUfaU 
                 742 
                 AD-15100 
               
               
                 2136 
                   
                   
                 fgAfgGfgUfgCf 
                   
                   
               
               
                   
                   
                   
                 cGfcTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GcGgCaCcCuCaUaGgCcUTsT 
                 743 
                 AGGCfCfUfAUfG 
                 744 
                 AD-15110 
               
               
                 2136 
                   
                   
                 AGGGUfGCfCfGC 
                   
                   
               
               
                   
                   
                   
                 fTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GfcGfgCfaCfcCfuCfaUfaG 
                 745 
                 AGGCCuaUGagGG 
                 746 
                 AD-15120 
               
               
                 2136 
                 fgCfcUfTsT 
                   
                 UGCcgcTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GCfGGCfACfCfCfUfCfAUfA 
                 747 
                 AGGCCuaUGagGG 
                 748 
                 AD-15130 
               
               
                 2136 
                 GGCfCfUfTsT 
                   
                 UGCcgcTsT 
                   
                   
               
               
                   
               
               
                 2118- 
                 GcGgCaCcCuCaUaGgCcUTsT 
                 749 
                 AGGCCuaUGagGG 
                 750 
                 AD-15140 
               
               
                 2136 
                   
                   
                 UGCcgcTsT 
                   
                   
               
               
                   
               
               
                 2122- 
                 AAGGAGCAUGGAAUCCCGGTsT 
                 751 
                 CCGGGAUUCCAUG 
                 752 
                 AD-9522 
               
               
                 2140 
                   
                   
                 CUCCUUTsT 
                   
                   
               
               
                   
               
               
                 2122- 
                 AAGGAGcAuGGAAucccGGTsT 
                 753 
                 CCGGGAUUCcAUG 
                 754 
                 AD-9648 
               
               
                 2140 
                   
                   
                 CUCCUUTsT 
                   
                   
               
               
                   
               
               
                 2123- 
                 AGGAGCAUGGAAUCCCGGCTsT 
                 755 
                 GCCGGGAUUCCAU 
                 756 
                 AD-9552 
               
               
                 2141 
                   
                   
                 GCUCCUTsT 
                   
                   
               
               
                   
               
               
                 2123- 
                 AGGAGcAuGGAAucccGGcTsT 
                 757 
                 GCCGGGAUUCcAU 
                 758 
                 AD-9678 
               
               
                 2141 
                   
                   
                 GCUCCUTsT 
                   
                   
               
               
                   
               
               
                 2125- 
                 GAGCAUGGAAUCCCGGCCCTsT 
                 759 
                 GGGCCGGGAUUCC 
                 760 
                 AD-9618 
               
               
                 2143 
                   
                   
                 AUGCUCTsT 
                   
                   
               
               
                   
               
               
                 2125- 
                 GAGcAuGGAAucccGGcccTsT 
                 761 
                 GGGCCGGGAUUCc 
                 762 
                 AD-9744 
               
               
                 2143 
                   
                   
                 AUGCUCTsT 
                   
                   
               
               
                   
               
               
                 2230- 
                 GCCUACGCCGUAGACAACATT 
                 763 
                 UGUUGUCUACGGC 
                 764 
                 AD-15239 
               
               
                 2248 
                   
                   
                 GUAGGCTT 
                   
                   
               
               
                   
               
               
                 2231- 
                 CCUACGCCGUAGACAACACTT 
                 765 
                 GUGUUGUCUACGG 
                 766 
                 AD-15212 
               
               
                 2249 
                   
                   
                 CGUAGGTT 
                   
                   
               
               
                   
               
               
                 2232- 
                 CUACGCCGUAGACAACACGTT 
                 767 
                 CGUGUUGUCUACG 
                 768 
                 AD-15240 
               
               
                 2250 
                   
                   
                 GCGUAGTT 
                   
                   
               
               
                   
               
               
                 2233- 
                 UACGCCGUAGACAACACGUTT 
                 769 
                 ACGUGUUGUCUAC 
                 770 
                 AD-15177 
               
               
                 2251 
                   
                   
                 GGCGUATT 
                   
                   
               
               
                   
               
               
                 2235- 
                 CGCCGUAGACAACACGUGUTT 
                 771 
                 ACACGUGUUGUCU 
                 772 
                 AD-15179 
               
               
                 2253 
                   
                   
                 ACGGCGTT 
                   
                   
               
               
                   
               
               
                 2236- 
                 GCCGUAGACAACACGUGUGTT 
                 773 
                 CACACGUGUUGUC 
                 774 
                 AD-15180 
               
               
                 2254 
                   
                   
                 UACGGCTT 
                   
                   
               
               
                   
               
               
                 2237- 
                 CCGUAGACAACACGUGUGUTT 
                 775 
                 ACACACGUGUUGU 
                 776 
                 AD-15241 
               
               
                 2255 
                   
                   
                 CUACGGTT 
                   
                   
               
               
                   
               
               
                 2238- 
                 CGUAGACAACACGUGUGUATT 
                 777 
                 UACACACGUGUUG 
                 778 
                 AD-15268 
               
               
                 2256 
                   
                   
                 UCUACGTT 
                   
                   
               
               
                   
               
               
                 2240- 
                 UAGACAACACGUGUGUAGUTT 
                 779 
                 ACUACACACGUGU 
                 780 
                 AD-15242 
               
               
                 2258 
                   
                   
                 UGUCUATT 
                   
                   
               
               
                   
               
               
                 2241- 
                 AGACAACACGUGUGUAGUCTT 
                 781 
                 GACUACACACGUG 
                 782 
                 AD-15216 
               
               
                 2259 
                   
                   
                 UUGUCUTT 
                   
                   
               
               
                   
               
               
                 2242- 
                 GACAACACGUGUGUAGUCATT 
                 783 
                 UGACUACACACGU 
                 784 
                 AD-15176 
               
               
                 2260 
                   
                   
                 GUUGUCTT 
                   
                   
               
               
                   
               
               
                 2243- 
                 ACAACACGUGUGUAGUCAGTT 
                 785 
                 CUGACUACACACG 
                 786 
                 AD-15181 
               
               
                 2261 
                   
                   
                 UGUUGUTT 
                   
                   
               
               
                   
               
               
                 2244- 
                 CAACACGUGUGUAGUCAGGTT 
                 787 
                 CCUGACUACACAC 
                 788 
                 AD-15243 
               
               
                 2262 
                   
                   
                 GUGUUGTT 
                   
                   
               
               
                   
               
               
                 2247- 
                 CACGUGUGUAGUCAGGAGCTT 
                 789 
                 GCUCCUGACUACA 
                 790 
                 AD-15182 
               
               
                 2265 
                   
                   
                 CACGUGTT 
                   
                   
               
               
                   
               
               
                 2248- 
                 ACGUGUGUAGUCAGGAGCCTT 
                 791 
                 GGCUCCUGACUAC 
                 792 
                 AD-15244 
               
               
                 2266 
                   
                   
                 ACACGUTT 
                   
                   
               
               
                   
               
               
                 2249- 
                 CGUGUGUAGUCAGGAGCCGTT 
                 793 
                 CGGCUCCUGACUA 
                 794 
                 AD-15387 
               
               
                 2267 
                   
                   
                 CACACGTT 
                   
                   
               
               
                   
               
               
                 2251- 
                 UGUGUAGUCAGGAGCCGGGTT 
                 795 
                 CCCGGCUCCUGAC 
                 796 
                 AD-15245 
               
               
                 2269 
                   
                   
                 UACACATT 
                   
                   
               
               
                   
               
               
                 2257- 
                 GUCAGGAGCCGGGACGUCATsT 
                 797 
                 UGACGUCCCGGCU 
                 798 
                 AD-9555 
               
               
                 2275 
                   
                   
                 CCUGACTsT 
                   
                   
               
               
                   
               
               
                 2257- 
                 GucAGGAGccGGGAcGucATsT 
                 799 
                 UGACGUCCCGGCU 
                 800 
                 AD-9681 
               
               
                 2275 
                   
                   
                 CCUGACTsT 
                   
                   
               
               
                   
               
               
                 2258- 
                 UCAGGAGCCGGGACGUCAGTsT 
                 801 
                 CUGACGUCCCGGC 
                 802 
                 AD-9619 
               
               
                 2276 
                   
                   
                 UCCUGATsT 
                   
                   
               
               
                   
               
               
                 2258- 
                 ucAGGAGccGGGAcGucAGTsT 
                 803 
                 CUGACGUCCCGGC 
                 804 
                 AD-9745 
               
               
                 2276 
                   
                   
                 UCCUGATsT 
                   
                   
               
               
                   
               
               
                 2259- 
                 CAGGAGCCGGGACGUCAGCTsT 
                 805 
                 GCUGACGUCCCGG 
                 806 
                 AD-9620 
               
               
                 2277 
                   
                   
                 CUCCUGTsT 
                   
                   
               
               
                   
               
               
                 2259- 
                 cAGGAGccGGGAcGucAGcTsT 
                 807 
                 GCUGACGUCCCGG 
                 808 
                 AD-9746 
               
               
                 2277 
                   
                   
                 CUCCUGTsT 
                   
                   
               
               
                   
               
               
                 2263- 
                 AGCCGGGACGUCAGCACUATT 
                 809 
                 UAGUGCUGACGUC 
                 810 
                 AD-15288 
               
               
                 2281 
                   
                   
                 CCGGCUTT 
                   
                   
               
               
                   
               
               
                 2265- 
                 CCGGGACGUCAGCACUACATT 
                 811 
                 UGUAGUGCUGACG 
                 812 
                 AD-15246 
               
               
                 2283 
                   
                   
                 UCCCGGTT 
                   
                   
               
               
                   
               
               
                 2303- 
                 CCGUGACAGCCGUUGCCAUTT 
                 813 
                 AUGGCAACGGCUG 
                 814 
                 AD-15289 
               
               
                 2321 
                   
                   
                 UCACGGTT 
                   
                   
               
               
                   
               
               
                 2317- 
                 GCCAUCUGCUGCCGGAGCCTsT 
                 815 
                 GGCUCCGGCAGCA 
                 816 
                 AD-9324 
               
               
                 2335 
                   
                   
                 GAUGGCTsT 
                   
                   
               
               
                   
               
               
                 2375- 
                 CCCAUCCCAGGAUGGGUGUTT 
                 817 
                 ACACCCAUCCUGG 
                 818 
                 AD-15329 
               
               
                 2393 
                   
                   
                 GAUGGGTT 
                   
                   
               
               
                   
               
               
                 2377- 
                 CAUCCCAGGAUGGGUGUCUTT 
                 819 
                 AGACACCCAUCCU 
                 820 
                 AD-15330 
               
               
                 2395 
                   
                   
                 GGGAUGTT 
                   
                   
               
               
                   
               
               
                 2420- 
                 AGCUUMAAAUGGUUCCGATT 
                 821 
                 UCGGAACCAUUUU 
                 822 
                 AD-15169 
               
               
                 2438 
                   
                   
                 AAAGCUTT 
                   
                   
               
               
                   
               
               
                 2421- 
                 GCUUUAAAAUGGUUCCGACTT 
                 823 
                 GUCGGAACCAUUU 
                 824 
                 AD-15201 
               
               
                 2439 
                   
                   
                 UAAAGCTT 
                   
                   
               
               
                   
               
               
                 2422- 
                 CUUMAAAUGGUUCCGACUTT 
                 825 
                 AGUCGGAACCAUU 
                 826 
                 AD-15331 
               
               
                 2440 
                   
                   
                 UUAAAGTT 
                   
                   
               
               
                   
               
               
                 2423- 
                 UUUAAAAUGGUUCCGACUUTT 
                 827 
                 AAGUCGGAACCAU 
                 828 
                 AD-15190 
               
               
                 2441 
                   
                   
                 UUUAAATT 
                   
                   
               
               
                   
               
               
                 2424- 
                 UUAAAAUGGUUCCGACUUGTT 
                 829 
                 CAAGUCGGAACCA 
                 830 
                 AD-15247 
               
               
                 2442 
                   
                   
                 UUUUAATT 
                   
                   
               
               
                   
               
               
                 2425- 
                 UAAAAUGGUUCCGACUUGUTT 
                 831 
                 ACAAGUCGGAACC 
                 832 
                 AD-15248 
               
               
                 2443 
                   
                   
                 AUUUUATT 
                   
                   
               
               
                   
               
               
                 2426- 
                 AAAAUGGUUCCGACUUGUCTT 
                 833 
                 GACAAGUCGGAAC 
                 834 
                 AD-15175 
               
               
                 2444 
                   
                   
                 CAUUUUTT 
                   
                   
               
               
                   
               
               
                 2427- 
                 AAAUGGUUCCGACUUGUCCTT 
                 835 
                 GGACAAGUCGGAA 
                 836 
                 AD-15249 
               
               
                 2445 
                   
                   
                 CCAUUUTT 
                   
                   
               
               
                   
               
               
                 2428- 
                 AAUGGUUCCGACUUGUCCCTT 
                 837 
                 GGGACAAGUCGGA 
                 838 
                 AD-15250 
               
               
                 2446 
                   
                   
                 ACCAUUTT 
                   
                   
               
               
                   
               
               
                 2431- 
                 GGUUCCGACUUGUCCCUCUTT 
                 839 
                 AGAGGGACAAGUC 
                 840 
                 AD-15400 
               
               
                 2449 
                   
                   
                 GGAACCTT 
                   
                   
               
               
                   
               
               
                 2457- 
                 CUCCAUGGCCUGGCACGAGTT 
                 841 
                 CUCGUGCCAGGCC 
                 842 
                 AD-15332 
               
               
                 2475 
                   
                   
                 AUGGAGTT 
                   
                   
               
               
                   
               
               
                 2459- 
                 CCAUGGCCUGGCACGAGGGTT 
                 843 
                 CCCUCGUGCCAGG 
                 844 
                 AD-15388 
               
               
                 2477 
                   
                   
                 CCAUGGTT 
                   
                   
               
               
                   
               
               
                 2545- 
                 GAACUCACUCACUCUGGGUTT 
                 845 
                 ACCCAGAGUGAGU 
                 846 
                 AD-15333 
               
               
                 2563 
                   
                   
                 GAGUUCTT 
                   
                   
               
               
                   
               
               
                 2549- 
                 UCACUCACUCUGGGUGCCUTT 
                 847 
                 AGGCACCCAGAGU 
                 848 
                 AD-15334 
               
               
                 2567 
                   
                   
                 GAGUGATT 
                   
                   
               
               
                   
               
               
                 2616- 
                 UUUCACCAUUCAAACAGGUTT 
                 849 
                 ACCUGUUUGAAUG 
                 850 
                 AD-15335 
               
               
                 2634 
                   
                   
                 GUGAAATT 
                   
                   
               
               
                   
               
               
                 2622- 
                 CAUUCAAACAGGUCGAGCUTT 
                 851 
                 AGCUCGACCUGUU 
                 852 
                 AD-15183 
               
               
                 2640 
                   
                   
                 UGAAUGTT 
                   
                   
               
               
                   
               
               
                 2623- 
                 AUUCAAACAGGUCGAGCUGTT 
                 853 
                 CAGCUCGACCUGU 
                 854 
                 AD-15202 
               
               
                 2641 
                   
                   
                 UUGAAUTT 
                   
                   
               
               
                   
               
               
                 2624- 
                 UUCAAACAGGUCGAGCUGUTT 
                 855 
                 ACAGCUCGACCUG 
                 856 
                 AD-15203 
               
               
                 2642 
                   
                   
                 UUUGAATT 
                   
                   
               
               
                   
               
               
                 2625- 
                 UCAAACAGGUCGAGCUGUGTT 
                 857 
                 CACAGCUCGACCU 
                 858 
                 AD-15272 
               
               
                 2643 
                   
                   
                 GUUUGATT 
                   
                   
               
               
                   
               
               
                 2626- 
                 CAAACAGGUCGAGCUGUGCTT 
                 859 
                 GCACAGCUCGACC 
                 860 
                 AD-15217 
               
               
                 2644 
                   
                   
                 UGUUUGTT 
                   
                   
               
               
                   
               
               
                 2627- 
                 AAACAGGUCGAGCUGUGCUTT 
                 861 
                 AGCACAGCUCGAC 
                 862 
                 AD-15290 
               
               
                 2645 
                   
                   
                 CUGUUUTT 
                   
                   
               
               
                   
               
               
                 2628- 
                 AACAGGUCGAGCUGUGCUCTT 
                 863 
                 GAGCACAGCUCGA 
                 864 
                 AD-15218 
               
               
                 2646 
                   
                   
                 CCUGUUTT 
                   
                   
               
               
                   
               
               
                 2630- 
                 CAGGUCGAGCUGUGCUCGGTT 
                 865 
                 CCGAGCACAGCUC 
                 866 
                 AD-15389 
               
               
                 2648 
                   
                   
                 GACCUGTT 
                   
                   
               
               
                   
               
               
                 2631- 
                 AGGUCGAGCUGUGCUCGGGTT 
                 867 
                 CCCGAGCACAGCU 
                 868 
                 AD-15336 
               
               
                 2649 
                   
                   
                 CGACCUTT 
                   
                   
               
               
                   
               
               
                 2633- 
                 GUCGAGCUGUGCUCGGGUGTT 
                 869 
                 CACCCGAGCACAG 
                 870 
                 AD-15337 
               
               
                 2651 
                   
                   
                 CUCGACTT 
                   
                   
               
               
                   
               
               
                 2634- 
                 UCGAGCUGUGCUCGGGUGCTT 
                 871 
                 GCACCCGAGCACA 
                 872 
                 AD-15191 
               
               
                 2652 
                   
                   
                 GCUCGATT 
                   
                   
               
               
                   
               
               
                 2657- 
                 AGCUGCUCCCAAUGUGCCGTT 
                 873 
                 CGGCACAUUGGGA 
                 874 
                 AD-15390 
               
               
                 2675 
                   
                   
                 GCAGCUTT 
                   
                   
               
               
                   
               
               
                 2658- 
                 GCUGCUCCCAAUGUGCCGATT 
                 875 
                 UCGGCACAUUGGG 
                 876 
                 AD-15338 
               
               
                 2676 
                   
                   
                 AGCAGCTT 
                   
                   
               
               
                   
               
               
                 2660- 
                 UGCUCCCAAUGUGCCGAUGTT 
                 877 
                 CAUCGGCACAUUG 
                 878 
                 AD-15204 
               
               
                 2678 
                   
                   
                 GGAGCATT 
                   
                   
               
               
                   
               
               
                 2663- 
                 UCCCAAUGUGCCGAUGUCCTT 
                 879 
                 GGACAUCGGCACA 
                 880 
                 AD-15251 
               
               
                 2681 
                   
                   
                 UUGGGATT 
                   
                   
               
               
                   
               
               
                 2665- 
                 CCAAUGUGCCGAUGUCCGUTT 
                 881 
                 ACGGACAUCGGCA 
                 882 
                 AD-15205 
               
               
                 2683 
                   
                   
                 CAUUGGTT 
                   
                   
               
               
                   
               
               
                 2666- 
                 CAAUGUGCCGAUGUCCGUGTT 
                 883 
                 CACGGACAUCGGC 
                 884 
                 AD-15171 
               
               
                 2684 
                   
                   
                 ACAUUGTT 
                   
                   
               
               
                   
               
               
                 2667- 
                 AAUGUGCCGAUGUCCGUGGTT 
                 885 
                 CCACGGACAUCGG 
                 886 
                 AD-15252 
               
               
                 2685 
                   
                   
                 CACAUUTT 
                   
                   
               
               
                   
               
               
                 2673- 
                 CCGAUGUCCGUGGGCAGAATT 
                 887 
                 UUCUGCCCACGGA 
                 888 
                 AD-15339 
               
               
                 2691 
                   
                   
                 CAUCGGTT 
                   
                   
               
               
                   
               
               
                 2675- 
                 GAUGUCCGUGGGCAGAAUGTT 
                 889 
                 CAUUCUGCCCACG 
                 890 
                 AD-15253 
               
               
                 2693 
                   
                   
                 GACAUCTT 
                   
                   
               
               
                   
               
               
                 2678- 
                 GUCCGUGGGCAGAAUGACUTT 
                 891 
                 AGUCAUUCUGCCC 
                 892 
                 AD-15340 
               
               
                 2696 
                   
                   
                 ACGGACTT 
                   
                   
               
               
                   
               
               
                 2679- 
                 UCCGUGGGCAGAAUGACUUTT 
                 893 
                 AAGUCAUUCUGCC 
                 894 
                 AD-15291 
               
               
                 2697 
                   
                   
                 CACGGATT 
                   
                   
               
               
                   
               
               
                 2683- 
                 UGGGCAGAAUGACUUDUAUTT 
                 895 
                 AUAAAAGUCAUUC 
                 896 
                 AD-15341 
               
               
                 2701 
                   
                   
                 UGCCCATT 
                   
                   
               
               
                   
               
               
                 2694- 
                 ACUUUUAUUGAGCUCUUGUTT 
                 897 
                 ACAAGAGCUCAAU 
                 898 
                 AD-15401 
               
               
                 2712 
                   
                   
                 AAAAGUTT 
                   
                   
               
               
                   
               
               
                 2700- 
                 AUUGAGCUCUUGUUCCGUGTT 
                 899 
                 CACGGAACAAGAG 
                 900 
                 AD-15342 
               
               
                 2718 
                   
                   
                 CUCAAUTT 
                   
                   
               
               
                   
               
               
                 2704- 
                 AGCUCUUGUUCCGUGCCAGTT 
                 901 
                 CUGGCACGGAACA 
                 902 
                 AD-15343 
               
               
                 2722 
                   
                   
                 AGAGCUTT 
                   
                   
               
               
                   
               
               
                 2705- 
                 GCUCUUGUUCCGUGCCAGGTT 
                 903 
                 CCUGGCACGGAAC 
                 904 
                 AD-15292 
               
               
                 2723 
                   
                   
                 AAGAGCTT 
                   
                   
               
               
                   
               
               
                 2710- 
                 UGUUCCGUGCCAGGCAUUCTT 
                 905 
                 GAAUGCCUGGCAC 
                 906 
                 AD-15344 
               
               
                 2728 
                   
                   
                 GGAACATT 
                   
                   
               
               
                   
               
               
                 2711- 
                 GUUCCGUGCCAGGCAUUCATT 
                 907 
                 UGAAUGCCUGGCA 
                 908 
                 AD-15254 
               
               
                 2729 
                   
                   
                 CGGAACTT 
                   
                   
               
               
                   
               
               
                 2712- 
                 UUCCGUGCCAGGCAUUCAATT 
                 909 
                 UUGAAUGCCUGGC 
                 910 
                 AD-15345 
               
               
                 2730 
                   
                   
                 ACGGAATT 
                   
                   
               
               
                   
               
               
                 2715- 
                 CGUGCCAGGCAUUCAAUCCTT 
                 911 
                 GGAUUGAAUGCCU 
                 912 
                 AD-15206 
               
               
                 2733 
                   
                   
                 GGCACGTT 
                   
                   
               
               
                   
               
               
                 2716- 
                 GUGCCAGGCAUUCAAUCCUTT 
                 913 
                 AGGAUUGAAUGCC 
                 914 
                 AD-15346 
               
               
                 2734 
                   
                   
                 UGGCACTT 
                   
                   
               
               
                   
               
               
                 2728- 
                 CAAUCCUCAGGUCUCCACCTT 
                 915 
                 GGUGGAGACCUGA 
                 916 
                 AD-15347 
               
               
                 2746 
                   
                   
                 GGAUUGTT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CACCAAGGAGGCAGGAUUCTsT 
                 917 
                 GAAUCCUGCCUCC 
                 918 
                 AD-9577 
               
               
                 2761 
                   
                   
                 UUGGUGTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 cAccAAGGAGGcAGGAuucTsT 
                 919 
                 GAAUCCUGCCUCC 
                 920 
                 AD-9703 
               
               
                 2761 
                   
                   
                 UUGGUGTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CfaCfcAfaGfgAfgGfcAfgG 
                 921 
                 P*gAfaUfcCfuG 
                 922 
                 AD-14678 
               
               
                 2761 
                 faUfuCfTsT 
                   
                 fcCfuCfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 gUfgTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CfACfCfAAGGAGGCfAGGAUf 
                 923 
                 GAAUfCfCfUfGC 
                 924 
                 AD-14688 
               
               
                 2761 
                 UfCfTsT 
                   
                 fCfUfCfCfUfUf 
                   
                   
               
               
                   
                   
                   
                 GGUfGTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CaCcAaGgAgGcAgGaUuCTsT 
                 925 
                 P*gAfaUfcCfuG 
                 926 
                 AD-14698 
               
               
                 2761 
                   
                   
                 fcCfuCfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 gUfgTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CaCcAaGgAgGcAgGaUuCTsT 
                 927 
                 GAAUfCfCfUfGC 
                 928 
                 AD-14708 
               
               
                 2761 
                   
                   
                 fCfUfCfCfUfUf 
                   
                   
               
               
                   
                   
                   
                 GGUfGTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CfaCfcAfaGfgAfgGfcAfgG 
                 929 
                 GAAUCcuGCcuCC 
                 930 
                 AD-14718 
               
               
                 2761 
                 faUfuCfTsT 
                   
                 UUGgugTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CfACfCfAAGGAGGCfAGGAUf 
                 931 
                 GAAUCcuGCcuCC 
                 932 
                 AD-14728 
               
               
                 2761 
                 UfCfTsT 
                   
                 UUGgugTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 CaCcAaGgAgGcAgGaUuCTsT 
                 933 
                 GAAUCcuGCcuCC 
                 934 
                 AD-14738 
               
               
                 2761 
                   
                   
                 UUGgugTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GfgCfcUfgGfaGfuUfuAfuU 
                 935 
                 P*uCfcGfaAfuA 
                 936 
                 AD-15084 
               
               
                 2761 
                 fcGfgAfTsT 
                   
                 faAfcUfcCfaGf 
                   
                   
               
               
                   
                   
                   
                 gCfcTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GGCfCfUfGGAGUfUfUfAUfU 
                 937 
                 UfCfCfGAAUfAA 
                 938 
                 AD-15094 
               
               
                 2761 
                 fCfGGATsT 
                   
                 ACfUfCfCfAGGC 
                   
                   
               
               
                   
                   
                   
                 fCfTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GgCcUgGaGuUuAuUcGgATsT 
                 939 
                 P*uCfcGfaAfuA 
                 940 
                 AD-15104 
               
               
                 2761 
                   
                   
                 faAfcUfcCfaGf 
                   
                   
               
               
                   
                   
                   
                 gCfcTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GgCcUgGaGuUuAuUcGgATsT 
                 941 
                 UfCfCfGAAUfAA 
                 942 
                 AD-15114 
               
               
                 2761 
                   
                   
                 ACfUfCfCfAGGC 
                   
                   
               
               
                   
                   
                   
                 fCfTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GfgCfcUfgGfaGfuUfuAfuU 
                 943 
                 UCCGAauAAacUC 
                 944 
                 AD-15124 
               
               
                 2761 
                 fcGfgAfTsT 
                   
                 CAGgccTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GGCfCfUfGGAGUfUfUfAUfU 
                 945 
                 UCCGAauAAacUC 
                 946 
                 AD-15134 
               
               
                 2761 
                 fCfGGATsT 
                   
                 CAGgccTsT 
                   
                   
               
               
                   
               
               
                 2743- 
                 GgCcUgGaGuUuAuUcGgATsT 
                 947 
                 UCCGAauAAacUC 
                 948 
                 AD-15144 
               
               
                 2761 
                   
                   
                 CAGgccTsT 
                   
                   
               
               
                   
               
               
                 2753- 
                 GCAGGAUUCUUCCCAUGGATT 
                 949 
                 UCCAUGGGAAGAA 
                 950 
                 AD-15391 
               
               
                 2771 
                   
                   
                 UCCUGCTT 
                   
                   
               
               
                   
               
               
                 2794- 
                 UGCAGGGACAAACAUCGUUTT 
                 951 
                 AACGAUGUUUGUC 
                 952 
                 AD-15348 
               
               
                 2812 
                   
                   
                 CCUGCATT 
                   
                   
               
               
                   
               
               
                 2795- 
                 GCAGGGACAAACAUCGUUGTT 
                 953 
                 CAACGAUGUUUGU 
                 954 
                 AD-15349 
               
               
                 2813 
                   
                   
                 CCCUGCTT 
                   
                   
               
               
                   
               
               
                 2797- 
                 AGGGACAAACAUCGUUGGGTT 
                 955 
                 CCCAACGAUGUUU 
                 956 
                 AD-15170 
               
               
                 2815 
                   
                   
                 GUCCCUTT 
                   
                   
               
               
                   
               
               
                 2841- 
                 CCCUCAUCUCCAGCUAACUTT 
                 957 
                 AGUUAGCUGGAGA 
                 958 
                 AD-15350 
               
               
                 2859 
                   
                   
                 UGAGGGTT 
                   
                   
               
               
                   
               
               
                 2845- 
                 CAUCUCCAGCUAACUGUGGTT 
                 959 
                 CCACAGUUAGCUG 
                 960 
                 AD-15402 
               
               
                 2863 
                   
                   
                 GAGAUGTT 
                   
                   
               
               
                   
               
               
                 2878- 
                 GCUCCCUGAUUAAUGGAGGTT 
                 961 
                 CCUCCAUUAAUCA 
                 962 
                 AD-15293 
               
               
                 2896 
                   
                   
                 GGGAGCTT 
                   
                   
               
               
                   
               
               
                 2881- 
                 CCCUGAUUAAUGGAGGCUUTT 
                 963 
                 AAGCCUCCAUUAA 
                 964 
                 AD-15351 
               
               
                 2899 
                   
                   
                 UCAGGGTT 
                   
                   
               
               
                   
               
               
                 2882- 
                 CCUGAUUAAUGGAGGCUUATT 
                 965 
                 UAAGCCUCCAUUA 
                 966 
                 AD-15403 
               
               
                 2900 
                   
                   
                 AUCAGGTT 
                   
                   
               
               
                   
               
               
                 2884- 
                 UGAUUAAUGGAGGCUUAGCTT 
                 967 
                 GCUAAGCCUCCAU 
                 968 
                 AD-15404 
               
               
                 2902 
                   
                   
                 UAAUCATT 
                   
                   
               
               
                   
               
               
                 2885- 
                 GAUUAAUGGAGGCUUAGCUTT 
                 969 
                 AGCUAAGCCUCCA 
                 970 
                 AD-15207 
               
               
                 2903 
                   
                   
                 UUAAUCTT 
                   
                   
               
               
                   
               
               
                 2886- 
                 AUUAAUGGAGGCUUAGCUUTT 
                 971 
                 AAGCUAAGCCUCC 
                 972 
                 AD-15352 
               
               
                 2904 
                   
                   
                 AUUAAUTT 
                   
                   
               
               
                   
               
               
                 2887- 
                 UUAAUGGAGGCUUAGCUUUTT 
                 973 
                 AAAGCUAAGCCUC 
                 974 
                 AD-15255 
               
               
                 2905 
                   
                   
                 CAUUAATT 
                   
                   
               
               
                   
               
               
                 2903- 
                 UUUCUGGAUGGCAUCUAGCTsT 
                 975 
                 GCUAGAUGCCAUC 
                 976 
                 AD-9603 
               
               
                 2921 
                   
                   
                 CAGAAATsT 
                   
                   
               
               
                   
               
               
                 2903- 
                 uuucuGGAuGGcAucuAGcTsT 
                 977 
                 GCuAGAUGCcAUC 
                 978 
                 AD-9729 
               
               
                 2921 
                   
                   
                 cAGAAATsT 
                   
                   
               
               
                   
               
               
                 2904- 
                 UUCUGGAUGGCAUCUAGCCTsT 
                 979 
                 GGCUAGAUGCCAU 
                 980 
                 AD-9599 
               
               
                 2922 
                   
                   
                 CCAGAATsT 
                   
                   
               
               
                   
               
               
                 2904- 
                 uucuGGAuGGcAucuAGccTsT 
                 981 
                 GGCuAGAUGCcAU 
                 982 
                 AD-9725 
               
               
                 2922 
                   
                   
                 CcAGAATsT 
                   
                   
               
               
                   
               
               
                 2905- 
                 UCUGGAUGGCAUCUAGCCATsT 
                 983 
                 UGGCUAGAUGCCA 
                 984 
                 AD-9621 
               
               
                 2923 
                   
                   
                 UCCAGATsT 
                   
                   
               
               
                   
               
               
                 2905- 
                 ucuGGAuGGcAucuAGccATsT 
                 985 
                 UGGCuAGAUGCcA 
                 986 
                 AD-9747 
               
               
                 2923 
                   
                   
                 UCcAGATsT 
                   
                   
               
               
                   
               
               
                 2925- 
                 AGGCUGGAGACAGGUGCGCTT 
                 987 
                 GCGCACCUGUCUC 
                 988 
                 AD-15405 
               
               
                 2943 
                   
                   
                 CAGCCUTT 
                   
                   
               
               
                   
               
               
                 2926- 
                 GGCUGGAGACAGGUGCGCCTT 
                 989 
                 GGCGCACCUGUCU 
                 990 
                 AD-15353 
               
               
                 2944 
                   
                   
                 CCAGCCTT 
                   
                   
               
               
                   
               
               
                 2927- 
                 GCUGGAGACAGGUGCGCCCTT 
                 991 
                 GGGCGCACCUGUC 
                 992 
                 AD-15354 
               
               
                 2945 
                   
                   
                 UCCAGCTT 
                   
                   
               
               
                   
               
               
                 2972- 
                 UUCCUGAGCCACCUUUACUTT 
                 993 
                 AGUAAAGGUGGCU 
                 994 
                 AD-15406 
               
               
                 2990 
                   
                   
                 CAGGAATT 
                   
                   
               
               
                   
               
               
                 2973- 
                 UCCUGAGCCACCUUUACUCTT 
                 995 
                 GAGUAAAGGUGGC 
                 996 
                 AD-15407 
               
               
                 2991 
                   
                   
                 UCAGGATT 
                   
                   
               
               
                   
               
               
                 2974- 
                 CCUGAGCCACCUUUACUCUTT 
                 997 
                 AGAGUAAAGGUGG 
                 998 
                 AD-15355 
               
               
                 2992 
                   
                   
                 CUCAGGTT 
                   
                   
               
               
                   
               
               
                 2976- 
                 UGAGCCACCUUUACUCUGCTT 
                 999 
                 GCAGAGUAAAGGU 
                 1000 
                 AD-15356 
               
               
                 2994 
                   
                   
                 GGCUCATT 
                   
                   
               
               
                   
               
               
                 2978- 
                 AGCCACCUUUACUCUGCUCTT 
                 1001 
                 GAGCAGAGUAAAG 
                 1002 
                 AD-15357 
               
               
                 2996 
                   
                   
                 GUGGCUTT 
                   
                   
               
               
                   
               
               
                 2981- 
                 CACCUUUACUCUGCUCUAUTT 
                 1003 
                 AUAGAGCAGAGUA 
                 1004 
                 AD-15269 
               
               
                 2999 
                   
                   
                 AAGGUGTT 
                   
                   
               
               
                   
               
               
                 2987- 
                 UACUCUGCUCUAUGCCAGGTsT 
                 1005 
                 CCUGGCAUAGAGC 
                 1006 
                 AD-9565 
               
               
                 3005 
                   
                   
                 AGAGUATsT 
                   
                   
               
               
                   
               
               
                 2987- 
                 uAcucuGcucuAuGccAGGTsT 
                 1007 
                 CCUGGcAuAGAGc 
                 1008 
                 AD-9691 
               
               
                 3005 
                   
                   
                 AGAGuATsT 
                   
                   
               
               
                   
               
               
                 2998- 
                 AUGCCAGGCUGUGCUAGCATT 
                 1009 
                 UGCUAGCACAGCC 
                 1010 
                 AD-15358 
               
               
                 3016 
                   
                   
                 UGGCAUTT 
                   
                   
               
               
                   
               
               
                 3003- 
                 AGGCUGUGCUAGCAACACCTT 
                 1011 
                 GGUGUUGCUAGCA 
                 1012 
                 AD-15359 
               
               
                 3021 
                   
                   
                 CAGCCUTT 
                   
                   
               
               
                   
               
               
                 3006- 
                 CUGUGCUAGCAACACCCAATT 
                 1013 
                 UUGGGUGUUGCUA 
                 1014 
                 AD-15360 
               
               
                 3024 
                   
                   
                 GCACAGTT 
                   
                   
               
               
                   
               
               
                 3010- 
                 GCUAGCAACACCCAAAGGUTT 
                 1015 
                 ACCUUUGGGUGUU 
                 1016 
                 AD-15219 
               
               
                 3028 
                   
                   
                 GCUAGCTT 
                   
                   
               
               
                   
               
               
                 3038- 
                 GGAGCCAUCACCUAGGACUTT 
                 1017 
                 AGUCCUAGGUGAU 
                 1018 
                 AD-15361 
               
               
                 3056 
                   
                   
                 GGCUCCTT 
                   
                   
               
               
                   
               
               
                 3046- 
                 CACCUAGGACUGACUCGGCTT 
                 1019 
                 GCCGAGUCAGUCC 
                 1020 
                 AD-15273 
               
               
                 3064 
                   
                   
                 UAGGUGTT 
                   
                   
               
               
                   
               
               
                 3051- 
                 AGGACUGACUCGGCAGUGUTT 
                 1021 
                 ACACUGCCGAGUC 
                 1022 
                 AD-15362 
               
               
                 3069 
                   
                   
                 AGUCCUTT 
                   
                   
               
               
                   
               
               
                 3052- 
                 GGACUGACUCGGCAGUGUGTT 
                 1023 
                 CACACUGCCGAGU 
                 1024 
                 AD-15192 
               
               
                 3070 
                   
                   
                 CAGUCCTT 
                   
                   
               
               
                   
               
               
                 3074- 
                 UGGUGCAUGCACUGUCUCATT 
                 1025 
                 UGAGACAGUGCAU 
                 1026 
                 AD-15256 
               
               
                 3092 
                   
                   
                 GCACCATT 
                   
                   
               
               
                   
               
               
                 3080- 
                 AUGCACUGUCUCAGCCAACTT 
                 1027 
                 GUUGGCUGAGACA 
                 1028 
                 AD-15363 
               
               
                 3098 
                   
                   
                 GUGCAUTT 
                   
                   
               
               
                   
               
               
                 3085- 
                 CUGUCUCAGCCAACCCGCUTT 
                 1029 
                 AGCGGGUUGGCUG 
                 1030 
                 AD-15364 
               
               
                 3103 
                   
                   
                 AGACAGTT 
                   
                   
               
               
                   
               
               
                 3089- 
                 CUCAGCCAACCCGCUCCACTsT 
                 1031 
                 GUGGAGCGGGUUG 
                 1032 
                 AD-9604 
               
               
                 3107 
                   
                   
                 GCUGAGTsT 
                   
                   
               
               
                   
               
               
                 3089- 
                 cucAGccAAcccGcuccAcTsT 
                 1033 
                 GUGGAGCGGGUUG 
                 1034 
                 AD-9730 
               
               
                 3107 
                   
                   
                 GCUGAGTsT 
                   
                   
               
               
                   
               
               
                 3093- 
                 GCCAACCCGCUCCACUACCTsT 
                 1035 
                 GGUAGUGGAGCGG 
                 1036 
                 AD-9527 
               
               
                 3111 
                   
                   
                 GUUGGCTsT 
                   
                   
               
               
                   
               
               
                 3093- 
                 GccAAcccGcuccAcuAccTsT 
                 1037 
                 GGuAGUGGAGCGG 
                 1038 
                 AD-9653 
               
               
                 3111 
                   
                   
                 GUUGGCTsT 
                   
                   
               
               
                   
               
               
                 3096- 
                 AACCCGCUCCACUACCCGGTT 
                 1039 
                 CCGGGUAGUGGAG 
                 1040 
                 AD-15365 
               
               
                 3114 
                   
                   
                 CGGGUUTT 
                   
                   
               
               
                   
               
               
                 3099- 
                 CCGCUCCACUACCCGGCAGTT 
                 1041 
                 CUGCCGGGUAGUG 
                 1042 
                 AD-15294 
               
               
                 3117 
                   
                   
                 GAGCGGTT 
                   
                   
               
               
                   
               
               
                 3107- 
                 CUACCCGGCAGGGUACACATT 
                 1043 
                 UGUGUACCCUGCC 
                 1044 
                 AD-15173 
               
               
                 3125 
                   
                   
                 GGGUAGTT 
                   
                   
               
               
                   
               
               
                 3108- 
                 UACCCGGCAGGGUACACAUTT 
                 1045 
                 AUGUGUACCCUGC 
                 1046 
                 AD-15366 
               
               
                 3126 
                   
                   
                 CGGGUATT 
                   
                   
               
               
                   
               
               
                 3109- 
                 ACCCGGCAGGGUACACAUUTT 
                 1047 
                 AAUGUGUACCCUG 
                 1048 
                 AD-15367 
               
               
                 3127 
                   
                   
                 CCGGGUTT 
                   
                   
               
               
                   
               
               
                 3110- 
                 CCCGGCAGGGUACACAUUCTT 
                 1049 
                 GAAUGUGUACCCU 
                 1050 
                 AD-15257 
               
               
                 3128 
                   
                   
                 GCCGGGTT 
                   
                   
               
               
                   
               
               
                 3112- 
                 CGGCAGGGUACACAUUCGCTT 
                 1051 
                 GCGAAUGUGUACC 
                 1052 
                 AD-15184 
               
               
                 3130 
                   
                   
                 CUGCCGTT 
                   
                   
               
               
                   
               
               
                 3114- 
                 GCAGGGUACACAUUCGCACTT 
                 1053 
                 GUGCGAAUGUGUA 
                 1054 
                 AD-15185 
               
               
                 3132 
                   
                   
                 CCCUGCTT 
                   
                   
               
               
                   
               
               
                 3115- 
                 CAGGGUACACAUUCGCACCTT 
                 1055 
                 GGUGCGAAUGUGU 
                 1056 
                 AD-15258 
               
               
                 3133 
                   
                   
                 ACCCUGTT 
                   
                   
               
               
                   
               
               
                 3116- 
                 AGGGUACACAUUCGCACCCTT 
                 1057 
                 GGGUGCGAAUGUG 
                 1058 
                 AD-15186 
               
               
                 3134 
                   
                   
                 UACCCUTT 
                   
                   
               
               
                   
               
               
                 3196- 
                 GGAACUGAGCCAGAAACGCTT 
                 1059 
                 GCGUUUCUGGCUC 
                 1060 
                 AD-15274 
               
               
                 3214 
                   
                   
                 AGUUCCTT 
                   
                   
               
               
                   
               
               
                 3197- 
                 GAACUGAGCCAGAAACGCATT 
                 1061 
                 UGCGUUUCUGGCU 
                 1062 
                 AD-15368 
               
               
                 3215 
                   
                   
                 CAGUUCTT 
                   
                   
               
               
                   
               
               
                 3198- 
                 AACUGAGCCAGAAACGCAGTT 
                 1063 
                 CUGCGUUUCUGGC 
                 1064 
                 AD-15369 
               
               
                 3216 
                   
                   
                 UCAGUUTT 
                   
                   
               
               
                   
               
               
                 3201- 
                 UGAGCCAGAAACGCAGAUUTT 
                 1065 
                 AAUCUGCGUUUCU 
                 1066 
                 AD-15370 
               
               
                 3219 
                   
                   
                 GGCUCATT 
                   
                   
               
               
                   
               
               
                 3207- 
                 AGAAACGCAGAUUGGGCUGTT 
                 1067 
                 CAGCCCAAUCUGC 
                 1068 
                 AD-15259 
               
               
                 3225 
                   
                   
                 GUUUCUTT 
                   
                   
               
               
                   
               
               
                 3210- 
                 AACGCAGAUUGGGCUGGCUTT 
                 1069 
                 AGCCAGCCCAAUC 
                 1070 
                 AD-15408 
               
               
                 3228 
                   
                   
                 UGCGUUTT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AGCCAAGCCUCUUCUUACUTsT 
                 1071 
                 AGUAAGAAGAGGC 
                 1072 
                 AD-9597 
               
               
                 3251 
                   
                   
                 UUGGCUTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AGccAAGccucuucuuAcuTsT 
                 1073 
                 AGuAAGAAGAGGC 
                 1074 
                 AD-9723 
               
               
                 3251 
                   
                   
                 UUGGCUTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AfgCfcAfaGfcCfuCfuUfcU 
                 1075 
                 P*aGfuAfaGfaA 
                 1076 
                 AD-14680 
               
               
                 3251 
                 fuAfcUfTsT 
                   
                 fgAfgGfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 gCfuTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AGCfCfAAGCfCfUfCfUfUfC 
                 1077 
                 AGUfAAGAAGAGG 
                 1078 
                 AD-14690 
               
               
                 3251 
                 fUfUfACfUfTsT 
                   
                 CfUfUfGGCfUfT 
                   
                   
               
               
                   
                   
                   
                 sT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AgCcAaGcCuCuUcUuAcUTsT 
                 1079 
                 P*aGfuAfaGfaA 
                 1080 
                 AD-14700 
               
               
                 3251 
                   
                   
                 fgAfgGfcUfuGf 
                   
                   
               
               
                   
                   
                   
                 gCfuTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AgCcAaGcCuCuUcUuAcUTsT 
                 1081 
                 AGUfAAGAAGAGG 
                 1082 
                 AD-14710 
               
               
                 3251 
                   
                   
                 CfUfUfGGCfUfT 
                   
                   
               
               
                   
                   
                   
                 sT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AfgCfcAfaGfcCfuCfuUfcU 
                 1083 
                 AGUAAgaAGagGC 
                 1084 
                 AD-14720 
               
               
                 3251 
                 fuAfcUfTsT 
                   
                 UUGgcuTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AGCfCfAAGCfCfUfCfUfUfC 
                 1085 
                 AGUAAgaAGagGC 
                 1086 
                 AD-14730 
               
               
                 3251 
                 fUfUfACfUfTsT 
                   
                 UUGgcuTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 AgCcAaGcCuCuUcUuAcUTsT 
                 1087 
                 AGUAAgaAGagGC 
                 1088 
                 AD-14740 
               
               
                 3251 
                   
                   
                 UUGgcuTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UfgGfuUfcCfcUfgAfgGfaC 
                 1089 
                 P*gCfuGfgUfcC 
                 1090 
                 AD-15086 
               
               
                 3251 
                 fcAfgCfTsT 
                   
                 fuCfaGfgGfaAf 
                   
                   
               
               
                   
                   
                   
                 cCfaTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UfGGUfUfCfCfCfUfGAGGAC 
                 1091 
                 GCfUfGGUfCfCf 
                 1092 
                 AD-15096 
               
               
                 3251 
                 fCfAGCfTsT 
                   
                 UfCfAGGGAACfC 
                   
                   
               
               
                   
                   
                   
                 fATsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UgGuUcCcUgAgGaCcAgCTsT 
                 1093 
                 P*gCfuGfgUfcC 
                 1094 
                 AD-15106 
               
               
                 3251 
                   
                   
                 fuCfaGfgGfaAf 
                   
                   
               
               
                   
                   
                   
                 cCfaTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UgGuUcCcUgAgGaCcAgCTsT 
                 1095 
                 GCfUfGGUfCfCf 
                 1096 
                 AD-15116 
               
               
                 3251 
                   
                   
                 UfCfAGGGAACfC 
                   
                   
               
               
                   
                   
                   
                 fATsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UfgGfuUfcCfcUfgAfgGfaC 
                 1097 
                 GCUGGucCUcaGG 
                 1098 
                 AD-15126 
               
               
                 3251 
                 fcAfgCfTsT 
                   
                 GAAccaTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UfGGUfUfCfCfCfUfGAGGAC 
                 1099 
                 GCUGGucCUcaGG 
                 1100 
                 AD-15136 
               
               
                 3251 
                 fCfAGCfTsT 
                   
                 GAAccaTsT 
                   
                   
               
               
                   
               
               
                 3233- 
                 UgGuUcCcUgAgGaCcAgCTsT 
                 1101 
                 GCUGGucCUcaGG 
                 1102 
                 AD-15146 
               
               
                 3251 
                   
                   
                 GAAccaTsT 
                   
                   
               
               
                   
               
               
                 3242- 
                 UCUUCUUACUUCACCCGGCTT 
                 1103 
                 GCCGGGUGAAGUA 
                 1104 
                 AD-15260 
               
               
                 3260 
                   
                   
                 AGAAGATT 
                   
                   
               
               
                   
               
               
                 3243- 
                 CUUCUUACUUCACCCGGCUTT 
                 1105 
                 AGCCGGGUGAAGU 
                 1106 
                 AD-15371 
               
               
                 3261 
                   
                   
                 AAGAAGTT 
                   
                   
               
               
                   
               
               
                 3244- 
                 UUCUUACUUCACCCGGCUGTT 
                 1107 
                 CAGCCGGGUGAAG 
                 1108 
                 AD-15372 
               
               
                 3262 
                   
                   
                 UAAGAATT 
                   
                   
               
               
                   
               
               
                 3262- 
                 GGGCUCCUCAUUUUUACGGTT 
                 1109 
                 CCGUAAAAAUGAG 
                 1110 
                 AD-15172 
               
               
                 3280 
                   
                   
                 GAGCCCTT 
                   
                   
               
               
                   
               
               
                 3263- 
                 GGCUCCUCAUUUUUACGGGTT 
                 1111 
                 CCCGUAAAAAUGA 
                 1112 
                 AD-15295 
               
               
                 3281 
                   
                   
                 GGAGCCTT 
                   
                   
               
               
                   
               
               
                 3264- 
                 GCUCCUCAUUUUUACGGGUTT 
                 1113 
                 ACCCGUAAAAAUG 
                 1114 
                 AD-15373 
               
               
                 3282 
                   
                   
                 AGGAGCTT 
                   
                   
               
               
                   
               
               
                 3265- 
                 CUCCUCAUUUUUACGGGUATT 
                 1115 
                 UACCCGUAAAAAU 
                 1116 
                 AD-15163 
               
               
                 3283 
                   
                   
                 GAGGAGTT 
                   
                   
               
               
                   
               
               
                 3266- 
                 UCCUCAUUUUUACGGGUAATT 
                 1117 
                 UUACCCGUAAAAA 
                 1118 
                 AD-15165 
               
               
                 3284 
                   
                   
                 UGAGGATT 
                   
                   
               
               
                   
               
               
                 3267- 
                 CCUCAUUUUUACGGGUAACTT 
                 1119 
                 GUUACCCGUAAAA 
                 1120 
                 AD-15374 
               
               
                 3285 
                   
                   
                 AUGAGGTT 
                   
                   
               
               
                   
               
               
                 3268- 
                 CUCAUUUUUACGGGUAACATT 
                 1121 
                 UGUUACCCGUAAA 
                 1122 
                 AD-15296 
               
               
                 3286 
                   
                   
                 AAUGAGTT 
                   
                   
               
               
                   
               
               
                 3270- 
                 CAUUUUUACGGGUAACAGUTT 
                 1123 
                 ACUGUUACCCGUA 
                 1124 
                 AD-15261 
               
               
                 3288 
                   
                   
                 AAAAUGTT 
                   
                   
               
               
                   
               
               
                 3271- 
                 AUUUUUACGGGUAACAGUGTT 
                 1125 
                 CACUGUUACCCGU 
                 1126 
                 AD-15375 
               
               
                 3289 
                   
                   
                 AAAAAUTT 
                   
                   
               
               
                   
               
               
                 3274- 
                 UUUACGGGUAACAGUGAGGTT 
                 1127 
                 CCUCACUGUUACC 
                 1128 
                 AD-15262 
               
               
                 3292 
                   
                   
                 CGUAAATT 
                   
                   
               
               
                   
               
               
                 3308- 
                 CAGACCAGGAAGCUCGGUGTT 
                 1129 
                 CACCGAGCUUCCU 
                 1130 
                 AD-15376 
               
               
                 3326 
                   
                   
                 GGUCUGTT 
                   
                   
               
               
                   
               
               
                 3310- 
                 GACCAGGAAGCUCGGUGAGTT 
                 1131 
                 CUCACCGAGCUUC 
                 1132 
                 AD-15377 
               
               
                 3328 
                   
                   
                 CUGGUCTT 
                   
                   
               
               
                   
               
               
                 3312- 
                 CCAGGAAGCUCGGUGAGUGTT 
                 1133 
                 CACUCACCGAGCU 
                 1134 
                 AD-15409 
               
               
                 3330 
                   
                   
                 UCCUGGTT 
                   
                   
               
               
                   
               
               
                 3315- 
                 GGAAGCUCGGUGAGUGAUGTT 
                 1135 
                 CAUCACUCACCGA 
                 1136 
                 AD-15378 
               
               
                 3333 
                   
                   
                 GCUUCCTT 
                   
                   
               
               
                   
               
               
                 3324- 
                 GUGAGUGAUGGCAGAACGATT 
                 1137 
                 UCGUUCUGCCAUC 
                 1138 
                 AD-15410 
               
               
                 3342 
                   
                   
                 ACUCACTT 
                   
                   
               
               
                   
               
               
                 3326- 
                 GAGUGAUGGCAGAACGAUGTT 
                 1139 
                 CAUCGUUCUGCCA 
                 1140 
                 AD-15379 
               
               
                 3344 
                   
                   
                 UCACUCTT 
                   
                   
               
               
                   
               
               
                 3330- 
                 GAUGGCAGAACGAUGCCUGTT 
                 1141 
                 CAGGCAUCGUUCU 
                 1142 
                 AD-15187 
               
               
                 3348 
                   
                   
                 GCCAUCTT 
                   
                   
               
               
                   
               
               
                 3336- 
                 AGAACGAUGCCUGCAGGCATT 
                 1143 
                 UGCCUGCAGGCAU 
                 1144 
                 AD-15263 
               
               
                 3354 
                   
                   
                 CGUUCUTT 
                   
                   
               
               
                   
               
               
                 3339- 
                 ACGAUGCCUGCAGGCAUGGTT 
                 1145 
                 CCAUGCCUGCAGG 
                 1146 
                 AD-15264 
               
               
                 3357 
                   
                   
                 CAUCGUTT 
                   
                   
               
               
                   
               
               
                 3348- 
                 GCAGGCAUGGAACUUUUUCTT 
                 1147 
                 GAAAAAGUUCCAU 
                 1148 
                 AD-15297 
               
               
                 3366 
                   
                   
                 GCCUGCTT 
                   
                   
               
               
                   
               
               
                 3356- 
                 GGAACUUUUUCCGUUAUCATT 
                 1149 
                 UGAUAACGGAAAA 
                 1150 
                 AD-15208 
               
               
                 3374 
                   
                   
                 AGUUCCTT 
                   
                   
               
               
                   
               
               
                 3357- 
                 GAACUUUUUCCGUUAUCACTT 
                 1151 
                 GUGAUAACGGAAA 
                 1152 
                 AD-15209 
               
               
                 3375 
                   
                   
                 AAGUUCTT 
                   
                   
               
               
                   
               
               
                 3358- 
                 AACUUUUUCCGUUAUCACCTT 
                 1153 
                 GGUGAUAACGGAA 
                 1154 
                 AD-15193 
               
               
                 3376 
                   
                   
                 AAAGUUTT 
                   
                   
               
               
                   
               
               
                 3370- 
                 UAUCACCCAGGCCUGAUUCTT 
                 1155 
                 GAAUCAGGCCUGG 
                 1156 
                 AD-15380 
               
               
                 3388 
                   
                   
                 GUGAUATT 
                   
                   
               
               
                   
               
               
                 3378- 
                 AGGCCUGAUUCACUGGCCUTT 
                 1157 
                 AGGCCAGUGAAUC 
                 1158 
                 AD-15298 
               
               
                 3396 
                   
                   
                 AGGCCUTT 
                   
                   
               
               
                   
               
               
                 3383- 
                 UGAUUCACUGGCCUGGCGGTT 
                 1159 
                 CCGCCAGGCCAGU 
                 1160 
                 AD-15299 
               
               
                 3401 
                   
                   
                 GAAUCATT 
                   
                   
               
               
                   
               
               
                 3385- 
                 AUUCACUGGCCUGGCGGAGTT 
                 1161 
                 CUCCGCCAGGCCA 
                 1162 
                 AD-15265 
               
               
                 3403 
                   
                   
                 GUGAAUTT 
                   
                   
               
               
                   
               
               
                 3406- 
                 GCUUCUAAGGCAUGGUCGGTT 
                 1163 
                 CCGACCAUGCCUU 
                 1164 
                 AD-15381 
               
               
                 3424 
                   
                   
                 AGAAGCTT 
                   
                   
               
               
                   
               
               
                 3407- 
                 CUUCUAAGGCAUGGUCGGGTT 
                 1165 
                 CCCGACCAUGCCU 
                 1166 
                 AD-15210 
               
               
                 3425 
                   
                   
                 UAGAAGTT 
                   
                   
               
               
                   
               
               
                 3429- 
                 GAGGGCCAACAACUGUCCCTT 
                 1167 
                 GGGACAGUUGUUG 
                 1168 
                 AD-15270 
               
               
                 3447 
                   
                   
                 GCCCUCTT 
                   
                   
               
               
                   
               
               
                 3440- 
                 ACUGUCCCUCCUUGAGCACTsT 
                 1169 
                 GUGCUCAAGGAGG 
                 1170 
                 AD-9591 
               
               
                 3458 
                   
                   
                 GACAGUTsT 
                   
                   
               
               
                   
               
               
                 3440- 
                 AcuGucccuccuuGAGcAcTsT 
                 1171 
                 GUGCUcAAGGAGG 
                 1172 
                 AD-9717 
               
               
                 3458 
                   
                   
                 GAcAGUTsT 
                   
                   
               
               
                   
               
               
                 3441- 
                 CUGUCCCUCCUUGAGCACCTsT 
                 1173 
                 GGUGCUCAAGGAG 
                 1174 
                 AD-9622 
               
               
                 3459 
                   
                   
                 GGACAGTsT 
                   
                   
               
               
                   
               
               
                 3441- 
                 cuGucccuccuuGAGcAccTsT 
                 1175 
                 GGUGCUcAAGGAG 
                 1176 
                 AD-9748 
               
               
                 3459 
                   
                   
                 GGAcAGTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 ACAUUUAUCUUUUGGGUCUTsT 
                 1177 
                 AGACCCAAAAGAU 
                 1178 
                 AD-9587 
               
               
                 3498 
                   
                   
                 AAAUGUTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AcAuuuAucuuuuGGGucuTsT 
                 1179 
                 AGACCcAAAAGAu 
                 1180 
                 AD-9713 
               
               
                 3498 
                   
                   
                 AAAUGUTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AfcAfuUfuAfuCfuUfuUfgG 
                 1181 
                 P*aGfaCfcCfaA 
                 1182 
                 AD-14679 
               
               
                 3498 
                 fgUfcUfTsT 
                   
                 faAfgAfuAfaAf 
                   
                   
               
               
                   
                   
                   
                 uGfuTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 ACfAUfUfUfAUfCfUfUfUfU 
                 1183 
                 AGACfCfCfAAAA 
                 1184 
                 AD-14689 
               
               
                 3498 
                 fGGGUfCfUfTsT 
                   
                 GAUfAAAUfGUfT 
                   
                   
               
               
                   
                   
                   
                 sT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AcAuUuAuCuUuUgGgUcUTsT 
                 1185 
                 P*aGfaCfcCfaA 
                 1186 
                 AD-14699 
               
               
                 3498 
                   
                   
                 faAfgAfuAfaAf 
                   
                   
               
               
                   
                   
                   
                 uGfuTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AcAuUuAuCuUuUgGgUcUTsT 
                 1187 
                 AGACfCfCfAAAA 
                 1188 
                 AD-14709 
               
               
                 3498 
                   
                   
                 GAUfAAAUfGUfT 
                   
                   
               
               
                   
                   
                   
                 sT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AfcAfuUfuAfuCfuUfuUfgG 
                 1189 
                 AGACCcaAAagAU 
                 1190 
                 AD-14719 
               
               
                 3498 
                 fgUfcUfTsT 
                   
                 AAAuguTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 ACfAUfUfUfAUfCfUfUfUfU 
                 1191 
                 AGACCcaAAagAU 
                 1192 
                 AD-14729 
               
               
                 3498 
                 fGGGUfCfUfTsT 
                   
                 AAAuguTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 AcAuUuAuCuUuUgGgUcUTsT 
                 1193 
                 AGACCcaAAagAU 
                 1194 
                 AD-14739 
               
               
                 3498 
                   
                   
                 AAAuguTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GfcCfaUfcUfgCfuGfcCfgG 
                 1195 
                 P*gGfcUfcCfgG 
                 1196 
                 AD-15085 
               
               
                 3498 
                 faGfcCfTsT 
                   
                 fcAfgCfaGfaUf 
                   
                   
               
               
                   
                   
                   
                 gGfcTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GCfCfAUfCfUfGCfUfGCfCf 
                 1197 
                 GGCfUfCfCfGGC 
                 1198 
                 AD-15095 
               
               
                 3498 
                 GGAGCfCfTsT 
                   
                 fAGCfAGAUfGGC 
                   
                   
               
               
                   
                   
                   
                 fTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GcCaUcUgCuGcCgGaGcCTsT 
                 1199 
                 P*gGfcUfcCfgG 
                 1200 
                 AD-15105 
               
               
                 3498 
                   
                   
                 fcAfgCfaGfaUf 
                   
                   
               
               
                   
                   
                   
                 gGfcTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GcCaUcUgCuGcCgGaGcCTsT 
                 1201 
                 GGCfUfCfCfGGC 
                 1202 
                 AD-15115 
               
               
                 3498 
                   
                   
                 fAGCfAGAUfGGC 
                   
                   
               
               
                   
                   
                   
                 fTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GfcCfaUfcUfgCfuGfcCfgG 
                 1203 
                 GGCUCauGCagCA 
                 1204 
                 AD-15125 
               
               
                 3498 
                 faGfcCfTsT 
                   
                 GAUggcTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GCfCfAUfCfUfGCfUfGCfCf 
                 1205 
                 GGCUCauGCagCA 
                 1206 
                 AD-15135 
               
               
                 3498 
                 GGAGCfCfTsT 
                   
                 GAUggcTsT 
                   
                   
               
               
                   
               
               
                 3480- 
                 GcCaUcUgCuGcCgGaGcCTsT 
                 1207 
                 GGCUCauGCagCA 
                 1208 
                 AD-15145 
               
               
                 3498 
                   
                   
                 GAUggcTsT 
                   
                   
               
               
                   
               
               
                 3481- 
                 CAUUUAUCUUUUGGGUCUGTsT 
                 1209 
                 CAGACCCAAAAGA 
                 1210 
                 AD-9578 
               
               
                 3499 
                   
                   
                 UAAAUGTsT 
                   
                   
               
               
                   
               
               
                 3481- 
                 cAuuuAucuuuuGGGucuGTsT 
                 1211 
                 cAGACCcAAAAGA 
                 1212 
                 AD-9704 
               
               
                 3499 
                   
                   
                 uAAAUGTsT 
                   
                   
               
               
                   
               
               
                 3485- 
                 UAUCUUUUGGGUCUGUCCUTsT 
                 1213 
                 AGGACAGACCCAA 
                 1214 
                 AD-9558 
               
               
                 3503 
                   
                   
                 AAGAUATsT 
                   
                   
               
               
                   
               
               
                 3485- 
                 uAucuuuuGGGucuGuccuTsT 
                 1215 
                 AGGAcAGACCcAA 
                 1216 
                 AD-9684 
               
               
                 3503 
                   
                   
                 AAGAuATsT 
                   
                   
               
               
                   
               
               
                 3504- 
                 CUCUGUUGCCUUUUUACAGTsT 
                 1217 
                 CUGUAAAAAGGCA 
                 1218 
                 AD-9634 
               
               
                 3522 
                   
                   
                 ACAGAGTsT 
                   
                   
               
               
                   
               
               
                 3504- 
                 cucuGuuGccuuuuuAcAGTsT 
                 1219 
                 CUGuAAAAAGGcA 
                 1220 
                 AD-9760 
               
               
                 3522 
                   
                   
                 AcAGAGTsT 
                   
                   
               
               
                   
               
               
                 3512- 
                 CCUUUUUACAGCCAACUUUTT 
                 1221 
                 AAAGUUGGCUGUA 
                 1222 
                 AD-15411 
               
               
                 3530 
                   
                   
                 AAAAGGTT 
                   
                   
               
               
                   
               
               
                 3521- 
                 AGCCAACUUUUCUAGACCUTT 
                 1223 
                 AGGUCUAGAAAAG 
                 1224 
                 AD-15266 
               
               
                 3539 
                   
                   
                 UUGGCUTT 
                   
                   
               
               
                   
               
               
                 3526- 
                 ACUUUUCUAGACCUGUUUUTT 
                 1225 
                 AAAACAGGUCUAG 
                 1226 
                 AD-15382 
               
               
                 3544 
                   
                   
                 AAAAGUTT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UUCUAGACCUGUUUUGCUUTsT 
                 1227 
                 AAGCAAAACAGGU 
                 1228 
                 AD-9554 
               
               
                 3548 
                   
                   
                 CUAGAATsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 uucuAGAccuGuuuuGcuuTsT 
                 1229 
                 AAGcAAAAcAGGU 
                 1230 
                 AD-9680 
               
               
                 3548 
                   
                   
                 CuAGAATsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UfuCfuAfgAfcCfuGfuUfuU 
                 1231 
                 P*aAfgCfaAfaA 
                 1232 
                 AD-14676 
               
               
                 3548 
                 fgCfuUfTsT 
                   
                 fcAfgGfuCfuAf 
                   
                   
               
               
                   
                   
                   
                 gAfaTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UfUfCfUfAGACfCfUfGUfUf 
                 1233 
                 AAGCfAAAACfAG 
                 1234 
                 AD-14686 
               
               
                 3548 
                 UfUfGCfUfUfTsT 
                   
                 GUfCfUfAGAATs 
                   
                   
               
               
                   
                   
                   
                 T 
                   
                   
               
               
                   
               
               
                 3530- 
                 UuCuAgAcCuGuUuUgCuUTsT 
                 1235 
                 P*aAfgCfaAfaA 
                 1236 
                 AD-14696 
               
               
                 3548 
                   
                   
                 fcAfgGfuCfuAf 
                   
                   
               
               
                   
                   
                   
                 gAfaTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UuCuAgAcCuGuUuUgCuUTsT 
                 1237 
                 AAGCfAAAACfAG 
                 1238 
                 AD-14706 
               
               
                 3548 
                   
                   
                 GUfCfUfAGAATs 
                   
                   
               
               
                   
                   
                   
                 T 
                   
                   
               
               
                   
               
               
                 3530- 
                 UfuCfuAfgAfcCfuGfuUfuU 
                 1239 
                 AAGcAaaACagGU 
                 1240 
                 AD-14716 
               
               
                 3548 
                 ffCfuUfTsT 
                   
                 CUAgaaTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UfUfCfUfAGACfCfUfGUfUf 
                 1241 
                 AAGcAaaACagGU 
                 1242 
                 AD-14726 
               
               
                 3548 
                 UfUfGCfUfUfTsT 
                   
                 CUAgaaTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 UuCuAgAcCuGuUuUgCuUTsT 
                 1243 
                 AAGcAaaACagGU 
                 1244 
                 AD-14736 
               
               
                 3548 
                   
                   
                 CUAgaaTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CfaUfaGfgCfcUfgGfaGfuU 
                 1245 
                 P*aAfuAfaAfcU 
                 1246 
                 AD-15082 
               
               
                 3548 
                 fuAfuUfTsT 
                   
                 fcCfaGfgCfcUf 
                   
                   
               
               
                   
                   
                   
                 aUfgTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CfAUfAGGCfCfUfGGAGUfUf 
                 1247 
                 AAUfAAACfUfCf 
                 1248 
                 AD-15092 
               
               
                 3548 
                 UfAUfUfTsT 
                   
                 CfAGGCfCfUfAU 
                   
                   
               
               
                   
                   
                   
                 fGTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CaUaGgCcUgGaGuUuAuUTsT 
                 1249 
                 P*aAfuAfaAfcU 
                 1250 
                 AD-15102 
               
               
                 3548 
                   
                   
                 fcCfaGfgCfcUf 
                   
                   
               
               
                   
                   
                   
                 aUfgTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CaUaGgCcUgGaGuUuAuUTsT 
                 1251 
                 AAUfAAACfUfCf 
                 1252 
                 AD-15112 
               
               
                 3548 
                   
                   
                 CfAGGCfCfUfAU 
                   
                   
               
               
                   
                   
                   
                 fGTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CfaUfaGfgCfcUfgGfaGfuU 
                 1253 
                 AAUAAacUCcaGG 
                 1254 
                 AD-15122 
               
               
                 3548 
                 fuAfuUfTsT 
                   
                 CCUaugTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CfAUfAGGCfCfUfGGAGUfUf 
                 1255 
                 AAUAAacUCcaGG 
                 1256 
                 AD-15132 
               
               
                 3548 
                 UfAUfUfTsT 
                   
                 CCUaugTsT 
                   
                   
               
               
                   
               
               
                 3530- 
                 CaUaGgCcUgGaGuUuAuUTsT 
                 1257 
                 AAUAAacUCcaGG 
                 1258 
                 AD-15142 
               
               
                 3548 
                   
                   
                 CCUaugTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UCUAGACCUGUUUUGCUUUTsT 
                 1259 
                 AAAGCAAAACAGG 
                 1260 
                 AD-9553 
               
               
                 3549 
                   
                   
                 UCUAGATsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 ucuAGAccuGuuuuGcuuuTsT 
                 1261 
                 AAAGcAAAAcAGG 
                 1262 
                 AD-9679 
               
               
                 3549 
                   
                   
                 UCuAGATsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfcUfaGfaCfcUfgUfuUfuG 
                 1263 
                 P*aAfaGfcAfaA 
                 1264 
                 AD-14675 
               
               
                 3549 
                 fcUfuUfTsT 
                   
                 faCfaGfgUfcUf 
                   
                   
               
               
                   
                   
                   
                 aGfaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfCfUfAGACfCfUfGUfUfUf 
                 1265 
                 AAAGCfAAAACfA 
                 1266 
                 AD-14685 
               
               
                 3549 
                 UfGCfUfUfUfTsT 
                   
                 GGUfCfUfAGATs 
                   
                   
               
               
                   
                   
                   
                 T 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcUaGaCcUgUuUuGcUuUTsT 
                 1267 
                 P*aAfaGfcAfaA 
                 1268 
                 AD-14695 
               
               
                 3549 
                   
                   
                 faCfaGfgUfcUf 
                   
                   
               
               
                   
                   
                   
                 aGfaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcUaGaCcUgUuUuGcUuUTsT 
                 1269 
                 AAAGCfAAAACfA 
                 1270 
                 AD-14705 
               
               
                 3549 
                   
                   
                 GGUfCfUfAGATs 
                   
                   
               
               
                   
                   
                   
                 T 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfcUfaGfaCfcUfgUfuUfuG 
                 1271 
                 AAAGCaaAAcaGG 
                 1272 
                 AD-14715 
               
               
                 3549 
                 fcUfuUfTsT 
                   
                 UCUagaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfCfUfAGACfCfUfGUfUfUf 
                 1273 
                 AAAGCaaAAcaGG 
                 1274 
                 AD-14725 
               
               
                 3549 
                 UfGCfUfUfUfTsT 
                   
                 UCUagaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcUaGaCcUgUuUuGcUuUTsT 
                 1275 
                 AAAGCaaAAcaGG 
                 1276 
                 AD-14735 
               
               
                 3549 
                   
                   
                 UCUagaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfcAfuAfgGfcCfuGfgAfgU 
                 1277 
                 P*aUfaAfaCfuC 
                 1278 
                 AD-15081 
               
               
                 3549 
                 fuUfaUfTsT 
                   
                 fcAfgGfcCfuAf 
                   
                   
               
               
                   
                   
                   
                 uGfaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfCfAUfAGGCfCfUfGGAGUf 
                 1297 
                 AUfAAACfUfCfC 
                 1280 
                 AD-15091 
               
               
                 3549 
                 UfUfAUfTsT 
                   
                 fAGGCfCfUfAUf 
                   
                   
               
               
                   
                   
                   
                 GATsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcAuAgGcCuGgAgUuUaUTsT 
                 1281 
                 P*aUfaAfaCfuC 
                 1282 
                 AD-15101 
               
               
                 3549 
                   
                   
                 fcAfgGfcCfuAf 
                   
                   
               
               
                   
                   
                   
                 uGfaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcAuAgGcCuGgAgUuUaUTsT 
                 1283 
                 AUfAAACfUfCfC 
                 1284 
                 AD-15111 
               
               
                 3549 
                   
                   
                 fAGGCfCfUfAUf 
                   
                   
               
               
                   
                   
                   
                 GATsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfcAfuAfgGfcCfuGfgAfgU 
                 1285 
                 AUAAAcuCCagGC 
                 1286 
                 AD-15121 
               
               
                 3549 
                 fuUfaUfTsT 
                   
                 CUAugaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UfCfAUfAGGCfCfUfGGAGUf 
                 1287 
                 AUAAAcuCCagGC 
                 1288 
                 AD-15131 
               
               
                 3549 
                 UfUfAUfTsT 
                   
                 CUAugaTsT 
                   
                   
               
               
                   
               
               
                 3531- 
                 UcAuAgGcCuGgAgUuUaUTsT 
                 1289 
                 AUAAAcuCCagGC 
                 1290 
                 AD-15141 
               
               
                 3549 
                   
                   
                 CUAugaTsT 
                   
                   
               
               
                   
               
               
                 3557- 
                 UGAAGAUAUUUAUUCUGGGTsT 
                 1291 
                 CCCAGAAUAAAUA 
                 1292 
                 AD-9626 
               
               
                 3575 
                   
                   
                 UCUUCATsT 
                   
                   
               
               
                   
               
               
                 3557- 
                 uGAAGAuAuuuAuucuGGGTsT 
                 1293 
                 CCcAGAAuAAAuA 
                 1294 
                 AD-9752 
               
               
                 3575 
                   
                   
                 UCUUcATsT 
                   
                   
               
               
                   
               
               
                 3570- 
                 UCUGGGUUUUGUAGCAUUUTsT 
                 1295 
                 AAAUGCUACAAAA 
                 1296 
                 AD-9629 
               
               
                 3588 
                   
                   
                 CCCAGATsT 
                   
                   
               
               
                   
               
               
                 3570- 
                 ucuGGGuuuuGuAGcAuuuTsT 
                 1297 
                 AAAUGCuAcAAAA 
                 1298 
                 AD-9755 
               
               
                 3588 
                   
                   
                 CCcAGATsT 
                   
                   
               
               
                   
               
               
                 3613- 
                 AUAAAAACAAACAAACGUUTT 
                 1299 
                 AACGUUUGUUUGU 
                 1300 
                 AD-15412 
               
               
                 3631 
                   
                   
                 UUUUAUTT 
                   
                   
               
               
                   
               
               
                 3617- 
                 AAACAAACAAACGUUGUCCTT 
                 1301 
                 GGACAACGUUUGU 
                 1302 
                 AD-15211 
               
               
                 3635 
                   
                   
                 UUGUUUTT 
                   
                   
               
               
                   
               
               
                 3618- 
                 AACAAACAAACGUUGUCCUTT 
                 1303 
                 AGGACAACGUUUG 
                 1304 
                 AD-15300 
               
               
                 3636 
                   
                   
                 UUUGUUTT 
               
               
                   
               
               
                 *Target: target in human PCSK9 gene, access. 
               
               
                 # NM_174936 
               
               
                 U, C, A, G: corresponding ribonucleotide; 
               
               
                 T: deoxythymidine; 
               
               
                 u, c, a, g: corresponding 2′-O-methyl ribonucleotide; 
               
               
                 Uf, Cf, Af, Gf: corresponding 2′-deoxy-2′-fluoro ribonucleotide; 
               
               
                 where nucleotides are written in sequence, they are connected by 3′-5′ phosphodiester groups; 
               
               
                 nucleotides with interjected “s” are connected by 3′-O-5′-O phosphorothiodiester groups; 
               
               
                 unless denoted by prefix “P*”, oligonucleotides are devoid of a 5′-phosphate group on the 5′-most nucleotide; 
               
               
                 all oligonucleotides bear 3′-OH on the 3′-most nucleotide. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Sequences of modified dsRNA targeted to PCSK9 
               
               
                 U, C, A, G: corresponding ribonucleotide; T: deoxythymidine; u, c, a, g: 
               
               
                 corresponding 2′-O-methyl ribonucleotide; Uf, Cf, Af, Gf: corresponding 2′-deoxy- 
               
               
                 2′-fluoro ribonucleotide; where nucleotides are written in sequence, they are 
               
               
                 connected by 3′-5′ phosphodiester groups; nucleotides with interjected “s” are 
               
               
                 connected by 3′-O-5′-O phosphorothiodiester groups; unless denoted by prefix “P*”,  
               
               
                 oligonucleotides are devoid of a 5′-phosphate group on the 5′-most nucleotide; all 
               
               
                 oligonucleotides bear 3′-OH on the 3′-most nucleotide. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sense strand sequence  
                 SEQ ID 
                 Antisense-strand 
                 SEQ ID 
               
               
                 Duplex # 
                 (5′-3′) 1   
                 NO: 
                 sequence (5′-3′) 1   
                 NO: 
               
               
                   
               
               
                 AD-10792 
                 GccuGGAGuuuAuucGGAATsT 
                 1305 
                 UUCCGAAuAAACUCcAGGCT 
                 1306 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-10793 
                 GccuGGAGuuuAuucGGAATsT 
                 1307 
                 uUcCGAAuAAACUccAGGCT 
                 1308 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-10796 
                 GccuGGAGuuuAuucGGAATsT 
                 1309 
                 UUCCGAAUAAACUCCAGGCT 
                 1310 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12038 
                 GccuGGAGuuuAuucGGAATsT 
                 1311 
                 uUCCGAAUAAACUCCAGGCT 
                 1312 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12039 
                 GccuGGAGuuuAuucGGAATsT 
                 1313 
                 UuCCGAAUAAACUCCAGGCT 
                 1314 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12040 
                 GccuGGAGuuuAuucGGAATsT 
                 1315 
                 UUcCGAAUAAACUCCAGGCT 
                 1316 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12041 
                 GccuGGAGuuuAuucGGAATsT 
                 1317 
                 UUCcGAAUAAACUCCAGGCT 
                 1318 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12042 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1319 
                 uUCCGAAUAAACUCCAGGCT 
                 1320 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12043 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1321 
                 UuCCGAAUAAACUCCAGGCT 
                 1322 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12044 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1323 
                 UUcCGAAUAAACUCCAGGCT 
                 1324 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12045 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1325 
                 UUCcGAAUAAACUCCAGGCT 
                 1326 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12046 
                 GccuGGAGuuuAuucGGAA 
                 1327 
                 UUCCGAAUAAACUCCAGGCs 
                 1328 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12047 
                 GccuGGAGuuuAuucGGAAA 
                 1329 
                 UUUCCGAAUAAACUCCAGGC 
                 1330 
               
               
                   
                   
                   
                 scsu 
                   
               
               
                   
               
               
                 AD-12048 
                 GccuGGAGuuuAuucGGAAAA 
                 1331 
                 UUUUCCGAAUAAACUCCAGG 
                 1332 
               
               
                   
                   
                   
                 Cscsu 
                   
               
               
                   
               
               
                 AD-12049 
                 GccuGGAGuuuAuucGGAAAAG 
                 1333 
                 CUUUUCCGAAUAAACUCCAG 
                 1334 
               
               
                   
                   
                   
                 GCscsu 
                   
               
               
                   
               
               
                 AD-12050 
                 GccuGGAGuuuAuucGGAATTab 
                 1335 
                 UUCCGAAUAAACUCCAGGCT 
                 1336 
               
               
                   
                   
                   
                 Tab 
                   
               
               
                   
               
               
                 AD-12051 
                 GccuGGAGuuuAuucGGAAATTab 
                 1337 
                 UUUCCGAAuAAACUCCAGGC 
                 1338 
               
               
                   
                   
                   
                 TTab 
                   
               
               
                   
               
               
                 AD-12052 
                 GccuGGAGuuuAuucGGAAAATTab 
                 1339 
                 UUUUCCGAAUAAACUCCAGG 
                 1340 
               
               
                   
                   
                   
                 CTTab 
                   
               
               
                   
               
               
                 AD-12053 
                 GccuGGAGuuuAuucGGAAAAGTTab 
                 1341 
                 CUUUUCCGAAUAAACUCCAG 
                 1342 
               
               
                   
                   
                   
                 GCTTab 
                   
               
               
                   
               
               
                 AD-12054 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1343 
                 UUCCGAAUAAACUCCAGGCs 
                 1344 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12055 
                 GccuGGAGuuuAuucGGAATsT 
                 1345 
                 UUCCGAAUAAACUCCAGGCs 
                 1346 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12056 
                 GcCuGgAgUuUaUuCgGaA 
                 1347 
                 UUCCGAAUAAACUCCAGGCT 
                 1348 
               
               
                   
                   
                   
                 Tab 
                   
               
               
                   
               
               
                 AD-12057 
                 GcCuGgAgUuUaUuCgGaA 
                 1349 
                 UUCCGAAUAAACUCCAGGCT 
                 1350 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12058 
                 GcCuGgAgUuUaUuCgGaA 
                 1351 
                 UUCCGAAuAAACUCcAGGCT 
                 1352 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12059 
                 GcCuGgAgUuUaUuCgGaA 
                 1353 
                 uUcCGAAuAAACUccAGGCT 
                 1354 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12060 
                 GcCuGgAgUuUaUuCgGaA 
                 1355 
                 UUCCGaaUAaaCUCCAggc 
                 1356 
               
               
                   
               
               
                 AD-12061 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1357 
                 UUCCGaaUAaaCUCCAggcT 
                 1358 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12062 
                 GcCuGgAgUuUaUuCgGaATTab 
                 1359 
                 UUCCGaaUAaaCUCCAggcT 
                 1360 
               
               
                   
                   
                   
                 Tab 
                   
               
               
                   
               
               
                 AD-12063 
                 GcCuGgAgUuUaUuCgGaA 
                 1361 
                 UUCCGaaUAaaCUCCAggcs 
                 1362 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12064 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1363 
                 UUCCGAAuAAACUCcAGGCT 
                 1364 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12065 
                 GcCuGgAgUuUaUuCgGaATTab 
                 1365 
                 UUCCGAAuAAACUCcAGGCT 
                 1366 
               
               
                   
                   
                   
                 Tab 
                   
               
               
                   
               
               
                 AD-12066 
                 GcCuGgAgUuUaUuCgGaA 
                 1367 
                 UUCCGAAuAAACUCcAGGCs 
                 1368 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12067 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1369 
                 UUCCGAAUAAACUCCAGGCT 
                 1370 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12068 
                 GcCuGgAgUuUaUuCgGaATTab 
                 1371 
                 UUCCGAAUAAACUCCAGGCT 
                 1372 
               
               
                   
                   
                   
                 Tab 
                   
               
               
                   
               
               
                 AD-12069 
                 GcCuGgAgUuUaUuCgGaA 
                 1373 
                 UUCCGAAUAAACUCCAGGCs 
                 1374 
               
               
                   
                   
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12338 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1375 
                 P*uUfcCfgAfaUfaAfaCf 
                 1376 
               
               
                   
                 f 
                   
                 uCfcAfgGfc 
                   
               
               
                   
               
               
                 AD-12339 
                 GcCuGgAgUuUaUuCgGaA 
                 1377 
                 P*uUfcCfgAfaUfaAfaCf 
                 1378 
               
               
                   
                   
                   
                 uCfcAfgGfc 
                   
               
               
                   
               
               
                 AD-12340 
                 GccuGGAGuuuAuucGGAA 
                 1379 
                 P*uUfcCfgAfaUfaAfaCf 
                 1380 
               
               
                   
                   
                   
                 uCfcAfgGfc 
                   
               
               
                   
               
               
                 AD-12341 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1381 
                 P*uUfcCfgAfaUfaAfaCf 
                 1382 
               
               
                   
                 fTsT 
                   
                 uCfcAfgGfcTsT 
                   
               
               
                   
               
               
                 AD-12342 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1383 
                 UUCCGAAuAAACUCcAGGCT 
                 1384 
               
               
                   
                 fTsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12343 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1385 
                 uUcCGAAuAAACUccAGGCT 
                 1386 
               
               
                   
                 fTsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12344 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1387 
                 UUCCGAAUAAACUCCAGGCT 
                 1388 
               
               
                   
                 fTsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12345 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1389 
                 UUCCGAAUAAACUCCAGGCs 
                 1390 
               
               
                   
                 fTsT 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12346 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1391 
                 UUCCGaaUAaaCUCCAggcs 
                 1392 
               
               
                   
                 fTsT 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12347 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1393 
                 P*uUfcCfgAfaUfaAfaCf 
                 1394 
               
               
                   
                   
                   
                 uCfcAfgGfcTsT 
                   
               
               
                   
               
               
                 AD-12348 
                 GccuGGAGuuuAuucGGAATsT 
                 1395 
                 P*uUfcCfgAfaUfaAfaCf 
                 1396 
               
               
                   
                   
                   
                 uCfcAfgGfcTsT 
                   
               
               
                   
               
               
                 AD-12349 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1397 
                 P*uUfcCfgAfaUfaAfaCf 
                 1398 
               
               
                   
                   
                   
                 uCfcAfgGfcTsT 
                   
               
               
                   
               
               
                 AD-12350 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1399 
                 P*uUfcCfgAfaUfaAfaCf 
                 1400 
               
               
                   
                 fTTab 
                   
                 uCfcAfgGfcTTab 
                   
               
               
                   
               
               
                 AD-12351 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1401 
                 P*uUfcCfgAfaUfaAfaCf 
                 1402 
               
               
                   
                 f 
                   
                 uCfcAfgGfcsCfsu 
                   
               
               
                   
               
               
                 AD-12352 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1403 
                 UUCCGaaUAaaCUCCAggcs 
                 1404 
               
               
                   
                 f 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12354 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1405 
                 UUCCGAAUAAACUCCAGGCs 
                 1406 
               
               
                   
                 f 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12355 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1407 
                 UUCCGAAuAAACUCcAGGCT 
                 1408 
               
               
                   
                 f 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12356 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1409 
                 uUcCGAAuAAACUccAGGCT 
                 1410 
               
               
                   
                 f 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12357 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1411 
                 UUCCGaaUAaaCUCCAggc 
                 1412 
               
               
                   
                 uCmogGmoaA 
                   
                   
                   
               
               
                   
               
               
                 AD-12358 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1413 
                 P*uUfcCfgAfaUfaAfaCf 
                 1414 
               
               
                   
                 uCmogGmoaA 
                   
                 uCfcAfgGfc 
                   
               
               
                   
               
               
                 AD-12359 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1415 
                 P*uUfcCfgAfaUfaAfaCf 
                 1416 
               
               
                   
                 uCmogGmoaA 
                   
                 uCfcAfgGfcsCfsu 
                   
               
               
                   
               
               
                 AD-12360 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1417 
                 UUCCGAAUAAACUCCAGGCs 
                 1418 
               
               
                   
                 uCmogGmoaA 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12361 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1419 
                 UUCCGAAuAAACUCcAGGCT 
                 1420 
               
               
                   
                 uCmogGmoaA 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12362 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1421 
                 uUcCGAAuAAACUccAGGCT 
                 1422 
               
               
                   
                 uCmogGmoaA 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12363 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1423 
                 UUCCGaaUAaaCUCCAggcs 
                 1424 
               
               
                   
                 uCmogGmoaA 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12364 
                 GmocCmouGmogAmogUmouUmoaUmou 
                 1425 
                 UUCCGaaUAaaCUCCAggcT 
                 1426 
               
               
                   
                 CmogGmoaATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12365 
                 GmocCmouGmogAmogUmouUmoaUmou 
                 1427 
                 UUCCGAAuAAACUCcAGGCT 
                 1428 
               
               
                   
                 CmogGmoaATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12366 
                 GmocCmouGmogAmogUmouUmoaUmou 
                 1429 
                 UUCCGAAUAAACUCCAGGCT 
                 1430 
               
               
                   
                 CmogGmoaATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12367 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1431 
                 UUCCGaaUAaaCUCCAggcT 
                 1432 
               
               
                   
                 oumocGGAATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12368 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1433 
                 UUCCGAAuAAACUCcAGGCT 
                 1434 
               
               
                   
                 oumocGGAATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12369 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1435 
                 UUCCGAAUAAACUCCAGGCT 
                 1436 
               
               
                   
                 oumocGGAATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12370 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1437 
                 P*UfUfCfCfGAAUfAAACf 
                 1438 
               
               
                   
                 oumocGGAATsT 
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12371 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1439 
                 P*UfUfCfCfGAAUfAAACf 
                 1440 
               
               
                   
                 oumocGGAATsT 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12372 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1441 
                 P*uUfcCfgAfaUfaAfaCf 
                 1442 
               
               
                   
                 oumocGGAATsT 
                   
                 uCfcAfgGfcsCfsu 
                   
               
               
                   
               
               
                 AD-12373 
                 GmocmocmouGGAGmoumoumouAmoum 
                 1443 
                 UUCCGAAUAAACUCCAGGCT 
                 1444 
               
               
                   
                 oumocGGAATsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12374 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1445 
                 UfUfCfCfGAAUfAAACfUf 
                 1446 
               
               
                   
                 TsT 
                   
                 CfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12375 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1447 
                 UUCCGAAUAAACUCCAGGCT 
                 1448 
               
               
                   
                 TsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12377 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1449 
                 uUcCGAAuAAACUccAGGCT 
                 1450 
               
               
                   
                 TsT 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12378 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1451 
                 UUCCGaaUAaaCUCCAggcs 
                 1452 
               
               
                   
                 TsT 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12379 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1453 
                 UUCCGAAUAAACUCCAGGCs 
                 1454 
               
               
                   
                 TsT 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12380 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1455 
                 P*uUfcCfgAfaUfaAfaCf 
                 1456 
               
               
                   
                 TsT 
                   
                 uCfcAfgGfcsCfsu 
                   
               
               
                   
               
               
                 AD-12381 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1457 
                 P*uUfcCfgAfaUfaAfaCf 
                 1458 
               
               
                   
                 TsT 
                   
                 uCfcAfgGfcTsT 
                   
               
               
                   
               
               
                 AD-12382 
                 GCfCfUfGGAGUfUfUfAUfUfCfGGAA 
                 1459 
                 P*UfUfCfCfGAAUfAAACf 
                 1460 
               
               
                   
                 TsT 
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12383 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1461 
                 P*UfUfCfCfGAAUfAAACf 
                 1462 
               
               
                   
                   
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12384 
                 GccuGGAGuuuAuucGGAATsT 
                 1463 
                 P*UfUfCfCfGAAUfAAACf 
                 1464 
               
               
                   
                   
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12385 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1465 
                 P*UfUfCfCfGAAUfAAACf 
                 1466 
               
               
                   
                   
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12386 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1467 
                 P*UfUfCfCfGAAUfAAACf 
                 1468 
               
               
                   
                 f 
                   
                 UfCfCfAGGCfTsT 
                   
               
               
                   
               
               
                 AD-12387 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1469 
                 UfUfCfCfGAAUfAAACfUf 
                 1470 
               
               
                   
                 A 
                   
                 CfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12388 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1471 
                 P*uUfcCfgAfaUfaAfaCf 
                 1472 
               
               
                   
                 A 
                   
                 uCfcAfgGfc 
                   
               
               
                   
               
               
                 AD-12389 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1473 
                 P*uUfcCfgAfaUfaAfaCf 
                 1474 
               
               
                   
                 A 
                   
                 uCfcAfgGfcsCfsu 
                   
               
               
                   
               
               
                 AD-12390 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1475 
                 UUCCGAAUAAACUCCAGGCs 
                 1476 
               
               
                   
                 A 
                   
                 csu 
                   
               
               
                   
               
               
                 AD-12391 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1477 
                 UUCCGaaUAaaCUCCAggc 
                 1478 
               
               
                   
                 A 
                   
                   
                   
               
               
                   
               
               
                 AD-12392 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1479 
                 UUCCGAAUAAACUCCAGGCT 
                 1480 
               
               
                   
                 A 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12393 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1481 
                 UUCCGAAuAAACUCcAGGCT 
                 1482 
               
               
                   
                 A 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12394 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1483 
                 uUcCGAAuAAACUccAGGCT 
                 1484 
               
               
                   
                 A 
                   
                 sT 
                   
               
               
                   
               
               
                 AD-12395 
                 GmocCmouGmogAmogUmouUmoaUmou 
                 1485 
                 P*UfUfCfCfGAAUfAAACf 
                 1486 
               
               
                   
                 CmogGmoaATsT 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12396 
                 GmocCmouGmogAm02gUmouUmoaUmo 
                 1487 
                 P*UfUfCfCfGAAUfAAACf 
                 1488 
               
               
                   
                 uCmogGmoaA 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12397 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1489 
                 P*UfUfCfCfGAAUfAAACf 
                 1490 
               
               
                   
                 f 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12398 
                 GfcCfuGfgAfgUfuUfaUfuCfgGfaA 
                 1491 
                 P*UfUfCfCfGAAUfAAACf 
                 1492 
               
               
                   
                 fTsT 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12399 
                 GcCuGgnAgUuUaUuCgGaATsT 
                 1493 
                 P*UfUfCfCfGAAUfAAACf 
                 1494 
               
               
                   
                   
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12400 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1495 
                 P*UfUfCfCfGAAUfAAACf 
                 1496 
               
               
                   
                   
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12401 
                 GccuGGAGuuuAuucGGAATsT 
                 1497 
                 P*UfUfCfCfGAAUfAAACf 
                 1498 
               
               
                   
                   
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12402 
                 GccuGGAGuuuAuucGGAA 
                 1499 
                 P*UfUfCfCfGAAUfAAACf 
                 1500 
               
               
                   
                   
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-12403 
                 GCfCfUfGGAGGUfUfUfAUfUfCfGGA 
                 1501 
                 P*UfUfCfCfGAAUfAAACf 
                 1502 
               
               
                   
                 A 
                   
                 UfCfCfAGGCfsCfsUf 
                   
               
               
                   
               
               
                 AD-9314 
                 GCCUGGAGUUUAUUCGGAATsT 
                 1503 
                 UUCCGAAUAAACUCCAGGCT 
                 1504 
               
               
                   
                   
                   
                 sT 
                   
               
               
                   
               
               
                 AD-10794 
                 ucAuAGGccuGGAGuuuAudTsdT 
                 1525 
                 AuAAACUCcAGGCCuAUGAd 
                 1526 
               
               
                   
                   
                   
                 TsdT 
                   
               
               
                   
               
               
                 AD-10795 
                 ucAuAGGccuGGAGuuuAudTsdT 
                 1527 
                 AuAAACUccAGGcCuAuGAd 
                 1528 
               
               
                   
                   
                   
                 TsdT 
                   
               
               
                   
               
               
                 AD-10797 
                 ucAuAGGccuGGAGuuuAudTsdT 
                 1529 
                 AUAAACUCCAGGCCUAUGAd 
                 1530 
               
               
                   
                   
                   
                 TsdT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 dsRNA targeted to PCSK9: mismatches and modifications 
               
               
                 Strand: S/Sense; AS/Antisense; U, C, A, G: corresponding ribonucleotide; 
               
               
                 T: deoxythymidine; u, c, a, g: corresponding 2′-O-methyl ribonucleotide; 
               
               
                 Uf, Cf, Af, Gf: corresponding 2′-deoxy-2′-fluoro ribonucleotide; Y1 
               
               
                 corresponds to DFT difluorotoluyl ribo(or deoxyribo)nucleotide; where 
               
               
                 nucleotides are written in sequence, they are connected by 3′-5′ phospho- 
               
               
                 diester groups; nucleotides with interjected “s” are connected by 3′-  
               
               
                 O-5′-O phosphorothiodiester groups; unless denoted by prefix “P*”, 
               
               
                 oligonucleotides are devoid of a 5′-phosphate group on the 5′-most 
               
               
                 nucleotide; all oligonucleotides bear 3′-OH on the 3′-most nucleotide 
               
            
           
           
               
               
               
               
            
               
                 Duplex # 
                 Strand 
                 SEQ ID NO: 
                 Sequence (5′ to 3′) 
               
               
                   
               
               
                 AD-9680 
                 S 
                 1531 
                 uucuAGAccuGuuuuGcuudTsdT 
               
               
                   
                 AS 
                 1532 
                 AAGcAAAAcAGGUCuAGAAdTsdT 
               
               
                   
               
               
                 AD-3267 
                 S 
                 1535 
                 uucuAGAcCuGuuuuGcuuTsT 
               
               
                   
                 AS 
                 1536 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3268 
                 S 
                 1537 
                 uucuAGAccUGuuuuGcuuTsT 
               
               
                   
                 AS 
                 1538 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3269 
                 S 
                 1539 
                 uucuAGAcCUGuuuuGcuuTsT 
               
               
                   
                 AS 
                 1540 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3270 
                 S 
                 1541 
                 uucuAGAcY1uGuuuuGcuuTsT 
               
               
                   
                 AS 
                 1542 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3271 
                 S 
                 1543 
                 uucuAGAcY1UGuuuuGcuuTsT 
               
               
                   
                 AS 
                 1544 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3272 
                 S 
                 1545 
                 uucuAGAccY1GuuuuGcuuTsT 
               
               
                   
                 AS 
                 1546 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3273 
                 S 
                 1547 
                 uucuAGAcCY1GuuuuGcuuTsT 
               
               
                   
                 AS 
                 1548 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3274 
                 S 
                 1549 
                 uucuAGAccuY1uuuuGcuuTsT 
               
               
                   
                 AS 
                 1550 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-3275 
                 S 
                 1551 
                 uucuAGAcCUY1uuuuGcuuTsT 
               
               
                   
                 AS 
                 1552 
                 AAGcAAAAcAGGUCuAGAATsT 
               
               
                   
               
               
                 AD-14676 
                 S 
                 1553 
                 UfuCfuAfgAfcCfuGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1554 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3276 
                 S 
                 1555 
                 UfuCfuAfgAfcCuGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1556 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3277 
                 S 
                 1557 
                 UfuCfuAfgAfcCfUGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1558 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3278 
                 S 
                 1559 
                 UfuCfuAfgAfcCUGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1560 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3279 
                 S 
                 1561 
                 UfuCfuAfgAfcY1uGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1562 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3280 
                 S 
                 1563 
                 UfuCfuAfgAfcY1UGfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1564 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3281 
                 S 
                 1565 
                 UfuCfuAfgAfcCfY1GfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1566 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3282 
                 S 
                 1567 
                 UfuCfuAfgAfcCY1GfuUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1568 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3283 
                 S 
                 1569 
                 UfuCfuAfgAfcCfuY1uUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1570 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-3284 
                 S 
                 1571 
                 UfuCfuAfgAfcCUY1uUfuUfgCfuUfTsT 
               
               
                   
                 AS 
                 1572 
                 P*aAfgCfaAfaAfcAfgGfuCfuAfgAfaTsT 
               
               
                   
               
               
                 AD-10792 
                 S 
                 459 
                 GccuGGAGuuuAuucGGAATsT 
               
               
                   
                 AS 
                 460 
                 UUCCGAAuAAACUCcAGGCTsT 
               
               
                   
               
               
                 AD-3254 
                 S 
                 1573 
                 GccuGGAGuY1uAuucGGAATsT 
               
               
                   
                 AS 
                 1574 
                 UUCCGAAuAAACUCcAGGCTsT 
               
               
                   
               
               
                 AD-3255 
                 S 
                 1575 
                 GccuGGAGUY1uAuucGGAATsT 
               
               
                   
                 AS 
                 1576 
                 UUCCGAAuAAACUCcAGGCTsT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Sequences of unmodified siRNA flanking AD-9680 
               
               
                 *Target: target in human PCSK9 gene, access. # NM_174936 U, C, A, G: 
               
               
                 corresponding ribonucleotide; dT: deoxythymidine; where nucleotides 
               
               
                 are written in sequence, they are connected by 3′-5′ phosphodiester 
               
               
                 groups; nucleotides with interjected “s” are connected by 3′-O-5′-O 
               
               
                 phosphorothiodiester groups. 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex # 
                 Strand 
                 Sequence (5′ to 3′) 
                 *Target 
                 SEQ ID NO: 
               
               
                   
               
               
                 AD-22169-b1 
                 sense 
                 CAGCCAACUUUUCUAGACCdTsdT 
                 3520 
                 1577 
               
               
                   
                 antis 
                 GGUCUAGAAAAGUUGGCUGdTsdT 
                 3520 
                 1578 
               
               
                   
               
               
                 AD-22170-b1 
                 sense 
                 AGCCAACUUUUCUAGACCUdTsdT 
                 3521 
                 1579 
               
               
                   
                 antis 
                 AGGUCUAGAAAAGUUGGCUdTsdT 
                 3521 
                 1580 
               
               
                   
               
               
                 AD-22171-b1 
                 sense 
                 GCCAACUUUUCUAGACCUGdTsdT 
                 3522 
                 1581 
               
               
                   
                 antis 
                 CAGGUCUAGAAAAGUUGGCdTsdT 
                 3522 
                 1582 
               
               
                   
               
               
                 AD-22172-b1 
                 sense 
                 CCAACUUUUCUAGACCUGUdTsdT 
                 3523 
                 1583 
               
               
                   
                 antis 
                 ACAGGUCUAGAAAAGUUGGdTsdT 
                 3523 
                 1584 
               
               
                   
               
               
                 AD-22173-b1 
                 sense 
                 CAACUUUUCUAGACCUGUUdTsdT 
                 3524 
                 1585 
               
               
                   
                 antis 
                 AACAGGUCUAGAAAAGUUGdTsdT 
                 3524 
                 1586 
               
               
                   
               
               
                 AD-22174-b1 
                 sense 
                 AACUUUUCUAGACCUGUUUdTsdT 
                 3525 
                 1587 
               
               
                   
                 antis 
                 AAACAGGUCUAGAAAAGUUdTsdT 
                 3525 
                 1588 
               
               
                   
               
               
                 AD-22175-b1 
                 sense 
                 ACUUUUCUAGACCUGUUUUdTsdT 
                 3526 
                 1589 
               
               
                   
                 antis 
                 AAAACAGGUCUAGAAAAGUdTsdT 
                 3526 
                 1590 
               
               
                   
               
               
                 AD-22176-b1 
                 sense 
                 CUUUUCUAGACCUGUUUUGdTsdT 
                 3527 
                 1591 
               
               
                   
                 antis 
                 CAAAACAGGUCUAGAAAAGdTsdT 
                 3527 
                 1592 
               
               
                   
               
               
                 AD-22177-b1 
                 sense 
                 UUUUCUAGACCUGUUUUGCdTsdT 
                 3528 
                 1593 
               
               
                   
                 antis 
                 GCAAAACAGGUCUAGAAAAdTsdT 
                 3528 
                 1594 
               
               
                   
               
               
                 AD-22178-b1 
                 sense 
                 UUUCUAGACCUGUUUUGCUdTsdT 
                 3529 
                 1595 
               
               
                   
                 antis 
                 AGCAAAACAGGUCUAGAAAdTsdT 
                 3529 
                 1596 
               
               
                   
               
               
                 AD-22179-b1 
                 sense 
                 UCUAGACCUGUUUUGCUUUdTsdT 
                 3531 
                 1597 
               
               
                   
                 antis 
                 AAAGCAAAACAGGUCUAGAdTsdT 
                 3531 
                 1598 
               
               
                   
               
               
                 AD-22180-b1 
                 sense 
                 CUAGACCUGUUUUGCUUUUdTsdT 
                 3532 
                 1599 
               
               
                   
                 antis 
                 AAAAGCAAAACAGGUCUAGdTsdT 
                 3532 
                 1600 
               
               
                   
               
               
                 AD-22181-b1 
                 sense 
                 UAGACCUGUUUUGCUUUUGdTsdT 
                 3533 
                 1601 
               
               
                   
                 antis 
                 CAAAAGCAAAACAGGUCUAdTsdT 
                 3533 
                 1602 
               
               
                   
               
               
                 AD-22182-b1 
                 sense 
                 AGACCUGUUUUGCUUUUGUdTsdT 
                 3534 
                 1603 
               
               
                   
                 antis 
                 ACAAAAGCAAAACAGGUCUdTsdT 
                 3534 
                 1604 
               
               
                   
               
               
                 AD-22183-b1 
                 sense 
                 GACCUGUUUUGCUUUUGUAdTsdT 
                 3535 
                 1605 
               
               
                   
                 antis 
                 UACAAAAGCAAAACAGGUCdTsdT 
                 3535 
                 1606 
               
               
                   
               
               
                 AD-22184-b1 
                 sense 
                 ACCUGUUUUGCUUUUGUAAdTsdT 
                 3536 
                 1607 
               
               
                   
                 antis 
                 UUACAAAAGCAAAACAGGUdTsdT 
                 3536 
                 1608 
               
               
                   
               
               
                 AD-22185-b1 
                 sense 
                 CCUGUUUUGCUUUUGUAACdTsdT 
                 3537 
                 1609 
               
               
                   
                 antis 
                 GUUACAAAAGCAAAACAGGdTsdT 
                 3537 
                 1610 
               
               
                   
               
               
                 AD-22186-b1 
                 sense 
                 CUGUUUUGCUUUUGUAACUdTsdT 
                 3538 
                 1611 
               
               
                   
                 antis 
                 AGUUACAAAAGCAAAACAGdTsdT 
                 3538 
                 1612 
               
               
                   
               
               
                 AD-22187-b1 
                 sense 
                 UGUUUUGCUUUUGUAACUUdTsdT 
                 3539 
                 1613 
               
               
                   
                 antis 
                 AAGUUACAAAAGCAAAACAdTsdT 
                 3539 
                 1614 
               
               
                   
               
               
                 AD-22188-b1 
                 sense 
                 GUUUUGCUUUUGUAACUUGdTsdT 
                 3540 
                 1615 
               
               
                   
                 antis 
                 CAAGUUACAAAAGCAAAACdTsdT 
                 3540 
                 1616 
               
               
                   
               
               
                 AD-22189-b1 
                 sense 
                 UUUUGCUUUUGUAACUUGAdTsdT 
                 3541 
                 1617 
               
               
                   
                 antis 
                 UCAAGUUACAAAAGCAAAAdTsdT 
                 3541 
                 1618 
               
               
                   
               
               
                 AD-22190-b1 
                 sense 
                 UUUGCUUUUGUAACUUGAAdTsdT 
                 3542 
                 1619 
               
               
                   
                 antis 
                 UUCAAGUUACAAAAGCAAAdTsdT 
                 3542 
                 1620 
               
               
                   
               
               
                 AD-22191-b1 
                 sense 
                 UUGCUUUUGUAACUUGAAGdTsdT 
                 3543 
                 1621 
               
               
                   
                 antis 
                 CUUCAAGUUACAAAAGCAAdTsdT 
                 3543 
                 1622 
               
               
                   
               
               
                 AD-22192-b1 
                 sense 
                 UGCUUUUGUAACUUGAAGAdTsdT 
                 3544 
                 1623 
               
               
                   
                 antis 
                 UCUUCAAGUUACAAAAGCAdTsdT 
                 3544 
                 1624 
               
               
                   
               
               
                 AD-22193-b1 
                 sense 
                 GCUUUUGUAACUUGAAGAUdTsdT 
                 3545 
                 1625 
               
               
                   
                 antis 
                 AUCUUCAAGUUACAAAAGCdTsdT 
                 3545 
                 1626 
               
               
                   
               
               
                 AD-22194-b1 
                 sense 
                 CUUUUGUAACUUGAAGAUAdTsdT 
                 3546 
                 1627 
               
               
                   
                 antis 
                 UAUCUUCAAGUUACAAAAGdTsdT 
                 3546 
                 1628 
               
               
                   
               
               
                 AD-22195-b1 
                 sense 
                 UUUUGUAACUUGAAGAUAUdTsdT 
                 3547 
                 1629 
               
               
                   
                 antis 
                 AUAUCUUCAAGUUACAAAAdTsdT 
                 3547 
                 1630 
               
               
                   
               
               
                 AD-22196-b1 
                 sense 
                 UUUGUAACUUGAAGAUAUUdTsdT 
                 3548 
                 1631 
               
               
                   
                 antis 
                 AAUAUCUUCAAGUUACAAAdTsdT 
                 3548 
                 1632 
               
               
                   
               
               
                 AD-22197-b1 
                 sense 
                 UUGUAACUUGAAGAUAUUUdTsdT 
                 3549 
                 1633 
               
               
                   
                 antis 
                 AAAUAUCUUCAAGUUACAAdTsdT 
                 3549 
                 1634 
               
               
                   
               
               
                 AD-22198-b1 
                 sense 
                 UGUAACUUGAAGAUAUUUAdTsdT 
                 3550 
                 1635 
               
               
                   
                 antis 
                 UAAABAUCUUCAAGUUACAdTsdT 
                 3550 
                 1636 
               
               
                   
               
               
                 AD-22199-b1 
                 sense 
                 GUAACUUGAAGAUAUUUAUdTsdT 
                 3551 
                 1637 
               
               
                   
                 antis 
                 AUAAAUAUCUUCAAGUUACdTsdT 
                 3551 
                 1638 
               
               
                   
               
               
                 AD-22200-b1 
                 sense 
                 UAACUUGAAGAUAUUUAUUdTsdT 
                 3552 
                 1639 
               
               
                   
                 antis 
                 AAUAAAUAUCUUCAAGUUAdTsdT 
                 3552 
                 1640 
               
               
                   
               
               
                 AD-22201-b1 
                 sense 
                 AACUUGAAGAUAUUUAUUCdTsdT 
                 3553 
                 1641 
               
               
                   
                 antis 
                 GAAUAAAUAUCUUCAAGUUdTsdT 
                 3553 
                 1642 
               
               
                   
               
               
                 AD-22202-b1 
                 sense 
                 ACUUGAAGAUAUUUAUUCUdTsdT 
                 3554 
                 1643 
               
               
                   
                 antis 
                 AGAAUAAAUAUCUUCAAGUdTsdT 
                 3554 
                 1644 
               
               
                   
               
               
                 AD-22203-b1 
                 sense 
                 CUUGAAGAUAUUUAUUCUGdTsdT 
                 3555 
                 1645 
               
               
                   
                 antis 
                 CAGAAUAAAUAUCUUCAAGdTsdT 
                 3555 
                 1646 
               
               
                   
               
               
                 AD-22204-b1 
                 sense 
                 UUGAAGAUAUUUAUUCUGGdTsdT 
                 3556 
                 1647 
               
               
                   
                 antis 
                 CCAGAAUAAAUAUCUUCAAdTsdT 
                 3556 
                 1648 
               
               
                   
               
               
                 AD-22205-b1 
                 sense 
                 UGAAGAUAUUUAUUCUGGGdTsdT 
                 3557 
                 1649 
               
               
                   
                 antis 
                 CCCAGAAUAAAUAUCUUCAdTsdT 
                 3557 
                 1650 
               
               
                   
               
               
                 AD-22206-b1 
                 sense 
                 GAAGAUAUUUAUUCUGGGUdTsdT 
                 3558 
                 1651 
               
               
                   
                 antis 
                 ACCCAGAAUAAAUAUCUUCdTsdT 
                 3558 
                 1652 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Sequences of modified siRNA flanking AD-9680 
               
               
                 *Target: 5′ nutlcoetide of target sequence in human PCSK9 gene, access. 
               
               
                 # NM_174936 U, C, A, G: corresponding ribonucleotide; dT: deoxythymidine; 
               
               
                 u, c, a, g: corresponding 2′-O-methyl ribonucleotide; Uf, Cf, Af, Gf: 
               
               
                 corresponding 2′-deoxy-2′-fluoro ribonucleotide; Y1 corresponds to DFT 
               
               
                 difluorotoluyl ribo(or deoxyribo)nucleotide; where nucleotides are  
               
               
                 written in sequence, they are connected by 3′-5′ phosphodiester groups; 
               
               
                 nucleotides with interjected “s” are connected by 3′-O-5′-O phosphoro- 
               
               
                 thiodiester groups; unless denoted by prefix “P*”, oligonucleotides are 
               
               
                 devoid of a 5′-phosphate group on the 5′-most nucleotide; all oligo- 
               
               
                 nucleotides bear 3′-OH on the 3′-most nucleotide 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex # 
                 Strand 
                 Sequence (5′ to 3′) 
                 *Target 
                 SEQ ID NO: 
               
               
                   
               
               
                 AD-22098-b1 
                 sense 
                 cAGccAAcuuuucuAGAccdTsdT 
                 3520 
                 1653 
               
               
                   
                 antis 
                 GGUCuAGAAAAGUUGGCUGdTsdT 
                 3520 
                 1654 
               
               
                   
               
               
                 AD-22099-b1 
                 sense 
                 AGccAAcuuuucuAGAccudTsdT 
                 3521 
                 1655 
               
               
                   
                 antis 
                 AGGUCuAGAAAAGUUGGCUdTsdT 
                 3521 
                 1656 
               
               
                   
               
               
                 AD-22100-b1 
                 sense 
                 GccAAcuuuucuAGAccuGdTsdT 
                 3522 
                 1657 
               
               
                   
                 antis 
                 cAGGUCuAGAAAAGUUGGCdTsdT 
                 3522 
                 1658 
               
               
                   
               
               
                 AD-22101-b1 
                 sense 
                 ccAAcuuuucuAGAccuGudTsdT 
                 3523 
                 1659 
               
               
                   
                 antis 
                 AcAGGUCuAGAAAAGUUGGdTsdT 
                 3523 
                 1660 
               
               
                   
               
               
                 AD-22102-b1 
                 sense 
                 cAAcuuuucuAGAccuGuudTsdT 
                 3524 
                 1661 
               
               
                   
                 antis 
                 AAcAGGUCuAGAAAAGUUGdTsdT 
                 3524 
                 1662 
               
               
                   
               
               
                 AD-22103-b1 
                 sense 
                 AAcuuuucuAGAccuGuuudTsdT 
                 3525 
                 1663 
               
               
                   
                 antis 
                 AAAcAGGUCuAGAAAAGUUdTsdT 
                 3525 
                 1664 
               
               
                   
               
               
                 AD-22104-b1 
                 sense 
                 AcuuuucuAGAccuGuuuudTsdT 
                 3526 
                 1665 
               
               
                   
                 antis 
                 AAAAcAGGUCuAGAAAAGUdTsdT 
                 3526 
                 1666 
               
               
                   
               
               
                 AD-22105-b1 
                 sense 
                 cuuuucuAGAccuGuuuuGdTsdT 
                 3527 
                 1667 
               
               
                   
                 antis 
                 cAAAAcAGGUCuAGAAAAGdTsdT 
                 3527 
                 1668 
               
               
                   
               
               
                 AD-22106-b1 
                 sense 
                 uuuucuAGAccuGuuuuGcdTsdT 
                 3528 
                 1669 
               
               
                   
                 antis 
                 GcAAAAcAGGUCuAGAAAAdTsdT 
                 3528 
                 1670 
               
               
                   
               
               
                 AD-22107-b1 
                 sense 
                 uuucuAGAccuGuuuuGcudTsdT 
                 3529 
                 1671 
               
               
                   
                 antis 
                 AGcAAAAcAGGUCuAGAAAdTsdT 
                 3529 
                 1672 
               
               
                   
               
               
                 AD-22108-b1 
                 sense 
                 ucuAGAccuGuuuuGcuuudTsdT 
                 3531 
                 1673 
               
               
                   
                 antis 
                 AAAGcAAAAcAGGUCuAGAdTsdT 
                 3531 
                 1674 
               
               
                   
               
               
                 AD-22109-b1 
                 sense 
                 cuAGAccuGuuuuGcuuuudTsdT 
                 3532 
                 1675 
               
               
                   
                 antis 
                 AAAAGcAAAAcAGGUCuAGdTsdT 
                 3532 
                 1676 
               
               
                   
               
               
                 AD-22110-b1 
                 sense 
                 uAGAccuGuuuuGcuuuuGdTsdT 
                 3533 
                 1677 
               
               
                   
                 antis 
                 cAAAAGcAAAAcAGGUCuAdTsdT 
                 3533 
                 1678 
               
               
                   
               
               
                 AD-22111-b1 
                 sense 
                 AGAccuGuuuuGcuuuuGudTsdT 
                 3534 
                 1679 
               
               
                   
                 antis 
                 AcAAAAGcAAAAcAGGUCUdTsdT 
                 3534 
                 1680 
               
               
                   
               
               
                 AD-22112-b1 
                 sense 
                 GAccuGuuuuGcuuuuGuAdTsdT 
                 3535 
                 1681 
               
               
                   
                 antis 
                 uAcAAAAGcAAAAcAGGUCdTsdT 
                 3535 
                 1682 
               
               
                   
               
               
                 AD-22113-b1 
                 sense 
                 AccuGuuuuGcuuuuGuAAdTsdT 
                 3536 
                 1683 
               
               
                   
                 antis 
                 UuAcAAAAGcAAAAcAGGUdTsdT 
                 3536 
                 1684 
               
               
                   
               
               
                 AD-22114-b1 
                 sense 
                 ccuGuuuuGcuuuuGuAAcdTsdT 
                 3537 
                 1685 
               
               
                   
                 antis 
                 GUuAcAAAAGcAAAAcAGGdTsdT 
                 3537 
                 1686 
               
               
                   
               
               
                 AD-22115-b1 
                 sense 
                 cuGuuuuGcuuuuGuAAcudTsdT 
                 3538 
                 1687 
               
               
                   
                 antis 
                 AGUuAcAAAAGcAAAAcAGdTsdT 
                 3538 
                 1688 
               
               
                   
                 sense 
                 uGuuuuGcuuuuGuAAcuudTsdT 
                 3539 
                 1689 
               
               
                   
                 antis 
                 AAGUuAcAAAAGcAAAAcAdTsdT 
                 3539 
                 1690 
               
               
                   
               
               
                 AD-22116-b1 
                 sense 
                 GuuuuGcuuuuGuAAcuuGdTsdT 
                 3540 
                 1691 
               
               
                   
                 antis 
                 cAAGUuAcAAAAGcAAAACdTsdT 
                 3540 
                 1692 
               
               
                   
               
               
                 AD-22117-b1 
                 sense 
                 uuuuGcuuuuGuAAcuuGAdTsdT 
                 3541 
                 1693 
               
               
                   
                 antis 
                 UcAAGUuAcAAAAGcAAAAdTsdT 
                 3541 
                 1694 
               
               
                   
               
               
                 AD-22118-b1 
                 sense 
                 uuuGcuuuuGuAAcuuGAAdTsdT 
                 3542 
                 1695 
               
               
                   
                 antis 
                 UUcAAGUuAcAAAAGcAAAdTsdT 
                 3542 
                 1696 
               
               
                   
               
               
                 AD-22119-b1 
                 sense 
                 uuGcuuuuGuAAcuuGAAGdTsdT 
                 3543 
                 1697 
               
               
                   
                 antis 
                 CUUcAAGUuAcAAAAGcAAdTsdT 
                 3543 
                 1698 
               
               
                   
               
               
                 AD-22120-b1 
                 sense 
                 uGcuuuuGuAAcuuGAAGAdTsdT 
                 3544 
                 1699 
               
               
                   
                 antis 
                 UCUUcAAGUuAcAAAAGcAdTsdT 
                 3544 
                 1700 
               
               
                   
               
               
                 AD-22121-b1 
                 sense 
                 GcuuuuGuAAcuuGAAGAudTsdT 
                 3545 
                 1701 
               
               
                   
                 antis 
                 AUCUUcAAGUuAcAAAAGCdTsdT 
                 3545 
                 1702 
               
               
                   
               
               
                 AD-22122-b1 
                 sense 
                 cuuuuGuAAcuuGAAGAuAdTsdT 
                 3546 
                 1703 
               
               
                   
                 antis 
                 uAUCUUcAAGUuAcAAAAGdTsdT 
                 3546 
                 1704 
               
               
                   
               
               
                 AD-22123-b1 
                 sense 
                 uuuuGuAAcuuGAAGAuAudTsdT 
                 3547 
                 1705 
               
               
                   
                 antis 
                 AuAUCUUcAAGUuAcAAAAdTsdT 
                 3547 
                 1706 
               
               
                   
               
               
                 AD-22124-b1 
                 sense 
                 uuuGuAAcuuGAAGAuAuudTsdT 
                 3548 
                 1707 
               
               
                   
                 antis 
                 AAuAUCUUcAAGUuAcAAAdTsdT 
                 3548 
                 1708 
               
               
                   
               
               
                 AD-22125-b1 
                 sense 
                 uuGuAAcuuGAAGAuAuuudTsdT 
                 3549 
                 1709 
               
               
                   
                 antis 
                 AAAuAUCUUcAAGUuAcAAdTsdT 
                 3549 
                 1710 
               
               
                   
               
               
                 AD-22126-b1 
                 sense 
                 uGuAAcuuGAAGAuAuuuAdTsdT 
                 3550 
                 1711 
               
               
                   
                 antis 
                 uAAAuAUCUUcAAGUuAcAdTsdT 
                 3550 
                 1712 
               
               
                   
               
               
                 AD-22127-b1 
                 sense 
                 GuAAcuuGAAGAuAuuuAudTsdT 
                 3551 
                 1713 
               
               
                   
                 antis 
                 AuAAAuAUCUUcAAGUuACdTsdT 
                 3551 
                 1714 
               
               
                   
               
               
                 AD-22128-b1 
                 sense 
                 uAAcuuGAAGAuAuuuAuudTsdT 
                 3552 
                 1715 
               
               
                   
                 antis 
                 AAuAAAuAUCUUcAAGUuAdTsdT 
                 3552 
                 1716 
               
               
                   
               
               
                 AD-22129-b1 
                 sense 
                 AAcuuGAAGAuAuuuAuucdTsdT 
                 3553 
                 1717 
               
               
                   
                 antis 
                 GAAuAAAuAUCUUcAAGUUdTsdT 
                 3553 
                 1718 
               
               
                   
               
               
                 AD-22130-b1 
                 sense 
                 AcuuGAAGAuAuuuAuucudTsdT 
                 3554 
                 1719 
               
               
                   
                 antis 
                 AGAAuAAAuAUCUUcAAGUdTsdT 
                 3554 
                 1720 
               
               
                   
               
               
                 AD-22131-b1 
                 sense 
                 cuuGAAGAuAuuuAuucuGdTsdT 
                 3555 
                 1721 
               
               
                   
                 antis 
                 cAGAAuAAAuAUCUUcAAGdTsdT 
                 3555 
                 1722 
               
               
                   
               
               
                 AD-22132-b1 
                 sense 
                 uuGAAGAuAuuuAuucuGGdTsdT 
                 3556 
                 1723 
               
               
                   
                 antis 
                 CcAGAAuAAAuAUCUUcAAdTsdT 
                 3556 
                 1724 
               
               
                   
               
               
                 AD-22133-b1 
                 sense 
                 uGAAGAuAuuuAuucuGGGdTsdT 
                 3557 
                 1725 
               
               
                   
                 antis 
                 CCcAGAAuAAAuAUCUUcAdTsdT 
                 3557 
                 1726 
               
               
                   
               
               
                 AD-22134-b1 
                 sense 
                 GAAGAuAuuuAuucuGGGudTsdT 
                 3558 
                 1727 
               
               
                   
                 antis 
                 ACCcAGAAuAAAuAUCUUCdTsdT 
                 3558 
                 1728 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Sequences of XBP-1 dsRNAs 
               
               
                 *Target refers to target gene and location of target sequence. 
               
               
                 NM_001004210 is the gene for rat XBP-1. XM_001103095 is the sequence 
               
               
                 for  Macaca   mulatta  (rhesus monkey) XBP-1. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 SEQ ID 
                   
                 SEQ ID 
                   
               
               
                 Target* 
                 NO 
                 sense (5′-3′) 
                 NO 
                 antisense (5′-3′) 
               
               
                   
               
               
                 NM_001004210 
                 1729 
                 CCCAGCUGAUUAGUGUCUA 
                 1753 
                 UAGACACUAAUCAGCUGGG 
               
               
                 1128-1146 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1730 
                 CCAGCUGAUUAGUGUCUAA 
                 1754 
                 UUAGACACUAAUCAGCUGG 
               
               
                 1129-1147 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1731 
                 CUCCCAGAGGUCUACCCAG 
                 1755 
                 CUGGGUAGACCUCUGGGAG 
               
               
                  677-695 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1732 
                 GAUCACCCUGAAUUCAUUG 
                 1756 
                 CAAUGAAUUCAGGGUGAUC 
               
               
                  893-911 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1733 
                 UCACCCUGAAUUCAUUGUC 
                 1757 
                 GACAAUGAAUUCAGGGUGA 
               
               
                  895-913 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1734 
                 CCCCAGCUGAUUAGUGUCU 
                 1758 
                 AGACACUAAUCAGCUGGGG 
               
               
                 1127-1145 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1735 
                 AUCACCCUGAAUUCAUUGU 
                 1759 
                 ACAAUGAAUUCAGGGUGAU 
               
               
                  894-912 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1736 
                 CAUUUAUUUAAAACUACCC 
                 1760 
                 GGGUAGUUUUAAAUAAAUG 
               
               
                 1760-1778 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1737 
                 ACUGAAAAACAGAGUAGCA 
                 1761 
                 UGCUACUCUGUUUUUCAGU 
               
               
                  215-233 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1738 
                 CCAUUUAUUUAAAACUACC 
                 1762 
                 GGUAGUUUUAAAUAAAUGG 
               
               
                 1759-1777 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1739 
                 UUGAGAACCAGGAGUUAAG 
                 1763 
                 CUUAACUCCUGGUUCUCAA 
               
               
                  367-385 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1740 
                 CACCCUGAAUUCAUUGUCU 
                 1764 
                 AGACAAUGAAUUCAGGGUG 
               
               
                  896-914 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1741 
                 AACUGAAAAACAGAGUAGC 
                 1765 
                 GCUACUCUGUUUUUCAGUU 
               
               
                  214-232 
                   
                   
                   
                   
               
               
                   
               
               
                 NM_001004210 
                 1742 
                 CUGAAAAACAGAGUAGCAG 
                 1766 
                 CUGCUACUCUGUUUUUCAG 
               
               
                  216-234 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1743 
                 AGAAAAUCAGCUUUUACGA 
                 1767 
                 UCGUAAAAGCUGAUUUUCU 
               
               
                  387-405 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1744 
                 UCCCCAGCUGAUUAGUGUC 
                 1768 
                 GACACUAAUCAGCUGGGGA 
               
               
                 1151-1169 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1745 
                 UACUUAUUAUGUAAGGGUC 
                 1769 
                 GACCCUUACAUAAUAAGUA 
               
               
                 1466-1484 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1746 
                 UAUCUUAAAAGGGUGGUAG 
                 1770 
                 CUACCACCCUUUUAAGAUA 
               
               
                 1435-1453 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1747 
                 CCAUGGAUUCUGGCGGUAU 
                 1771 
                 AUACCGCCAGAAUCCAUGG 
               
               
                  577-595 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1748 
                 UUAAUGAACUAAUUCGUUU 
                 1772 
                 AAACGAAUUAGUUCAUUAA 
               
               
                  790-808 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1749 
                 AGGGUCAUUAGACAAAUGU 
                 1773 
                 ACAUUUGUCUAAUGACCCU 
               
               
                 1479-1497 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1750 
                 UGAACUAAUUCGUUUUGAC 
                 1774 
                 GUCAAAACGAAUUAGUUCA 
               
               
                  794-812 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1751 
                 UUCCCCAGCUGAUUAGUGU 
                 1775 
                 ACACUAAUCAGCUGGGGAA 
               
               
                 1150-1168 
                   
                   
                   
                   
               
               
                   
               
               
                 XM_001103095 
                 1752 
                 UAUGUAAGGGUCAUUAGAC 
                 1776 
                 GUCUAAUGACCCUUACAUA 
               
               
                 1473-1491 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Target gene name and target sequence  
               
               
                 location for dsRNA targeting XBP-1 
               
            
           
           
               
               
               
            
               
                   
                 Duplex # 
                 Target gene and location of target sequence 
               
               
                   
                   
               
               
                   
                 AD18027 
                 NM_001004210_1128-1146 
               
               
                   
                 AD18028 
                 NM_001004210_1129-1147 
               
               
                   
                 AD18029 
                 NM_001004210_677-695 
               
               
                   
                 AD18030 
                 NM_001004210_893-911 
               
               
                   
                 AD18031 
                 NM_001004210_895-913 
               
               
                   
                 AD18032 
                 NM_001004210_1127-1145 
               
               
                   
                 AD18033 
                 NM_001004210_894-912 
               
               
                   
                 AD18034 
                 NM_001004210_1760-1778 
               
               
                   
                 AD18035 
                 NM_001004210_215-233 
               
               
                   
                 AD18036 
                 NM_001004210_1759-1777 
               
               
                   
                 AD18037 
                 NM_001004210_367-385 
               
               
                   
                 AD18038 
                 NM_001004210_896-914 
               
               
                   
                 AD18039 
                 NM_001004210_214-232 
               
               
                   
                 AD18040 
                 NM_001004210_216-234 
               
               
                   
                 AD18041 
                 XM_001103095_387-405 
               
               
                   
                 AD18042 
                 XM_001103095_1151-1169 
               
               
                   
                 AD18043 
                 XM_001103095_1466-1484 
               
               
                   
                 AD18044 
                 XM_001103095_1435-1453 
               
               
                   
                 AD18045 
                 XM_001103095_577-595 
               
               
                   
                 AD18046 
                 XM_001103095_790-808 
               
               
                   
                 AD18047 
                 XM_001103095_1479-1497 
               
               
                   
                 AD18048 
                 XM_001103095_794-812 
               
               
                   
                 AD18049 
                 XM_001103095_1150-1168 
               
               
                   
                 AD18050 
                 XM_001103095_1473-1491 
               
               
                   
                   
               
               
                   
                 *Target refers to target gene and location of target sequence. 
               
               
                   
                 NM_001004210 is the gene for rat XBP-1. 
               
               
                   
                 XM_001103095 is the sequence for Macaca mulatta (rhesus monkey) XBP-1. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Sequences of dsRNA targeting XBP-1, with Endolight chemistry modifications 
               
               
                 U, C, A, G: corresponding ribonucleotide; dT: deoxythymidine; u, c, a, g: 
               
               
                 corresponding 2′-O-methyl ribonucleotide; where nucleotides are written in 
               
               
                 sequence, they are connected by 3′-5′ phosphodiester groups; nucleotides 
               
               
                 with interjected “s” are connected by 3′-O-5′-O phosphorothiodiester 
               
               
                 groups. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                 SEQ 
                   
               
               
                   
                 ID 
                   
                 ID 
                   
               
               
                 Duplex # 
                 NO 
                 Sense (5′-3′) 
                 NO 
                 Antisense (5′-3′) 
               
               
                   
               
               
                 AD18027 
                 4166 
                 cccAGcuGAuuAGuGucuAdTsdT 
                 1800 
                 uAGAcACuAAUcAGCUGGGdTsdT 
               
               
                   
               
               
                 AD18028 
                 1777 
                 ccAGcuGAuuAGuGucuAAdTsdT 
                 1801 
                 UuAGAcACuAAUcAGCUGGdTsdT 
               
               
                   
               
               
                 AD18029 
                 1778 
                 cucccAGAGGucuAcccAGdTsdT 
                 1802 
                 CUGGGuAGACCUCUGGGAGdTsdT 
               
               
                   
               
               
                 AD18030 
                 1779 
                 GAucAcccuGAAuucAuuGdTsdT 
                 1803 
                 cAAUGAAUUcAGGGUGAUCdTsdT 
               
               
                   
               
               
                 AD18031 
                 1780 
                 ucAcccuGAAuucAuuGucdTsdT 
                 1804 
                 GAcAAUGAAUUcAGGGUGAdTsdT 
               
               
                   
               
               
                 AD18032 
                 1781 
                 ccccAGcuGAuuAGuGucudTsdT 
                 1805 
                 AGAcACuAAUcAGCUGGGGdTsdT 
               
               
                   
               
               
                 AD18033 
                 1782 
                 AucAcccuGAAuucAuuGudTsdT 
                 1806 
                 AcAAUGAAUUcAGGGUGAUdTsdT 
               
               
                   
               
               
                 AD18034 
                 1783 
                 cAuuuAuuuAAAAcuAcccdTsdT 
                 1807 
                 GGGuAGUUUuAAAuAAAUGdTsdT 
               
               
                   
               
               
                 AD18035 
                 1784 
                 AcuGAAAAAcAGAGuAGcAdTsdT 
                 1808 
                 UGCuACUCUGUUUUUcAGUdTsdT 
               
               
                   
               
               
                 AD18036 
                 1785 
                 ccAuuuAuuuAAAAcuAccdTsdT 
                 1809 
                 GGuAGUUUuAAAuAAAUGGdTsdT 
               
               
                   
               
               
                 AD18037 
                 1786 
                 uuGAGAAccAGGAGuuAAGdTsdT 
                 1810 
                 CUuAACUCCUGGUUCUcAAdTsdT 
               
               
                   
               
               
                 AD18038 
                 1787 
                 cAcccuGAAuucAuuGucudTsdT 
                 1811 
                 AGAcAAUGAAUUcAGGGUGdTsdT 
               
               
                   
               
               
                 AD18039 
                 1788 
                 AAcuGAAAAAcAGAGuAGcdTsdT 
                 1812 
                 GCuACUCUGUUUUUcAGUUdTsdT 
               
               
                   
               
               
                 AD18040 
                 1789 
                 cuGAAAAAcAGAGuAGcAGdTsdT 
                 1813 
                 CUGCuACUCUGUUUUUcAGdTsdT 
               
               
                   
               
               
                 AD18041 
                 1790 
                 AGAAAAucAGcuuuuAcGAdTsdT 
                 1814 
                 UCGuAAAAGCUGAUUUUCUdTsdT 
               
               
                   
               
               
                 AD18042 
                 1791 
                 uccccAGcuGAuuAGuGucdTsdT 
                 1815 
                 GAcACuAAUcAGCUGGGGAdTsdT 
               
               
                   
               
               
                 AD18043 
                 1792 
                 uAcuuAuuAuGuAAGGGucdTsdT 
                 1816 
                 GACCCUuAcAuAAuAAGuAdTsdT 
               
               
                   
               
               
                 AD18044 
                 1793 
                 uAucuuAAAAGGGuGGuAGdTsdT 
                 1817 
                 CuACcACCCUUUuAAGAuAdTsdT 
               
               
                   
               
               
                 AD18045 
                 1794 
                 ccAuGGAuucuGGcGGuAudTsdT 
                 1818 
                 AuACCGCcAGAAUCcAUGGdTsdT 
               
               
                   
               
               
                 AD18046 
                 1795 
                 uuAAuGAAcuAAuucGuuudTsdT 
                 1819 
                 AAACGAAUuAGUUcAUuAAdTsdT 
               
               
                   
               
               
                 AD18047 
                 1796 
                 AGGGucAuuAGAcAAAuGudTsdT 
                 1820 
                 AcAUUUGUCuAAUGACCCUdTsdT 
               
               
                   
               
               
                 AD18048 
                 1797 
                 uGAAcuAAuucGuuuuGAcdTsdT 
                 1821 
                 GUcAAAACGAAUuAGUUcAdTsdT 
               
               
                   
               
               
                 AD18049 
                 1798 
                 uuccccAGcuGAuuAGuGudTsdT 
                 1822 
                 AcACuAAUcAGCUGGGGAAdTsdT 
               
               
                   
               
               
                 AD18050 
                 1799 
                 uAuGuAAGGGucAuuAGAcdTsdT 
                 1823 
                 GUCuAAUGACCCUuAcAuAdTsdT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Sequences of dsRNA targeting both human and rhesus monkey XBP-1. 
               
               
                 *Target refers location of target sequence in NM_005080 (human XBP-1 mRNA). 
               
               
                  Sense and antisense sequences are described with optional dinucleotide 
               
               
                 (NN) overhangs. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ ID 
                   
                 SEQ ID 
               
               
                 Target* 
                 sense (5′-3′) 
                 NO 
                 antisense (5′-3′) 
                 NO 
               
               
                   
               
               
                  100-118 
                 CUGCUUCUGUCGGGGCAGCNN 
                 1824 
                 GCUGCCCCGACAGAAGCAGNN 
                 28 
               
               
                   
               
               
                 1011-1029 
                 GAGCUGGGUAUCUCAAAUCNN 
                 1825 
                 GAUUUGAGAUACCCAGCUCNN 
                 28 
               
               
                   
               
               
                  101-119 
                 UGCUUCUGUCGGGGCAGCCNN 
                 1826 
                 GGCUGCCCCGACAGAAGCANN 
                 28 
               
               
                   
               
               
                 1012-1030 
                 AGCUGGGUAUCUCAAAUCUNN 
                 1827 
                 AGAUUUGAGAUACCCAGCUNN 
                 28 
               
               
                   
               
               
                 1013-1031 
                 GCUGGGUAUCUCAAAUCUGNN 
                 1828 
                 CAGAUUUGAGAUACCCAGCNN 
                 28 
               
               
                   
               
               
                 1014-1032 
                 CUGGGUAUCUCAAAUCUGCNN 
                 1829 
                 GCAGAUUUGAGAUACCCAGNN 
                 28 
               
               
                   
               
               
                 1015-1033 
                 UGGGUAUCUCAAAUCUGCUNN 
                 1830 
                 AGCAGAUUUGAGAUACCCANN 
                 28 
               
               
                   
               
               
                 1016-1034 
                 GGGUAUCUCAAAUCUGCUUNN 
                 1831 
                 AAGCAGAUUUGAGAUACCCNN 
                 28 
               
               
                   
               
               
                 1017-1035 
                 GGUAUCUCAAAUCUGCUUUNN 
                 1832 
                 AAAGCAGAUUUGAGAUACCNN 
                 28 
               
               
                   
               
               
                 1018-1036 
                 GUAUCUCAAAUCUGCUUUCNN 
                 1833 
                 GAAAGCAGAUUUGAGAUACNN 
                 28 
               
               
                   
               
               
                 1019-1037 
                 UAUCUCAAAUCUGCUUUCANN 
                 1834 
                 UGAAAGCAGAUUUGAGAUANN 
                 28 
               
               
                   
               
               
                 1020-1038 
                 AUCUCAAAUCUGCUUUCAUNN 
                 1835 
                 AUGAAAGCAGAUUUGAGAUNN 
                 28 
               
               
                   
               
               
                 1021-1039 
                 UCUCAAAUCUGCUUUCAUCNN 
                 1836 
                 GAUGAAAGCAGAUUUGAGANN 
                 28 
               
               
                   
               
               
                  102-120 
                 GCUUCUGUCGGGGCAGCCCNN 
                 1837 
                 GGGCUGCCCCGACAGAAGCNN 
                 28 
               
               
                   
               
               
                 1022-1040 
                 CUCAAAUCUGCUUUCAUCCNN 
                 1838 
                 GGAUGAAAGCAGAUUUGAGNN 
                 28 
               
               
                   
               
               
                 1023-1041 
                 UCAAAUCUGCUUUCAUCCANN 
                 1839 
                 UGGAUGAAAGCAGAUUUGANN 
                 28 
               
               
                   
               
               
                 1024-1042 
                 CAAAUCUGCUUUCAUCCAGNN 
                 1840 
                 CUGGAUGAAAGCAGAUUUGNN 
                 28 
               
               
                   
               
               
                 1025-1043 
                 AAAUCUGCUUUCAUCCAGCNN 
                 1841 
                 GCUGGAUGAAAGCAGAUUUNN 
                 29 
               
               
                   
               
               
                 1026-1044 
                 AAUCUGCUUUCAUCCAGCCNN 
                 1842 
                 GGCUGGAUGAAAGCAGAUUNN 
                 29 
               
               
                   
               
               
                 1027-1045 
                 AUCUGCUUUCAUCCAGCCANN 
                 1843 
                 UGGCUGGAUGAAAGCAGAUNN 
                 29 
               
               
                   
               
               
                 1028-1046 
                 UCUGCUUUCAUCCAGCCACNN 
                 1844 
                 GUGGCUGGAUGAAAGCAGANN 
                 29 
               
               
                   
               
               
                 1029-1047 
                 CUGCUUUCAUCCAGCCACUNN 
                 1845 
                 AGUGGCUGGAUGAAAGCAGNN 
                 29 
               
               
                   
               
               
                 1030-1048 
                 UGCUUUCAUCCAGCCACUGNN 
                 1846 
                 CAGUGGCUGGAUGAAAGCANN 
                 29 
               
               
                   
               
               
                 1031-1049 
                 GCUUUCAUCCAGCCACUGCNN 
                 1847 
                 GCAGUGGCUGGAUGAAAGCNN 
                 29 
               
               
                   
               
               
                  103-121 
                 CUUCUGUCGGGGCAGCCCGNN 
                 1848 
                 CGGGCUGCCCCGACAGAAGNN 
                 29 
               
               
                   
               
               
                 1032-1050 
                 CUUUCAUCCAGCCACUGCCNN 
                 1849 
                 GGCAGUGGCUGGAUGAAAGNN 
                 29 
               
               
                   
               
               
                 1033-1051 
                 UUUCAUCCAGCCACUGCCCNN 
                 1850 
                 GGGCAGUGGCUGGAUGAAANN 
                 29 
               
               
                   
               
               
                  104-122 
                 UUCUGUCGGGGCAGCCCGCNN 
                 1851 
                 GCGGGCUGCCCCGACAGAANN 
                 29 
               
               
                   
               
               
                  105-123 
                 UCUGUCGGGGCAGCCCGCCNN 
                 1852 
                 GGCGGGCUGCCCCGACAGANN 
                 29 
               
               
                   
               
               
                 1056-1074 
                 CCAUCUUCCUGCCUACUGGNN 
                 1853 
                 CCAGUAGGCAGGAAGAUGGNN 
                 29 
               
               
                   
               
               
                 1057-1075 
                 CAUCUUCCUGCCUACUGGANN 
                 1854 
                 UCCAGUAGGCAGGAAGAUGNN 
                 29 
               
               
                   
               
               
                 1058-1076 
                 AUCUUCCUGCCUACUGGAUNN 
                 1855 
                 AUCCAGUAGGCAGGAAGAUNN 
                 29 
               
               
                   
               
               
                 1059-1077 
                 UCUUCCUGCCUACUGGAUGNN 
                 1856 
                 CAUCCAGUAGGCAGGAAGANN 
                 29 
               
               
                   
               
               
                 1060-1078 
                 CUUCCUGCCUACUGGAUGCNN 
                 1857 
                 GCAUCCAGUAGGCAGGAAGNN 
                 29 
               
               
                   
               
               
                 1061-1079 
                 UUCCUGCCUACUGGAUGCUNN 
                 1858 
                 AGCAUCCAGUAGGCAGGAANN 
                 29 
               
               
                   
               
               
                  106-124 
                 CUGUCGGGGCAGCCCGCCUNN 
                 1859 
                 AGGCGGGCUGCCCCGACAGNN 
                 29 
               
               
                   
               
               
                 1062-1080 
                 UCCUGCCUACUGGAUGCUUNN 
                 1860 
                 AAGCAUCCAGUAGGCAGGANN 
                 29 
               
               
                   
               
               
                 1063-1081 
                 CCUGCCUACUGGAUGCUUANN 
                 1861 
                 UAAGCAUCCAGUAGGCAGGNN 
                 29 
               
               
                   
               
               
                 1064-1082 
                 CUGCCUACUGGAUGCUUACNN 
                 1862 
                 GUAAGCAUCCAGUAGGCAGNN 
                 29 
               
               
                   
               
               
                 1065-1083 
                 UGCCUACUGGAUGCUUACANN 
                 1863 
                 UGUAAGCAUCCAGUAGGCANN 
                 29 
               
               
                   
               
               
                 1066-1084 
                 GCCUACUGGAUGCUUACAGNN 
                 1864 
                 CUGUAAGCAUCCAGUAGGCNN 
                 29 
               
               
                   
               
               
                 1067-1085 
                 CCUACUGGAUGCUUACAGUNN 
                 1865 
                 ACUGUAAGCAUCCAGUAGGNN 
                 29 
               
               
                   
               
               
                 1068-1086 
                 CUACUGGAUGCUUACAGUGNN 
                 1866 
                 CACUGUAAGCAUCCAGUAGNN 
                 29 
               
               
                   
               
               
                 1069-1087 
                 UACUGGAUGCUUACAGUGANN 
                 1867 
                 UCACUGUAAGCAUCCAGUANN 
                 29 
               
               
                   
               
               
                 1070-1088 
                 ACUGGAUGCUUACAGUGACNN 
                 1868 
                 GUCACUGUAAGCAUCCAGUNN 
                 29 
               
               
                   
               
               
                 1071-1089 
                 CUGGAUGCUUACAGUGACUNN 
                 1869 
                 AGUCACUGUAAGCAUCCAGNN 
                 29 
               
               
                   
               
               
                  107-125 
                 UGUCGGGGCAGCCCGCCUCNN 
                 1870 
                 GAGGCGGGCUGCCCCGACANN 
                 29 
               
               
                   
               
               
                 1072-1090 
                 UGGAUGCUUACAGUGACUGNN 
                 1871 
                 CAGUCACUGUAAGCAUCCANN 
                 29 
               
               
                   
               
               
                 1073-1091 
                 GGAUGCUUACAGUGACUGUNN 
                 1872 
                 ACAGUCACUGUAAGCAUCCNN 
                 29 
               
               
                   
               
               
                 1074-1092 
                 GAUGCUUACAGUGACUGUGNN 
                 1873 
                 CACAGUCACUGUAAGCAUCNN 
                 29 
               
               
                   
               
               
                 1075-1093 
                 AUGCUUACAGUGACUGUGGNN 
                 1874 
                 CCACAGUCACUGUAAGCAUNN 
                 29 
               
               
                   
               
               
                 1076-1094 
                 UGCUUACAGUGACUGUGGANN 
                 1875 
                 UCCACAGUCACUGUAAGCANN 
                 29 
               
               
                   
               
               
                 1077-1095 
                 GCUUACAGUGACUGUGGAUNN 
                 1876 
                 AUCCACAGUCACUGUAAGCNN 
                 29 
               
               
                   
               
               
                 1078-1096 
                 CUUACAGUGACUGUGGAUANN 
                 1877 
                 UAUCCACAGUCACUGUAAGNN 
                 29 
               
               
                   
               
               
                  108-126 
                 GUCGGGGCAGCCCGCCUCCNN 
                 1878 
                 GGAGGCGGGCUGCCCCGACNN 
                 29 
               
               
                   
               
               
                  109-127 
                 UCGGGGCAGCCCGCCUCCGNN 
                 1879 
                 CGGAGGCGGGCUGCCCCGANN 
                 29 
               
               
                   
               
               
                  110-128 
                 CGGGGCAGCCCGCCUCCGCNN 
                 1880 
                 GCGGAGGCGGGCUGCCCCGNN 
                 29 
               
               
                   
               
               
                  111-129 
                 GGGGCAGCCCGCCUCCGCCNN 
                 1881 
                 GGCGGAGGCGGGCUGCCCCNN 
                 29 
               
               
                   
               
               
                 1116-1134 
                 UUCAGUGACAUGUCCUCUCNN 
                 1882 
                 GAGAGGACAUGUCACUGAANN 
                 29 
               
               
                   
               
               
                  112-130 
                 GGGCAGCCCGCCUCCGCCGNN 
                 1883 
                 CGGCGGAGGCGGGCUGCCCNN 
                 29 
               
               
                   
               
               
                  113-131 
                 GGCAGCCCGCCUCCGCCGCNN 
                 1884 
                 GCGGCGGAGGCGGGCUGCCNN 
                 29 
               
               
                   
               
               
                 1136-1154 
                 GCUUGGUGUAAACCAUUCUNN 
                 1885 
                 AGAAUGGUUUACACCAAGCNN 
                 29 
               
               
                   
               
               
                 1137-1155 
                 CUUGGUGUAAACCAUUCUUNN 
                 1886 
                 AAGAAUGGUUUACACCAAGNN 
                 29 
               
               
                   
               
               
                 1138-1156 
                 UUGGUGUAAACCAUUCUUGNN 
                 1887 
                 CAAGAAUGGUUUACACCAANN 
                 29 
               
               
                   
               
               
                 1139-1157 
                 UGGUGUAAACCAUUCUUGGNN 
                 1888 
                 CCAAGAAUGGUUUACACCANN 
                 29 
               
               
                   
               
               
                 1140-1158 
                 GGUGUAAACCAUUCUUGGGNN 
                 1889 
                 CCCAAGAAUGGUUUACACCNN 
                 29 
               
               
                   
               
               
                 1141-1159 
                 GUGUAAACCAUUCUUGGGANN 
                 1890 
                 UCCCAAGAAUGGUUUACACNN 
                 29 
               
               
                   
               
               
                  114-132 
                 GCAGCCCGCCUCCGCCGCCNN 
                 1891 
                 GGCGGCGGAGGCGGGCUGCNN 
                 29 
               
               
                   
               
               
                 1142-1160 
                 UGUAAACCAUUCUUGGGAGNN 
                 1892 
                 CUCCCAAGAAUGGUUUACANN 
                 29 
               
               
                   
               
               
                 1143-1161 
                 GUAAACCAUUCUUGGGAGGNN 
                 1893 
                 CCUCCCAAGAAUGGUUUACNN 
                 29 
               
               
                   
               
               
                 1144-1162 
                 UAAACCAUUCUUGGGAGGANN 
                 1894 
                 UCCUCCCAAGAAUGGUUUANN 
                 29 
               
               
                   
               
               
                 1145-1163 
                 AAACCAUUCUUGGGAGGACNN 
                 1895 
                 GUCCUCCCAAGAAUGGUUUNN 
                 29 
               
               
                   
               
               
                 1146-1164 
                 AACCAUUCUUGGGAGGACANN 
                 1896 
                 UGUCCUCCCAAGAAUGGUUNN 
                 29 
               
               
                   
               
               
                 1147-1165 
                 ACCAUUCUUGGGAGGACACNN 
                 1897 
                 GUGUCCUCCCAAGAAUGGUNN 
                 29 
               
               
                   
               
               
                 1148-1166 
                 CCAUUCUUGGGAGGACACUNN 
                 1898 
                 AGUGUCCUCCCAAGAAUGGNN 
                 29 
               
               
                   
               
               
                 1149-1167 
                 CAUUCUUGGGAGGACACUUNN 
                 1899 
                 AAGUGUCCUCCCAAGAAUGNN 
                 29 
               
               
                   
               
               
                 1150-1168 
                 AUUCUUGGGAGGACACUUUNN 
                 1900 
                 AAAGUGUCCUCCCAAGAAUNN 
                 29 
               
               
                   
               
               
                 1151-1169 
                 UUCUUGGGAGGACACUUUUNN 
                 1901 
                 AAAAGUGUCCUCCCAAGAANN 
                 29 
               
               
                   
               
               
                  115-133 
                 CAGCCCGCCUCCGCCGCCGNN 
                 1902 
                 CGGCGGCGGAGGCGGGCUGNN 
                 29 
               
               
                   
               
               
                 1152-1170 
                 UCUUGGGAGGACACUUUUGNN 
                 1903 
                 CAAAAGUGUCCUCCCAAGANN 
                 29 
               
               
                   
               
               
                 1153-1171 
                 CUUGGGAGGACACUUUUGCNN 
                 1904 
                 GCAAAAGUGUCCUCCCAAGNN 
                 29 
               
               
                   
               
               
                 1154-1172 
                 UUGGGAGGACACUUUUGCCNN 
                 1905 
                 GGCAAAAGUGUCCUCCCAANN 
                 29 
               
               
                   
               
               
                 1155-1173 
                 UGGGAGGACACUUUUGCCANN 
                 1906 
                 UGGCAAAAGUGUCCUCCCANN 
                 29 
               
               
                   
               
               
                 1156-1174 
                 GGGAGGACACUUUUGCCAANN 
                 1907 
                 UUGGCAAAAGUGUCCUCCCNN 
                 29 
               
               
                   
               
               
                 1157-1175 
                 GGAGGACACUUUUGCCAAUNN 
                 1908 
                 AUUGGCAAAAGUGUCCUCCNN 
                 29 
               
               
                   
               
               
                 1158-1176 
                 GAGGACACUUUUGCCAAUGNN 
                 1909 
                 CAUUGGCAAAAGUGUCCUCNN 
                 29 
               
               
                   
               
               
                 1159-1177 
                 AGGACACUUUUGCCAAUGANN 
                 1910 
                 UCAUUGGCAAAAGUGUCCUNN 
                 29 
               
               
                   
               
               
                 1160-1178 
                 GGACACUUUUGCCAAUGAANN 
                 1911 
                 UUCAUUGGCAAAAGUGUCCNN 
                 29 
               
               
                   
               
               
                 1161-1179 
                 GACACUUUUGCCAAUGAACNN 
                 1912 
                 GUUCAUUGGCAAAAGUGUCNN 
                 29 
               
               
                   
               
               
                  116-134 
                 AGCCCGCCUCCGCCGCCGGNN 
                 1913 
                 CCGGCGGCGGAGGCGGGCUNN 
                 29 
               
               
                   
               
               
                 1162-1180 
                 ACACUUUUGCCAAUGAACUNN 
                 1914 
                 AGUUCAUUGGCAAAAGUGUNN 
                 29 
               
               
                   
               
               
                  117-135 
                 GCCCGCCUCCGCCGCCGGANN 
                 1915 
                 UCCGGCGGCGGAGGCGGGCNN 
                 29 
               
               
                   
               
               
                  118-136 
                 CCCGCCUCCGCCGCCGGAGNN 
                 1916 
                 CUCCGGCGGCGGAGGCGGGNN 
                 29 
               
               
                   
               
               
                 1182-1200 
                 UUUCCCCAGCUGAUUAGUGNN 
                 1917 
                 CACUAAUCAGCUGGGGAAANN 
                 29 
               
               
                   
               
               
                 1183-1201 
                 UUCCCCAGCUGAUUAGUGUNN 
                 1918 
                 ACACUAAUCAGCUGGGGAANN 
                 29 
               
               
                   
               
               
                 1184-1202 
                 UCCCCAGCUGAUUAGUGUCNN 
                 1919 
                 GACACUAAUCAGCUGGGGANN 
                 29 
               
               
                   
               
               
                 1185-1203 
                 CCCCAGCUGAUUAGUGUCUNN 
                 1920 
                 AGACACUAAUCAGCUGGGGNN 
                 29 
               
               
                   
               
               
                 1186-1204 
                 CCCAGCUGAUUAGUGUCUANN 
                 1921 
                 UAGACACUAAUCAGCUGGGNN 
                 29 
               
               
                   
               
               
                 1187-1205 
                 CCAGCUGAUUAGUGUCUAANN 
                 1922 
                 UUAGACACUAAUCAGCUGGNN 
                 29 
               
               
                   
               
               
                 1188-1206 
                 CAGCUGAUUAGUGUCUAAGNN 
                 1923 
                 CUUAGACACUAAUCAGCUGNN 
                 29 
               
               
                   
               
               
                 1189-1207 
                 AGCUGAUUAGUGUCUAAGGNN 
                 1924 
                 CCUUAGACACUAAUCAGCUNN 
                 29 
               
               
                   
               
               
                 1190-1208 
                 GCUGAUUAGUGUCUAAGGANN 
                 1925 
                 UCCUUAGACACUAAUCAGCNN 
                 29 
               
               
                   
               
               
                 1191-1209 
                 CUGAUUAGUGUCUAAGGAANN 
                 1926 
                 UUCCUUAGACACUAAUCAGNN 
                 29 
               
               
                   
               
               
                  119-137 
                 CCGCCUCCGCCGCCGGAGCNN 
                 1927 
                 GCUCCGGCGGCGGAGGCGGNN 
                 29 
               
               
                   
               
               
                 1192-1210 
                 UGAUUAGUGUCUAAGGAAUNN 
                 1928 
                 AUUCCUUAGACACUAAUCANN 
                 29 
               
               
                   
               
               
                 1193-1211 
                 GAUUAGUGUCUAAGGAAUGNN 
                 1929 
                 CAUUCCUUAGACACUAAUCNN 
                 29 
               
               
                   
               
               
                 1194-1212 
                 AUUAGUGUCUAAGGAAUGANN 
                 1930 
                 UCAUUCCUUAGACACUAAUNN 
                 29 
               
               
                   
               
               
                 1195-1213 
                 UUAGUGUCUAAGGAAUGAUNN 
                 1931 
                 AUCAUUCCUUAGACACUAANN 
                 29 
               
               
                   
               
               
                 1196-1214 
                 UAGUGUCUAAGGAAUGAUCNN 
                 1932 
                 GAUCAUUCCUUAGACACUANN 
                 29 
               
               
                   
               
               
                 1197-1215 
                 AGUGUCUAAGGAAUGAUCCNN 
                 1933 
                 GGAUCAUUCCUUAGACACUNN 
                 29 
               
               
                   
               
               
                 1198-1216 
                 GUGUCUAAGGAAUGAUCCANN 
                 1934 
                 UGGAUCAUUCCUUAGACACNN 
                 29 
               
               
                   
               
               
                  120-138 
                 CGCCUCCGCCGCCGGAGCCNN 
                 1935 
                 GGCUCCGGCGGCGGAGGCGNN 
                 29 
               
               
                   
               
               
                  121-139 
                 GCCUCCGCCGCCGGAGCCCNN 
                 1936 
                 GGGCUCCGGCGGCGGAGGCNN 
                 29 
               
               
                   
               
               
                 1218-1236 
                 UACUGUUGCCCUUUUCCUUNN 
                 1937 
                 AAGGAAAAGGGCAACAGUANN 
                 29 
               
               
                   
               
               
                 1219-1237 
                 ACUGUUGCCCUUUUCCUUGNN 
                 1938 
                 CAAGGAAAAGGGCAACAGUNN 
                 29 
               
               
                   
               
               
                 1220-1238 
                 CUGUUGCCCUUUUCCUUGANN 
                 1939 
                 UCAAGGAAAAGGGCAACAGNN 
                 29 
               
               
                   
               
               
                 1221-1239 
                 UGUUGCCCUUUUCCUUGACNN 
                 1940 
                 GUCAAGGAAAAGGGCAACANN 
                 29 
               
               
                   
               
               
                  122-140 
                 CCUCCGCCGCCGGAGCCCCNN 
                 1941 
                 GGGGCUCCGGCGGCGGAGGNN 
                 30 
               
               
                   
               
               
                 1222-1240 
                 GUUGCCCUUUUCCUUGACUNN 
                 1942 
                 AGUCAAGGAAAAGGGCAACNN 
                 30 
               
               
                   
               
               
                 1223-1241 
                 UUGCCCUUUUCCUUGACUANN 
                 1943 
                 UAGUCAAGGAAAAGGGCAANN 
                 30 
               
               
                   
               
               
                 1224-1242 
                 UGCCCUUUUCCUUGACUAUNN 
                 1944 
                 AUAGUCAAGGAAAAGGGCANN 
                 30 
               
               
                   
               
               
                 1225-1243 
                 GCCCUUUUCCUUGACUAUUNN 
                 1945 
                 AAUAGUCAAGGAAAAGGGCNN 
                 30 
               
               
                   
               
               
                 1226-1244 
                 CCCUUUUCCUUGACUAUUANN 
                 1946 
                 UAAUAGUCAAGGAAAAGGGNN 
                 30 
               
               
                   
               
               
                 1227-1245 
                 CCUUUUCCUUGACUAUUACNN 
                 1947 
                 GUAAUAGUCAAGGAAAAGGNN 
                 30 
               
               
                   
               
               
                 1228-1246 
                 CUUUUCCUUGACUAUUACANN 
                 1948 
                 UGUAAUAGUCAAGGAAAAGNN 
                 30 
               
               
                   
               
               
                 1229-1247 
                 UUUUCCUUGACUAUUACACNN 
                 1949 
                 GUGUAAUAGUCAAGGAAAANN 
                 30 
               
               
                   
               
               
                 1230-1248 
                 UUUCCUUGACUAUUACACUNN 
                 1950 
                 AGUGUAAUAGUCAAGGAAANN 
                 30 
               
               
                   
               
               
                 1231-1249 
                 UUCCUUGACUAUUACACUGNN 
                 1951 
                 CAGUGUAAUAGUCAAGGAANN 
                 30 
               
               
                   
               
               
                  123-141 
                 CUCCGCCGCCGGAGCCCCGNN 
                 1952 
                 CGGGGCUCCGGCGGCGGAGNN 
                 30 
               
               
                   
               
               
                 1232-1250 
                 UCCUUGACUAUUACACUGCNN 
                 1953 
                 GCAGUGUAAUAGUCAAGGANN 
                 30 
               
               
                   
               
               
                 1233-1251 
                 CCUUGACUAUUACACUGCCNN 
                 1954 
                 GGCAGUGUAAUAGUCAAGGNN 
                 30 
               
               
                   
               
               
                 1234-1252 
                 CUUGACUAUUACACUGCCUNN 
                 1955 
                 AGGCAGUGUAAUAGUCAAGNN 
                 30 
               
               
                   
               
               
                 1235-1253 
                 UUGACUAUUACACUGCCUGNN 
                 1956 
                 CAGGCAGUGUAAUAGUCAANN 
                 30 
               
               
                   
               
               
                 1236-1254 
                 UGACUAUUACACUGCCUGGNN 
                 1957 
                 CCAGGCAGUGUAAUAGUCANN 
                 30 
               
               
                   
               
               
                 1237-1255 
                 GACUAUUACACUGCCUGGANN 
                 1958 
                 UCCAGGCAGUGUAAUAGUCNN 
                 30 
               
               
                   
               
               
                 1238-1256 
                 ACUAUUACACUGCCUGGAGNN 
                 1959 
                 CUCCAGGCAGUGUAAUAGUNN 
                 30 
               
               
                   
               
               
                 1239-1257 
                 CUAUUACACUGCCUGGAGGNN 
                 1960 
                 CCUCCAGGCAGUGUAAUAGNN 
                 30 
               
               
                   
               
               
                 1240-1258 
                 UAUUACACUGCCUGGAGGANN 
                 1961 
                 UCCUCCAGGCAGUGUAAUANN 
                 30 
               
               
                   
               
               
                 1241-1259 
                 AUUACACUGCCUGGAGGAUNN 
                 1962 
                 AUCCUCCAGGCAGUGUAAUNN 
                 30 
               
               
                   
               
               
                  124-142 
                 UCCGCCGCCGGAGCCCCGGNN 
                 1963 
                 CCGGGGCUCCGGCGGCGGANN 
                 30 
               
               
                   
               
               
                 1242-1260 
                 UUACACUGCCUGGAGGAUANN 
                 1964 
                 UAUCCUCCAGGCAGUGUAANN 
                 30 
               
               
                   
               
               
                 1243-1261 
                 UACACUGCCUGGAGGAUAGNN 
                 1965 
                 CUAUCCUCCAGGCAGUGUANN 
                 30 
               
               
                   
               
               
                 1244-1262 
                 ACACUGCCUGGAGGAUAGCNN 
                 1966 
                 GCUAUCCUCCAGGCAGUGUNN 
                 30 
               
               
                   
               
               
                 1245-1263 
                 CACUGCCUGGAGGAUAGCANN 
                 1967 
                 UGCUAUCCUCCAGGCAGUGNN 
                 30 
               
               
                   
               
               
                 1246-1264 
                 ACUGCCUGGAGGAUAGCAGNN 
                 1968 
                 CUGCUAUCCUCCAGGCAGUNN 
                 30 
               
               
                   
               
               
                  125-143 
                 CCGCCGCCGGAGCCCCGGCNN 
                 1969 
                 GCCGGGGCTCCGGCGGCGGNN 
                 30 
               
               
                   
               
               
                  126-144 
                 CGCCGCCGGAGCCCCGGCCNN 
                 1970 
                 GGCCGGGGCTCCGGCGGCGNN 
                 30 
               
               
                   
               
               
                  127-145 
                 GCCGCCGGAGCCCCGGCCGNN 
                 1971 
                 CGGCCGGGGCTCCGGCGGCNN 
                 30 
               
               
                   
               
               
                 1280-1298 
                 CUUCAUUCAAAAAGCCAAANN 
                 1972 
                 UUUGGCUUUUUGAAUGAAGNN 
                 30 
               
               
                   
               
               
                 1281-1299 
                 UUCAUUCAAAAAGCCAAAANN 
                 1973 
                 UUUUGGCUUUUUGAAUGAANN 
                 30 
               
               
                   
               
               
                  128-146 
                 CCGCCGGAGCCCCGGCCGGNN 
                 1974 
                 CCGGCCGGGGCTCCGGCGGNN 
                 30 
               
               
                   
               
               
                 1282-1300 
                 UCAUUCAAAAAGCCAAAAUNN 
                 1975 
                 AUUUUGGCUUUUUGAAUGANN 
                 30 
               
               
                   
               
               
                 1283-1301 
                 CAUUCAAAAAGCCAAAAUANN 
                 1976 
                 UAUUUUGGCUUUUUGAAUGNN 
                 30 
               
               
                   
               
               
                 1284-1302 
                 AUUCAAAAAGCCAAAAUAGNN 
                 1977 
                 CUAUUUUGGCUUUUUGAAUNN 
                 30 
               
               
                   
               
               
                 1285-1303 
                 UUCAAAAAGCCAAAAUAGANN 
                 1978 
                 UCUAUUUUGGCUUUUUGAANN 
                 30 
               
               
                   
               
               
                 1286-1304 
                 UCAAAAAGCCAAAAUAGAGNN 
                 1979 
                 CUCUAUUUUGGCUUUUUGANN 
                 30 
               
               
                   
               
               
                 1287-1305 
                 CAAAAAGCCAAAAUAGAGANN 
                 1980 
                 UCUCUAUUUUGGCUUUUUGNN 
                 30 
               
               
                   
               
               
                 1288-1306 
                 AAAAAGCCAAAAUAGAGAGNN 
                 1981 
                 CUCUCUAUUUUGGCUUUUUNN 
                 30 
               
               
                   
               
               
                 1289-1307 
                 AAAAGCCAAAAUAGAGAGUNN 
                 1982 
                 ACUCUCUAUUUUGGCUUUUNN 
                 30 
               
               
                   
               
               
                 1290-1308 
                 AAAGCCAAAAUAGAGAGUANN 
                 1983 
                 UACUCUCUAUUUUGGCUUUNN 
                 30 
               
               
                   
               
               
                  129-147 
                 CGCCGGAGCCCCGGCCGGCNN 
                 1984 
                 GCCGGCCGGGGCTCCGGCGNN 
                 30 
               
               
                   
               
               
                  130-148 
                 GCCGGAGCCCCGGCCGGCCNN 
                 1985 
                 GGCCGGCCGGGGCTCCGGCNN 
                 30 
               
               
                   
               
               
                 1310-1328 
                 ACAGUCCUAGAGAAUUCCUNN 
                 1986 
                 AGGAAUUCUCUAGGACUGUNN 
                 30 
               
               
                   
               
               
                  131-149 
                 CCGGAGCCCCGGCCGGCCANN 
                 1987 
                 TGGCCGGCCGGGGCTCCGGNN 
                 30 
               
               
                   
               
               
                  132-150 
                 CGGAGCCCCGGCCGGCCAGNN 
                 1988 
                 CTGGCCGGCCGGGGCTCCGNN 
                 30 
               
               
                   
               
               
                 1330-1348 
                 UAUUUGUUCAGAUCUCAUANN 
                 1989 
                 UAUGAGAUCUGAACAAAUANN 
                 30 
               
               
                   
               
               
                 1331-1349 
                 AUUUGUUCAGAUCUCAUAGNN 
                 1990 
                 CUAUGAGAUCUGAACAAAUNN 
                 30 
               
               
                   
               
               
                  133-151 
                 GGAGCCCCGGCCGGCCAGGNN 
                 1991 
                 CCTGGCCGGCCGGGGCTCCNN 
                 30 
               
               
                   
               
               
                 1332-1350 
                 UUUGUUCAGAUCUCAUAGANN 
                 1992 
                 UCUAUGAGAUCUGAACAAANN 
                 30 
               
               
                   
               
               
                 1333-1351 
                 UUGUUCAGAUCUCAUAGAUNN 
                 1993 
                 AUCUAUGAGAUCUGAACAANN 
                 30 
               
               
                   
               
               
                 1334-1352 
                 UGUUCAGAUCUCAUAGAUGNN 
                 1994 
                 CAUCUAUGAGAUCUGAACANN 
                 30 
               
               
                   
               
               
                 1335-1353 
                 GUUCAGAUCUCAUAGAUGANN 
                 1995 
                 UCAUCUAUGAGAUCUGAACNN 
                 30 
               
               
                   
               
               
                  134-152 
                 GAGCCCCGGCCGGCCAGGCNN 
                 1996 
                 GCCTGGCCGGCCGGGGCTCNN 
                 30 
               
               
                   
               
               
                  135-153 
                 AGCCCCGGCCGGCCAGGCCNN 
                 1997 
                 GGCCTGGCCGGCCGGGGCTNN 
                 30 
               
               
                   
               
               
                  136-154 
                 GCCCCGGCCGGCCAGGCCCNN 
                 1998 
                 GGGCCTGGCCGGCCGGGGCNN 
                 30 
               
               
                   
               
               
                 1365-1383 
                 UGUCUUUUGACAUCCAGCANN 
                 1999 
                 UGCUGGAUGUCAAAAGACANN 
                 30 
               
               
                   
               
               
                 1366-1384 
                 GUCUUUUGACAUCCAGCAGNN 
                 2000 
                 CUGCUGGAUGUCAAAAGACNN 
                 30 
               
               
                   
               
               
                 1367-1385 
                 UCUUUUGACAUCCAGCAGUNN 
                 2001 
                 ACUGCUGGAUGUCAAAAGANN 
                 30 
               
               
                   
               
               
                 1368-1386 
                 CUUUUGACAUCCAGCAGUCNN 
                 2002 
                 GACUGCUGGAUGUCAAAAGNN 
                 30 
               
               
                   
               
               
                 1369-1387 
                 UUUUGACAUCCAGCAGUCCNN 
                 2003 
                 GGACUGCUGGAUGUCAAAANN 
                 30 
               
               
                   
               
               
                 1370-1388 
                 UUUGACAUCCAGCAGUCCANN 
                 2004 
                 UGGACUGCUGGAUGUCAAANN 
                 30 
               
               
                   
               
               
                 1371-1389 
                 UUGACAUCCAGCAGUCCAANN 
                 2005 
                 UUGGACUGCUGGAUGUCAANN 
                 30 
               
               
                   
               
               
                  137-155 
                 CCCCGGCCGGCCAGGCCCUNN 
                 2006 
                 AGGGCCUGGCCGGCCGGGGNN 
                 30 
               
               
                   
               
               
                  138-156 
                 CCCGGCCGGCCAGGCCCUGNN 
                 2007 
                 CAGGGCCUGGCCGGCCGGGNN 
                 30 
               
               
                   
               
               
                 1391-1409 
                 GUAUUGAGACAUAUUACUGNN 
                 2008 
                 CAGUAAUAUGUCUCAAUACNN 
                 30 
               
               
                   
               
               
                  139-157 
                 CCGGCCGGCCAGGCCCUGCNN 
                 2009 
                 GCAGGGCCUGGCCGGCCGGNN 
                 30 
               
               
                   
               
               
                  140-158 
                 CGGCCGGCCAGGCCCUGCCNN 
                 2010 
                 GGCAGGGCCUGGCCGGCCGNN 
                 30 
               
               
                   
               
               
                  141-159 
                 GGCCGGCCAGGCCCUGCCGNN 
                 2011 
                 CGGCAGGGCCUGGCCGGCCNN 
                 30 
               
               
                   
               
               
                 1414-1432 
                 UAAGAAAUAUUACUAUAAUNN 
                 2012 
                 AUUAUAGUAAUAUUUCUUANN 
                 30 
               
               
                   
               
               
                 1415-1433 
                 AAGAAAUAUUACUAUAAUUNN 
                 2013 
                 AAUUAUAGUAAUAUUUCUUNN 
                 30 
               
               
                   
               
               
                 1416-1434 
                 AGAAAUAUUACUAUAAUUGNN 
                 2014 
                 CAAUUAUAGUAAUAUUUCUNN 
                 30 
               
               
                   
               
               
                 1417-1435 
                 GAAAUAUUACUAUAAUUGANN 
                 2015 
                 UCAAUUAUAGUAAUAUUUCNN 
                 30 
               
               
                   
               
               
                 1418-1436 
                 AAAUAUUACUAUAAUUGAGNN 
                 2016 
                 CUCAAUUAUAGUAAUAUUUNN 
                 30 
               
               
                   
               
               
                 1419-1437 
                 AAUAUUACUAUAAUUGAGANN 
                 2017 
                 UCUCAAUUAUAGUAAUAUUNN 
                 30 
               
               
                   
               
               
                 1420-1438 
                 AUAUUACUAUAAUUGAGAANN 
                 2018 
                 UUCUCAAUUAUAGUAAUAUNN 
                 30 
               
               
                   
               
               
                 1421-1439 
                 UAUUACUAUAAUUGAGAACNN 
                 2019 
                 GUUCUCAAUUAUAGUAAUANN 
                 30 
               
               
                   
               
               
                  142-160 
                 GCCGGCCAGGCCCUGCCGCNN 
                 2020 
                 GCGGCAGGGCCUGGCCGGCNN 
                 30 
               
               
                   
               
               
                 1422-1440 
                 AUUACUAUAAUUGAGAACUNN 
                 2021 
                 AGUUCUCAAUUAUAGUAAUNN 
                 30 
               
               
                   
               
               
                 1423-1441 
                 UUACUAUAAUUGAGAACUANN 
                 2022 
                 UAGUUCUCAAUUAUAGUAANN 
                 30 
               
               
                   
               
               
                 1424-1442 
                 UACUAUAAUUGAGAACUACNN 
                 2023 
                 GUAGUUCUCAAUUAUAGUANN 
                 30 
               
               
                   
               
               
                 1425-1443 
                 ACUAUAAUUGAGAACUACANN 
                 2024 
                 UGUAGUUCUCAAUUAUAGUNN 
                 30 
               
               
                   
               
               
                 1426-1444 
                 CUAUAAUUGAGAACUACAGNN 
                 2025 
                 CUGUAGUUCUCAAUUAUAGNN 
                 30 
               
               
                   
               
               
                 1427-1445 
                 UAUAAUUGAGAACUACAGCNN 
                 2026 
                 GCUGUAGUUCUCAAUUAUANN 
                 30 
               
               
                   
               
               
                 1428-1446 
                 AUAAUUGAGAACUACAGCUNN 
                 2027 
                 AGCUGUAGUUCUCAAUUAUNN 
                 30 
               
               
                   
               
               
                 1429-1447 
                 UAAUUGAGAACUACAGCUUNN 
                 2028 
                 AAGCUGUAGUUCUCAAUUANN 
                 30 
               
               
                   
               
               
                 1430-1448 
                 AAUUGAGAACUACAGCUUUNN 
                 2029 
                 AAAGCUGUAGUUCUCAAUUNN 
                 30 
               
               
                   
               
               
                 1431-1449 
                 AUUGAGAACUACAGCUUUUNN 
                 2030 
                 AAAAGCUGUAGUUCUCAAUNN 
                 30 
               
               
                   
               
               
                  143-161 
                 CCGGCCAGGCCCUGCCGCUNN 
                 2031 
                 AGCGGCAGGGCCUGGCCGGNN 
                 30 
               
               
                   
               
               
                 1432-1450 
                 UUGAGAACUACAGCUUUUANN 
                 2032 
                 UAAAAGCUGUAGUUCUCAANN 
                 30 
               
               
                   
               
               
                 1433-1451 
                 UGAGAACUACAGCUUUUAANN 
                 2033 
                 UUAAAAGCUGUAGUUCUCANN 
                 30 
               
               
                   
               
               
                 1434-1452 
                 GAGAACUACAGCUUUUAAGNN 
                 2034 
                 CUUAAAAGCUGUAGUUCUCNN 
                 30 
               
               
                   
               
               
                 1435-1453 
                 AGAACUACAGCUUUUAAGANN 
                 2035 
                 UCUUAAAAGCUGUAGUUCUNN 
                 30 
               
               
                   
               
               
                 1436-1454 
                 GAACUACAGCUUUUAAGAUNN 
                 2036 
                 AUCUUAAAAGCUGUAGUUCNN 
                 30 
               
               
                   
               
               
                 1437-1455 
                 AACUACAGCUUUUAAGAUUNN 
                 2037 
                 AAUCUUAAAAGCUGUAGUUNN 
                 30 
               
               
                   
               
               
                 1438-1456 
                 ACUACAGCUUUUAAGAUUGNN 
                 2038 
                 CAAUCUUAAAAGCUGUAGUNN 
                 30 
               
               
                   
               
               
                 1439-1457 
                 CUACAGCUUUUAAGAUUGUNN 
                 2039 
                 ACAAUCUUAAAAGCUGUAGNN 
                 30 
               
               
                   
               
               
                 1440-1458 
                 UACAGCUUUUAAGAUUGUANN 
                 2040 
                 UACAAUCUUAAAAGCUGUANN 
                 30 
               
               
                   
               
               
                 1441-1459 
                 ACAGCUUUUAAGAUUGUACNN 
                 2041 
                 GUACAAUCUUAAAAGCUGUNN 
                 31 
               
               
                   
               
               
                  144-162 
                 CGGCCAGGCCCUGCCGCUCNN 
                 2042 
                 GAGCGGCAGGGCCUGGCCGNN 
                 31 
               
               
                   
               
               
                 1442-1460 
                 CAGCUUUUAAGAUUGUACUNN 
                 2043 
                 AGUACAAUCUUAAAAGCUGNN 
                 31 
               
               
                   
               
               
                 1443-1461 
                 AGCUUUUAAGAUUGUACUUNN 
                 2044 
                 AAGUACAAUCUUAAAAGCUNN 
                 31 
               
               
                   
               
               
                 1444-1462 
                 GCUUUUAAGAUUGUACUUUNN 
                 2045 
                 AAAGUACAAUCUUAAAAGCNN 
                 31 
               
               
                   
               
               
                 1445-1463 
                 CUUUUAAGAUUGUACUUUUNN 
                 2046 
                 AAAAGUACAAUCUUAAAAGNN 
                 31 
               
               
                   
               
               
                 1446-1464 
                 UUUUAAGAUUGUACUUUUANN 
                 2047 
                 UAAAAGUACAAUCUUAAAANN 
                 31 
               
               
                   
               
               
                 1447-1465 
                 UUUAAGAUUGUACUUUUAUNN 
                 2048 
                 AUAAAAGUACAAUCUUAAANN 
                 31 
               
               
                   
               
               
                 1448-1466 
                 UUAAGAUUGUACUUUUAUCNN 
                 2049 
                 GAUAAAAGUACAAUCUUAANN 
                 31 
               
               
                   
               
               
                 1449-1467 
                 UAAGAUUGUACUUUUAUCUNN 
                 2050 
                 AGAUAAAAGUACAAUCUUANN 
                 31 
               
               
                   
               
               
                 1450-1468 
                 AAGAUUGUACUUUUAUCUUNN 
                 2051 
                 AAGAUAAAAGUACAAUCUUNN 
                 31 
               
               
                   
               
               
                 1451-1469 
                 AGAUUGUACUUUUAUCUUANN 
                 2052 
                 UAAGAUAAAAGUACAAUCUNN 
                 31 
               
               
                   
               
               
                  145-163 
                 GGCCAGGCCCUGCCGCUCANN 
                 2053 
                 UGAGCGGCAGGGCCUGGCCNN 
                 31 
               
               
                   
               
               
                 1452-1470 
                 GAUUGUACUUUUAUCUUAANN 
                 2054 
                 UUAAGAUAAAAGUACAAUCNN 
                 31 
               
               
                   
               
               
                 1453-1471 
                 AUUGUACUUUUAUCUUAAANN 
                 2055 
                 UUUAAGAUAAAAGUACAAUNN 
                 31 
               
               
                   
               
               
                 1454-1472 
                 UUGUACUUUUAUCUUAAAANN 
                 2056 
                 UUUUAAGAUAAAAGUACAANN 
                 31 
               
               
                   
               
               
                 1455-1473 
                 UGUACUUUUAUCUUAAAAGNN 
                 2057 
                 CUUUUAAGAUAAAAGUACANN 
                 31 
               
               
                   
               
               
                 1456-1474 
                 GUACUUUUAUCUUAAAAGGNN 
                 2058 
                 CCUUUUAAGAUAAAAGUACNN 
                 31 
               
               
                   
               
               
                 1457-1475 
                 UACUUUUAUCUUAAAAGGGNN 
                 2059 
                 CCCUUUUAAGAUAAAAGUANN 
                 31 
               
               
                   
               
               
                 1458-1476 
                 ACUUUUAUCUUAAAAGGGUNN 
                 2060 
                 ACCCUUUUAAGAUAAAAGUNN 
                 31 
               
               
                   
               
               
                 1459-1477 
                 CUUUUAUCUUAAAAGGGUGNN 
                 2061 
                 CACCCUUUUAAGAUAAAAGNN 
                 31 
               
               
                   
               
               
                 1460-1478 
                 UUUUAUCUUAAAAGGGUGGNN 
                 2062 
                 CCACCCUUUUAAGAUAAAANN 
                 31 
               
               
                   
               
               
                 1461-1479 
                 UUUAUCUUAAAAGGGUGGUNN 
                 2063 
                 ACCACCCUUUUAAGAUAAANN 
                 31 
               
               
                   
               
               
                  146-164 
                 GCCAGGCCCUGCCGCUCAUNN 
                 2064 
                 AUGAGCGGCAGGGCCUGGCNN 
                 31 
               
               
                   
               
               
                 1462-1480 
                 UUAUCUUAAAAGGGUGGUANN 
                 2065 
                 UACCACCCUUUUAAGAUAANN 
                 31 
               
               
                   
               
               
                 1463-1481 
                 UAUCUUAAAAGGGUGGUAGNN 
                 2066 
                 CUACCACCCUUUUAAGAUANN 
                 31 
               
               
                   
               
               
                 1464-1482 
                 AUCUUAAAAGGGUGGUAGUNN 
                 2067 
                 ACUACCACCCUUUUAAGAUNN 
                 31 
               
               
                   
               
               
                 1465-1483 
                 UCUUAAAAGGGUGGUAGUUNN 
                 2068 
                 AACUACCACCCUUUUAAGANN 
                 31 
               
               
                   
               
               
                 1466-1484 
                 CUUAAAAGGGUGGUAGUUUNN 
                 2069 
                 AAACUACCACCCUUUUAAGNN 
                 31 
               
               
                   
               
               
                  147-165 
                 CCAGGCCCUGCCGCUCAUGNN 
                 2070 
                 CAUGAGCGGCAGGGCCUGGNN 
                 31 
               
               
                   
               
               
                  148-166 
                 CAGGCCCUGCCGCUCAUGGNN 
                 2071 
                 CCAUGAGCGGCAGGGCCUGNN 
                 31 
               
               
                   
               
               
                 1486-1504 
                 CCCUAAAAUACUUAUUAUGNN 
                 2072 
                 CAUAAUAAGUAUUUUAGGGNN 
                 31 
               
               
                   
               
               
                 1487-1505 
                 CCUAAAAUACUUAUUAUGUNN 
                 2073 
                 ACAUAAUAAGUAUUUUAGGNN 
                 31 
               
               
                   
               
               
                 1488-1506 
                 CUAAAAUACUUAUUAUGUANN 
                 2074 
                 UACAUAAUAAGUAUUUUAGNN 
                 31 
               
               
                   
               
               
                 1489-1507 
                 UAAAAUACUUAUUAUGUAANN 
                 2075 
                 UUACAUAAUAAGUAUUUUANN 
                 31 
               
               
                   
               
               
                 1490-1508 
                 AAAAUACUUAUUAUGUAAGNN 
                 2076 
                 CUUACAUAAUAAGUAUUUUNN 
                 31 
               
               
                   
               
               
                 1491-1509 
                 AAAUACUUAUUAUGUAAGGNN 
                 2077 
                 CCUUACAUAAUAAGUAUUUNN 
                 31 
               
               
                   
               
               
                  149-167 
                 AGGCCCUGCCGCUCAUGGUNN 
                 2078 
                 ACCAUGAGCGGCAGGGCCUNN 
                 31 
               
               
                   
               
               
                 1492-1510 
                 AAUACUUAUUAUGUAAGGGNN 
                 2079 
                 CCCUUACAUAAUAAGUAUUNN 
                 31 
               
               
                   
               
               
                 1493-1511 
                 AUACUUAUUAUGUAAGGGUNN 
                 2080 
                 ACCCUUACAUAAUAAGUAUNN 
                 31 
               
               
                   
               
               
                 1494-1512 
                 UACUUAUUAUGUAAGGGUCNN 
                 2081 
                 GACCCUUACAUAAUAAGUANN 
                 31 
               
               
                   
               
               
                 1495-1513 
                 ACUUAUUAUGUAAGGGUCANN 
                 2082 
                 UGACCCUUACAUAAUAAGUNN 
                 31 
               
               
                   
               
               
                 1496-1514 
                 CUUAUUAUGUAAGGGUCAUNN 
                 2083 
                 AUGACCCUUACAUAAUAAGNN 
                 31 
               
               
                   
               
               
                 1497-1515 
                 UUAUUAUGUAAGGGUCAUUNN 
                 2084 
                 AAUGACCCUUACAUAAUAANN 
                 31 
               
               
                   
               
               
                 1498-1516 
                 UAUUAUGUAAGGGUCAUUANN 
                 2085 
                 UAAUGACCCUUACAUAAUANN 
                 31 
               
               
                   
               
               
                 1499-1517 
                 AUUAUGUAAGGGUCAUUAGNN 
                 2086 
                 CUAAUGACCCUUACAUAAUNN 
                 31 
               
               
                   
               
               
                 1500-1518 
                 UUAUGUAAGGGUCAUUAGANN 
                 2087 
                 UCUAAUGACCCUUACAUAANN 
                 31 
               
               
                   
               
               
                 1501-1519 
                 UAUGUAAGGGUCAUUAGACNN 
                 2088 
                 GUCUAAUGACCCUUACAUANN 
                 31 
               
               
                   
               
               
                  150-168 
                 GGCCCUGCCGCUCAUGGUGNN 
                 2089 
                 CACCAUGAGCGGCAGGGCCNN 
                 31 
               
               
                   
               
               
                 1502-1520 
                 AUGUAAGGGUCAUUAGACANN 
                 2090 
                 UGUCUAAUGACCCUUACAUNN 
                 31 
               
               
                   
               
               
                 1503-1521 
                 UGUAAGGGUCAUUAGACAANN 
                 2091 
                 UUGUCUAAUGACCCUUACANN 
                 31 
               
               
                   
               
               
                 1504-1522 
                 GUAAGGGUCAUUAGACAAANN 
                 2092 
                 UUUGUCUAAUGACCCUUACNN 
                 31 
               
               
                   
               
               
                 1505-1523 
                 UAAGGGUCAUUAGACAAAUNN 
                 2093 
                 AUUUGUCUAAUGACCCUUANN 
                 31 
               
               
                   
               
               
                 1506-1524 
                 AAGGGUCAUUAGACAAAUGNN 
                 2094 
                 CAUUUGUCUAAUGACCCUUNN 
                 31 
               
               
                   
               
               
                 1507-1525 
                 AGGGUCAUUAGACAAAUGUNN 
                 2095 
                 ACAUUUGUCUAAUGACCCUNN 
                 31 
               
               
                   
               
               
                 1508-1526 
                 GGGUCAUUAGACAAAUGUCNN 
                 2096 
                 GACAUUUGUCUAAUGACCCNN 
                 31 
               
               
                   
               
               
                 1509-1527 
                 GGUCAUUAGACAAAUGUCUNN 
                 2097 
                 AGACAUUUGUCUAAUGACCNN 
                 31 
               
               
                   
               
               
                 1510-1528 
                 GUCAUUAGACAAAUGUCUUNN 
                 2098 
                 AAGACAUUUGUCUAAUGACNN 
                 31 
               
               
                   
               
               
                 1511-1529 
                 UCAUUAGACAAAUGUCUUGNN 
                 2099 
                 CAAGACAUUUGUCUAAUGANN 
                 31 
               
               
                   
               
               
                  151-169 
                 GCCCUGCCGCUCAUGGUGCNN 
                 2100 
                 GCACCAUGAGCGGCAGGGCNN 
                 31 
               
               
                   
               
               
                 1512-1530 
                 CAUUAGACAAAUGUCUUGANN 
                 2101 
                 UCAAGACAUUUGUCUAAUGNN 
                 31 
               
               
                   
               
               
                 1513-1531 
                 AUUAGACAAAUGUCUUGAANN 
                 2102 
                 UUCAAGACAUUUGUCUAAUNN 
                 31 
               
               
                   
               
               
                 1514-1532 
                 UUAGACAAAUGUCUUGAAGNN 
                 2103 
                 CUUCAAGACAUUUGUCUAANN 
                 31 
               
               
                   
               
               
                 1515-1533 
                 UAGACAAAUGUCUUGAAGUNN 
                 2104 
                 ACUUCAAGACAUUUGUCUANN 
                 31 
               
               
                   
               
               
                 1516-1534 
                 AGACAAAUGUCUUGAAGUANN 
                 2105 
                 UACUUCAAGACAUUUGUCUNN 
                 31 
               
               
                   
               
               
                 1517-1535 
                 GACAAAUGUCUUGAAGUAGNN 
                 2106 
                 CUACUUCAAGACAUUUGUCNN 
                 31 
               
               
                   
               
               
                 1518-1536 
                 ACAAAUGUCUUGAAGUAGANN 
                 2107 
                 UCUACUUCAAGACAUUUGUNN 
                 31 
               
               
                   
               
               
                  152-170 
                 CCCUGCCGCUCAUGGUGCCNN 
                 2108 
                 GGCACCAUGAGCGGCAGGGNN 
                 31 
               
               
                   
               
               
                  153-171 
                 CCUGCCGCUCAUGGUGCCANN 
                 2109 
                 UGGCACCAUGAGCGGCAGGNN 
                 31 
               
               
                   
               
               
                 1541-1559 
                 GAAUUUAUGAAUGGUUCUUNN 
                 2110 
                 AAGAACCAUUCAUAAAUUCNN 
                 31 
               
               
                   
               
               
                  154-172 
                 CUGCCGCUCAUGGUGCCAGNN 
                 2111 
                 CUGGCACCAUGAGCGGCAGNN 
                 31 
               
               
                   
               
               
                 1542-1560 
                 AAUUUAUGAAUGGUUCUUUNN 
                 2112 
                 AAAGAACCAUUCAUAAAUUNN 
                 31 
               
               
                   
               
               
                 1543-1561 
                 AUUUAUGAAUGGUUCUUUANN 
                 2113 
                 UAAAGAACCAUUCAUAAAUNN 
                 31 
               
               
                   
               
               
                 1544-1562 
                 UUUAUGAAUGGUUCUUUAUNN 
                 2114 
                 AUAAAGAACCAUUCAUAAANN 
                 31 
               
               
                   
               
               
                 1545-1563 
                 UUAUGAAUGGUUCUUUAUCNN 
                 2115 
                 GAUAAAGAACCAUUCAUAANN 
                 31 
               
               
                   
               
               
                 1546-1564 
                 UAUGAAUGGUUCUUUAUCANN 
                 2116 
                 UGAUAAAGAACCAUUCAUANN 
                 31 
               
               
                   
               
               
                 1547-1565 
                 AUGAAUGGUUCUUUAUCAUNN 
                 2117 
                 AUGAUAAAGAACCAUUCAUNN 
                 31 
               
               
                   
               
               
                 1548-1566 
                 UGAAUGGUUCUUUAUCAUUNN 
                 2118 
                 AAUGAUAAAGAACCAUUCANN 
                 31 
               
               
                   
               
               
                 1549-1567 
                 GAAUGGUUCUUUAUCAUUUNN 
                 2119 
                 AAAUGAUAAAGAACCAUUCNN 
                 31 
               
               
                   
               
               
                 1550-1568 
                 AAUGGUUCUUUAUCAUUUCNN 
                 2120 
                 GAAAUGAUAAAGAACCAUUNN 
                 31 
               
               
                   
               
               
                 1551-1569 
                 AUGGUUCUUUAUCAUUUCUNN 
                 2121 
                 AGAAAUGAUAAAGAACCAUNN 
                 31 
               
               
                   
               
               
                  155-173 
                 UGCCGCUCAUGGUGCCAGCNN 
                 2122 
                 GCUGGCACCAUGAGCGGCANN 
                 31 
               
               
                   
               
               
                 1552-1570 
                 UGGUUCUUUAUCAUUUCUCNN 
                 2123 
                 GAGAAAUGAUAAAGAACCANN 
                 31 
               
               
                   
               
               
                 1553-1571 
                 GGUUCUUUAUCAUUUCUCUNN 
                 2124 
                 AGAGAAAUGAUAAAGAACCNN 
                 31 
               
               
                   
               
               
                 1554-1572 
                 GUUCUUUAUCAUUUCUCUUNN 
                 2125 
                 AAGAGAAAUGAUAAAGAACNN 
                 31 
               
               
                   
               
               
                 1555-1573 
                 UUCUUUAUCAUUUCUCUUCNN 
                 2126 
                 GAAGAGAAAUGAUAAAGAANN 
                 31 
               
               
                   
               
               
                 1556-1574 
                 UCUUUAUCAUUUCUCUUCCNN 
                 2127 
                 GGAAGAGAAAUGAUAAAGANN 
                 31 
               
               
                   
               
               
                 1557-1575 
                 CUUUAUCAUUUCUCUUCCCNN 
                 2128 
                 GGGAAGAGAAAUGAUAAAGNN 
                 31 
               
               
                   
               
               
                 1558-1576 
                 UUUAUCAUUUCUCUUCCCCNN 
                 2129 
                 GGGGAAGAGAAAUGAUAAANN 
                 31 
               
               
                   
               
               
                 1559-1577 
                 UUAUCAUUUCUCUUCCCCCNN 
                 2130 
                 GGGGGAAGAGAAAUGAUAANN 
                 31 
               
               
                   
               
               
                 1560-1578 
                 UAUCAUUUCUCUUCCCCCUNN 
                 2131 
                 AGGGGGAAGAGAAAUGAUANN 
                 31 
               
               
                   
               
               
                 1561-1579 
                 AUCAUUUCUCUUCCCCCUUNN 
                 2132 
                 AAGGGGGAAGAGAAAUGAUNN 
                 31 
               
               
                   
               
               
                  156-174 
                 GCCGCUCAUGGUGCCAGCCNN 
                 2133 
                 GGCUGGCACCAUGAGCGGCNN 
                 31 
               
               
                   
               
               
                 1562-1580 
                 UCAUUUCUCUUCCCCCUUUNN 
                 2134 
                 AAAGGGGGAAGAGAAAUGANN 
                 31 
               
               
                   
               
               
                 1563-1581 
                 CAUUUCUCUUCCCCCUUUUNN 
                 2135 
                 AAAAGGGGGAAGAGAAAUGNN 
                 31 
               
               
                   
               
               
                 1564-1582 
                 AUUUCUCUUCCCCCUUUUUNN 
                 2136 
                 AAAAAGGGGGAAGAGAAAUNN 
                 31 
               
               
                   
               
               
                 1565-1583 
                 UUUCUCUUCCCCCUUUUUGNN 
                 2137 
                 CAAAAAGGGGGAAGAGAAANN 
                 31 
               
               
                   
               
               
                 1566-1584 
                 UUCUCUUCCCCCUUUUUGGNN 
                 2138 
                 CCAAAAAGGGGGAAGAGAANN 
                 31 
               
               
                   
               
               
                 1567-1585 
                 UCUCUUCCCCCUUUUUGGCNN 
                 2139 
                 GCCAAAAAGGGGGAAGAGANN 
                 31 
               
               
                   
               
               
                 1568-1586 
                 CUCUUCCCCCUUUUUGGCANN 
                 2140 
                 UGCCAAAAAGGGGGAAGAGNN 
                 31 
               
               
                   
               
               
                 1569-1587 
                 UCUUCCCCCUUUUUGGCAUNN 
                 2141 
                 AUGCCAAAAAGGGGGAAGANN 
                 32 
               
               
                   
               
               
                 1570-1588 
                 CUUCCCCCUUUUUGGCAUCNN 
                 2142 
                 GAUGCCAAAAAGGGGGAAGNN 
                 32 
               
               
                   
               
               
                 1571-1589 
                 UUCCCCCUUUUUGGCAUCCNN 
                 2143 
                 GGAUGCCAAAAAGGGGGAANN 
                 32 
               
               
                   
               
               
                  157-175 
                 CCGCUCAUGGUGCCAGCCCNN 
                 2144 
                 GGGCUGGCACCAUGAGCGGNN 
                 32 
               
               
                   
               
               
                 1572-1590 
                 UCCCCCUUUUUGGCAUCCUNN 
                 2145 
                 AGGAUGCCAAAAAGGGGGANN 
                 32 
               
               
                   
               
               
                 1573-1591 
                 CCCCCUUUUUGGCAUCCUGNN 
                 2146 
                 CAGGAUGCCAAAAAGGGGGNN 
                 32 
               
               
                   
               
               
                 1574-1592 
                 CCCCUUUUUGGCAUCCUGGNN 
                 2147 
                 CCAGGAUGCCAAAAAGGGGNN 
                 32 
               
               
                   
               
               
                 1575-1593 
                 CCCUUUUUGGCAUCCUGGCNN 
                 2148 
                 GCCAGGAUGCCAAAAAGGGNN 
                 32 
               
               
                   
               
               
                 1576-1594 
                 CCUUUUUGGCAUCCUGGCUNN 
                 2149 
                 AGCCAGGAUGCCAAAAAGGNN 
                 32 
               
               
                   
               
               
                 1577-1595 
                 CUUUUUGGCAUCCUGGCUUNN 
                 2150 
                 AAGCCAGGAUGCCAAAAAGNN 
                 32 
               
               
                   
               
               
                 1578-1596 
                 UUUUUGGCAUCCUGGCUUGNN 
                 2151 
                 CAAGCCAGGAUGCCAAAAANN 
                 32 
               
               
                   
               
               
                 1579-1597 
                 UUUUGGCAUCCUGGCUUGCNN 
                 2152 
                 GCAAGCCAGGAUGCCAAAANN 
                 32 
               
               
                   
               
               
                 1580-1598 
                 UUUGGCAUCCUGGCUUGCCNN 
                 2153 
                 GGCAAGCCAGGAUGCCAAANN 
                 32 
               
               
                   
               
               
                 1581-1599 
                 UUGGCAUCCUGGCUUGCCUNN 
                 2154 
                 AGGCAAGCCAGGAUGCCAANN 
                 32 
               
               
                   
               
               
                  158-176 
                 CGCUCAUGGUGCCAGCCCANN 
                 2155 
                 UGGGCUGGCACCAUGAGCGNN 
                 32 
               
               
                   
               
               
                 1582-1600 
                 UGGCAUCCUGGCUUGCCUCNN 
                 2156 
                 GAGGCAAGCCAGGAUGCCANN 
                 32 
               
               
                   
               
               
                 1583-1601 
                 GGCAUCCUGGCUUGCCUCCNN 
                 2157 
                 GGAGGCAAGCCAGGAUGCCNN 
                 32 
               
               
                   
               
               
                 1584-1602 
                 GCAUCCUGGCUUGCCUCCANN 
                 2158 
                 UGGAGGCAAGCCAGGAUGCNN 
                 32 
               
               
                   
               
               
                 1585-1603 
                 CAUCCUGGCUUGCCUCCAGNN 
                 2159 
                 CUGGAGGCAAGCCAGGAUGNN 
                 32 
               
               
                   
               
               
                 1586-1604 
                 AUCCUGGCUUGCCUCCAGUNN 
                 2160 
                 ACUGGAGGCAAGCCAGGAUNN 
                 32 
               
               
                   
               
               
                 1587-1605 
                 UCCUGGCUUGCCUCCAGUUNN 
                 2161 
                 AACUGGAGGCAAGCCAGGANN 
                 32 
               
               
                   
               
               
                 1588-1606 
                 CCUGGCUUGCCUCCAGUUUNN 
                 2162 
                 AAACUGGAGGCAAGCCAGGNN 
                 32 
               
               
                   
               
               
                 1589-1607 
                 CUGGCUUGCCUCCAGUUUUNN 
                 2163 
                 AAAACUGGAGGCAAGCCAGNN 
                 32 
               
               
                   
               
               
                 1590-1608 
                 UGGCUUGCCUCCAGUUUUANN 
                 2164 
                 UAAAACUGGAGGCAAGCCANN 
                 32 
               
               
                   
               
               
                 1591-1609 
                 GGCUUGCCUCCAGUUUUAGNN 
                 2165 
                 CUAAAACUGGAGGCAAGCCNN 
                 32 
               
               
                   
               
               
                  159-177 
                 GCUCAUGGUGCCAGCCCAGNN 
                 2166 
                 CUGGGCUGGCACCAUGAGCNN 
                 32 
               
               
                   
               
               
                 1592-1610 
                 GCUUGCCUCCAGUUUUAGGNN 
                 2167 
                 CCUAAAACUGGAGGCAAGCNN 
                 32 
               
               
                   
               
               
                 1593-1611 
                 CUUGCCUCCAGUUUUAGGUNN 
                 2168 
                 ACCUAAAACUGGAGGCAAGNN 
                 32 
               
               
                   
               
               
                 1594-1612 
                 UUGCCUCCAGUUUUAGGUCNN 
                 2169 
                 GACCUAAAACUGGAGGCAANN 
                 32 
               
               
                   
               
               
                 1595-1613 
                 UGCCUCCAGUUUUAGGUCCNN 
                 2170 
                 GGACCUAAAACUGGAGGCANN 
                 32 
               
               
                   
               
               
                  160-178 
                 CUCAUGGUGCCAGCCCAGANN 
                 2171 
                 UCUGGGCUGGCACCAUGAGNN 
                 32 
               
               
                   
               
               
                  161-179 
                 UCAUGGUGCCAGCCCAGAGNN 
                 2172 
                 CUCUGGGCUGGCACCAUGANN 
                 32 
               
               
                   
               
               
                 1615-1633 
                 UUAGUUUGCUUCUGUAAGCNN 
                 2173 
                 GCUUACAGAAGCAAACUAANN 
                 32 
               
               
                   
               
               
                 1616-1634 
                 UAGUUUGCUUCUGUAAGCANN 
                 2174 
                 UGCUUACAGAAGCAAACUANN 
                 32 
               
               
                   
               
               
                 1617-1635 
                 AGUUUGCUUCUGUAAGCAANN 
                 2175 
                 UUGCUUACAGAAGCAAACUNN 
                 32 
               
               
                   
               
               
                  162-180 
                 CAUGGUGCCAGCCCAGAGANN 
                 2176 
                 UCUCUGGGCUGGCACCAUGNN 
                 32 
               
               
                   
               
               
                  163-181 
                 AUGGUGCCAGCCCAGAGAGNN 
                 2177 
                 CUCUCUGGGCUGGCACCAUNN 
                 32 
               
               
                   
               
               
                 1639-1657 
                 GAACACCUGCUGAGGGGGCNN 
                 2178 
                 GCCCCCUCAGCAGGUGUUCNN 
                 32 
               
               
                   
               
               
                 1640-1658 
                 AACACCUGCUGAGGGGGCUNN 
                 2179 
                 AGCCCCCUCAGCAGGUGUUNN 
                 32 
               
               
                   
               
               
                 1641-1659 
                 ACACCUGCUGAGGGGGCUCNN 
                 2180 
                 GAGCCCCCUCAGCAGGUGUNN 
                 32 
               
               
                   
               
               
                  164-182 
                 UGGUGCCAGCCCAGAGAGGNN 
                 2181 
                 CCUCUCUGGGCUGGCACCANN 
                 32 
               
               
                   
               
               
                 1642-1660 
                 CACCUGCUGAGGGGGCUCUNN 
                 2182 
                 AGAGCCCCCUCAGCAGGUGNN 
                 32 
               
               
                   
               
               
                 1643-1661 
                 ACCUGCUGAGGGGGCUCUUNN 
                 2183 
                 AAGAGCCCCCUCAGCAGGUNN 
                 32 
               
               
                   
               
               
                 1644-1662 
                 CCUGCUGAGGGGGCUCUUUNN 
                 2184 
                 AAAGAGCCCCCUCAGCAGGNN 
                 32 
               
               
                   
               
               
                 1645-1663 
                 CUGCUGAGGGGGCUCUUUCNN 
                 2185 
                 GAAAGAGCCCCCUCAGCAGNN 
                 32 
               
               
                   
               
               
                 1646-1664 
                 UGCUGAGGGGGCUCUUUCCNN 
                 2186 
                 GGAAAGAGCCCCCUCAGCANN 
                 32 
               
               
                   
               
               
                 1647-1665 
                 GCUGAGGGGGCUCUUUCCCNN 
                 2187 
                 GGGAAAGAGCCCCCUCAGCNN 
                 32 
               
               
                   
               
               
                 1648-1666 
                 CUGAGGGGGCUCUUUCCCUNN 
                 2188 
                 AGGGAAAGAGCCCCCUCAGNN 
                 32 
               
               
                   
               
               
                 1649-1667 
                 UGAGGGGGCUCUUUCCCUCNN 
                 2189 
                 GAGGGAAAGAGCCCCCUCANN 
                 32 
               
               
                   
               
               
                 1650-1668 
                 GAGGGGGCUCUUUCCCUCANN 
                 2190 
                 UGAGGGAAAGAGCCCCCUCNN 
                 32 
               
               
                   
               
               
                  165-183 
                 GGUGCCAGCCCAGAGAGGGNN 
                 2191 
                 CCCUCUCUGGGCUGGCACCNN 
                 32 
               
               
                   
               
               
                  166-184 
                 GUGCCAGCCCAGAGAGGGGNN 
                 2192 
                 CCCCUCUCUGGGCUGGCACNN 
                 32 
               
               
                   
               
               
                 1670-1688 
                 GUAUACUUCAAGUAAGAUCNN 
                 2193 
                 GAUCUUACUUGAAGUAUACNN 
                 32 
               
               
                   
               
               
                 1671-1689 
                 UAUACUUCAAGUAAGAUCANN 
                 2194 
                 UGAUCUUACUUGAAGUAUANN 
                 32 
               
               
                   
               
               
                  167-185 
                 UGCCAGCCCAGAGAGGGGCNN 
                 2195 
                 GCCCCUCUCUGGGCUGGCANN 
                 32 
               
               
                   
               
               
                 1672-1690 
                 AUACUUCAAGUAAGAUCAANN 
                 2196 
                 UUGAUCUUACUUGAAGUAUNN 
                 32 
               
               
                   
               
               
                 1673-1691 
                 UACUUCAAGUAAGAUCAAGNN 
                 2197 
                 CUUGAUCUUACUUGAAGUANN 
                 32 
               
               
                   
               
               
                 1674-1692 
                 ACUUCAAGUAAGAUCAAGANN 
                 2198 
                 UCUUGAUCUUACUUGAAGUNN 
                 32 
               
               
                   
               
               
                 1675-1693 
                 CUUCAAGUAAGAUCAAGAANN 
                 2199 
                 UUCUUGAUCUUACUUGAAGNN 
                 32 
               
               
                   
               
               
                 1676-1694 
                 UUCAAGUAAGAUCAAGAAUNN 
                 2200 
                 AUUCUUGAUCUUACUUGAANN 
                 32 
               
               
                   
               
               
                 1677-1695 
                 UCAAGUAAGAUCAAGAAUCNN 
                 2201 
                 GAUUCUUGAUCUUACUUGANN 
                 32 
               
               
                   
               
               
                 1678-1696 
                 CAAGUAAGAUCAAGAAUCUNN 
                 2202 
                 AGAUUCUUGAUCUUACUUGNN 
                 32 
               
               
                   
               
               
                 1679-1697 
                 AAGUAAGAUCAAGAAUCUUNN 
                 2203 
                 AAGAUUCUUGAUCUUACUUNN 
                 32 
               
               
                   
               
               
                 1680-1698 
                 AGUAAGAUCAAGAAUCUUUNN 
                 2204 
                 AAAGAUUCUUGAUCUUACUNN 
                 32 
               
               
                   
               
               
                 1681-1699 
                 GUAAGAUCAAGAAUCUUUUNN 
                 2205 
                 AAAAGAUUCUUGAUCUUACNN 
                 32 
               
               
                   
               
               
                 1682-1700 
                 UAAGAUCAAGAAUCUUUUGNN 
                 2206 
                 CAAAAGAUUCUUGAUCUUANN 
                 32 
               
               
                   
               
               
                 1683-1701 
                 AAGAUCAAGAAUCUUUUGUNN 
                 2207 
                 ACAAAAGAUUCUUGAUCUUNN 
                 32 
               
               
                   
               
               
                 1684-1702 
                 AGAUCAAGAAUCUUUUGUGNN 
                 2208 
                 CACAAAAGAUUCUUGAUCUNN 
                 32 
               
               
                   
               
               
                 1685-1703 
                 GAUCAAGAAUCUUUUGUGANN 
                 2209 
                 UCACAAAAGAUUCUUGAUCNN 
                 32 
               
               
                   
               
               
                 1686-1704 
                 AUCAAGAAUCUUUUGUGAANN 
                 2210 
                 UUCACAAAAGAUUCUUGAUNN 
                 32 
               
               
                   
               
               
                 1687-1705 
                 UCAAGAAUCUUUUGUGAAANN 
                 2211 
                 UUUCACAAAAGAUUCUUGANN 
                 32 
               
               
                   
               
               
                 1707-1725 
                 UAUAGAAAUUUACUAUGUANN 
                 2212 
                 UACAUAGUAAAUUUCUAUANN 
                 32 
               
               
                   
               
               
                 1708-1726 
                 AUAGAAAUUUACUAUGUAANN 
                 2213 
                 UUACAUAGUAAAUUUCUAUNN 
                 32 
               
               
                   
               
               
                 1709-1727 
                 UAGAAAUUUACUAUGUAAANN 
                 2214 
                 UUUACAUAGUAAAUUUCUANN 
                 32 
               
               
                   
               
               
                 1710-1728 
                 AGAAAUUUACUAUGUAAAUNN 
                 2215 
                 AUUUACAUAGUAAAUUUCUNN 
                 32 
               
               
                   
               
               
                 1711-1729 
                 GAAAUUUACUAUGUAAAUGNN 
                 2216 
                 CAUUUACAUAGUAAAUUUCNN 
                 32 
               
               
                   
               
               
                 1712-1730 
                 AAAUUUACUAUGUAAAUGCNN 
                 2217 
                 GCAUUUACAUAGUAAAUUUNN 
                 32 
               
               
                   
               
               
                 1713-1731 
                 AAUUUACUAUGUAAAUGCUNN 
                 2218 
                 AGCAUUUACAUAGUAAAUUNN 
                 32 
               
               
                   
               
               
                 1714-1732 
                 AUUUACUAUGUAAAUGCUUNN 
                 2219 
                 AAGCAUUUACAUAGUAAAUNN 
                 32 
               
               
                   
               
               
                 1715-1733 
                 UUUACUAUGUAAAUGCUUGNN 
                 2220 
                 CAAGCAUUUACAUAGUAAANN 
                 32 
               
               
                   
               
               
                 1716-1734 
                 UUACUAUGUAAAUGCUUGANN 
                 2221 
                 UCAAGCAUUUACAUAGUAANN 
                 32 
               
               
                   
               
               
                 1717-1735 
                 UACUAUGUAAAUGCUUGAUNN 
                 2222 
                 AUCAAGCAUUUACAUAGUANN 
                 32 
               
               
                   
               
               
                 1718-1736 
                 ACUAUGUAAAUGCUUGAUGNN 
                 2223 
                 CAUCAAGCAUUUACAUAGUNN 
                 32 
               
               
                   
               
               
                 1719-1737 
                 CUAUGUAAAUGCUUGAUGGNN 
                 2224 
                 CCAUCAAGCAUUUACAUAGNN 
                 32 
               
               
                   
               
               
                 1720-1738 
                 UAUGUAAAUGCUUGAUGGANN 
                 2225 
                 UCCAUCAAGCAUUUACAUANN 
                 32 
               
               
                   
               
               
                 1721-1739 
                 AUGUAAAUGCUUGAUGGAANN 
                 2226 
                 UUCCAUCAAGCAUUUACAUNN 
                 32 
               
               
                   
               
               
                 1722-1740 
                 UGUAAAUGCUUGAUGGAAUNN 
                 2227 
                 AUUCCAUCAAGCAUUUACANN 
                 32 
               
               
                   
               
               
                 1723-1741 
                 GUAAAUGCUUGAUGGAAUUNN 
                 2228 
                 AAUUCCAUCAAGCAUUUACNN 
                 32 
               
               
                   
               
               
                 1724-1742 
                 UAAAUGCUUGAUGGAAUUUNN 
                 2229 
                 AAAUUCCAUCAAGCAUUUANN 
                 32 
               
               
                   
               
               
                 1725-1743 
                 AAAUGCUUGAUGGAAUUUUNN 
                 2230 
                 AAAAUUCCAUCAAGCAUUUNN 
                 32 
               
               
                   
               
               
                 1726-1744 
                 AAUGCUUGAUGGAAUUUUUNN 
                 2231 
                 AAAAAUUCCAUCAAGCAUUNN 
                 32 
               
               
                   
               
               
                 1727-1745 
                 AUGCUUGAUGGAAUUUUUUNN 
                 2232 
                 AAAAAAUUCCAUCAAGCAUNN 
                 32 
               
               
                   
               
               
                 1728-1746 
                 UGCUUGAUGGAAUUUUUUCNN 
                 2233 
                 GAAAAAAUUCCAUCAAGCANN 
                 32 
               
               
                   
               
               
                 1729-1747 
                 GCUUGAUGGAAUUUUUUCCNN 
                 2234 
                 GGAAAAAAUUCCAUCAAGCNN 
                 32 
               
               
                   
               
               
                 1730-1748 
                 CUUGAUGGAAUUUUUUCCUNN 
                 2235 
                 AGGAAAAAAUUCCAUCAAGNN 
                 32 
               
               
                   
               
               
                 1731-1749 
                 UUGAUGGAAUUUUUUCCUGNN 
                 2236 
                 CAGGAAAAAAUUCCAUCAANN 
                 32 
               
               
                   
               
               
                 1732-1750 
                 UGAUGGAAUUUUUUCCUGCNN 
                 2237 
                 GCAGGAAAAAAUUCCAUCANN 
                 32 
               
               
                   
               
               
                 1733-1751 
                 GAUGGAAUUUUUUCCUGCUNN 
                 2238 
                 AGCAGGAAAAAAUUCCAUCNN 
                 32 
               
               
                   
               
               
                 1734-1752 
                 AUGGAAUUUUUUCCUGCUANN 
                 2239 
                 UAGCAGGAAAAAAUUCCAUNN 
                 32 
               
               
                   
               
               
                 1735-1753 
                 UGGAAUUUUUUCCUGCUAGNN 
                 2240 
                 CUAGCAGGAAAAAAUUCCANN 
                 32 
               
               
                   
               
               
                 1736-1754 
                 GGAAUUUUUUCCUGCUAGUNN 
                 2241 
                 ACUAGCAGGAAAAAAUUCCNN 
                 33 
               
               
                   
               
               
                 1737-1755 
                 GAAUUUUUUCCUGCUAGUGNN 
                 2242 
                 CACUAGCAGGAAAAAAUUCNN 
                 33 
               
               
                   
               
               
                 1738-1756 
                 AAUUUUUUCCUGCUAGUGUNN 
                 2243 
                 ACACUAGCAGGAAAAAAUUNN 
                 33 
               
               
                   
               
               
                 1739-1757 
                 AUUUUUUCCUGCUAGUGUANN 
                 2244 
                 UACACUAGCAGGAAAAAAUNN 
                 33 
               
               
                   
               
               
                 1740-1758 
                 UUUUUUCCUGCUAGUGUAGNN 
                 2245 
                 CUACACUAGCAGGAAAAAANN 
                 33 
               
               
                   
               
               
                 1741-1759 
                 UUUUUCCUGCUAGUGUAGCNN 
                 2246 
                 GCUACACUAGCAGGAAAAANN 
                 33 
               
               
                   
               
               
                 1742-1760 
                 UUUUCCUGCUAGUGUAGCUNN 
                 2247 
                 AGCUACACUAGCAGGAAAANN 
                 33 
               
               
                   
               
               
                 1743-1761 
                 UUUCCUGCUAGUGUAGCUUNN 
                 2248 
                 AAGCUACACUAGCAGGAAANN 
                 33 
               
               
                   
               
               
                 1744-1762 
                 UUCCUGCUAGUGUAGCUUCNN 
                 2249 
                 GAAGCUACACUAGCAGGAANN 
                 33 
               
               
                   
               
               
                 1745-1763 
                 UCCUGCUAGUGUAGCUUCUNN 
                 2250 
                 AGAAGCUACACUAGCAGGANN 
                 33 
               
               
                   
               
               
                 1746-1764 
                 CCUGCUAGUGUAGCUUCUGNN 
                 2251 
                 CAGAAGCUACACUAGCAGGNN 
                 33 
               
               
                   
               
               
                 1747-1765 
                 CUGCUAGUGUAGCUUCUGANN 
                 2252 
                 UCAGAAGCUACACUAGCAGNN 
                 33 
               
               
                   
               
               
                 1748-1766 
                 UGCUAGUGUAGCUUCUGAANN 
                 2253 
                 UUCAGAAGCUACACUAGCANN 
                 33 
               
               
                   
               
               
                 1749-1767 
                 GCUAGUGUAGCUUCUGAAANN 
                 2254 
                 UUUCAGAAGCUACACUAGCNN 
                 33 
               
               
                   
               
               
                 1750-1768 
                 CUAGUGUAGCUUCUGAAAGNN 
                 2255 
                 CUUUCAGAAGCUACACUAGNN 
                 33 
               
               
                   
               
               
                 1751-1769 
                 UAGUGUAGCUUCUGAAAGGNN 
                 2256 
                 CCUUUCAGAAGCUACACUANN 
                 33 
               
               
                   
               
               
                 1752-1770 
                 AGUGUAGCUUCUGAAAGGUNN 
                 2257 
                 ACCUUUCAGAAGCUACACUNN 
                 33 
               
               
                   
               
               
                 1753-1771 
                 GUGUAGCUUCUGAAAGGUGNN 
                 2258 
                 CACCUUUCAGAAGCUACACNN 
                 33 
               
               
                   
               
               
                 1754-1772 
                 UGUAGCUUCUGAAAGGUGCNN 
                 2259 
                 GCACCUUUCAGAAGCUACANN 
                 33 
               
               
                   
               
               
                 1755-1773 
                 GUAGCUUCUGAAAGGUGCUNN 
                 2260 
                 AGCACCUUUCAGAAGCUACNN 
                 33 
               
               
                   
               
               
                 1756-1774 
                 UAGCUUCUGAAAGGUGCUUNN 
                 2261 
                 AAGCACCUUUCAGAAGCUANN 
                 33 
               
               
                   
               
               
                 1757-1775 
                 AGCUUCUGAAAGGUGCUUUNN 
                 2262 
                 AAAGCACCUUUCAGAAGCUNN 
                 33 
               
               
                   
               
               
                 1758-1776 
                 GCUUCUGAAAGGUGCUUUCNN 
                 2263 
                 GAAAGCACCUUUCAGAAGCNN 
                 33 
               
               
                   
               
               
                 1777-1795 
                 UCCAUUUAUUUAAAACUACNN 
                 2264 
                 GUAGUUUUAAAUAAAUGGANN 
                 33 
               
               
                   
               
               
                 1778-1796 
                 CCAUUUAUUUAAAACUACCNN 
                 2265 
                 GGUAGUUUUAAAUAAAUGGNN 
                 33 
               
               
                   
               
               
                 1779-1797 
                 CAUUUAUUUAAAACUACCCNN 
                 2266 
                 GGGUAGUUUUAAAUAAAUGNN 
                 33 
               
               
                   
               
               
                 1780-1798 
                 AUUUAUUUAAAACUACCCANN 
                 2267 
                 UGGGUAGUUUUAAAUAAAUNN 
                 33 
               
               
                   
               
               
                 1781-1799 
                 UUUAUUUAAAACUACCCAUNN 
                 2268 
                 AUGGGUAGUUUUAAAUAAANN 
                 33 
               
               
                   
               
               
                 1782-1800 
                 UUAUUUAAAACUACCCAUGNN 
                 2269 
                 CAUGGGUAGUUUUAAAUAANN 
                 33 
               
               
                   
               
               
                 1783-1801 
                 UAUUUAAAACUACCCAUGCNN 
                 2270 
                 GCAUGGGUAGUUUUAAAUANN 
                 33 
               
               
                   
               
               
                 1784-1802 
                 AUUUAAAACUACCCAUGCANN 
                 2271 
                 UGCAUGGGUAGUUUUAAAUNN 
                 33 
               
               
                   
               
               
                 1785-1803 
                 UUUAAAACUACCCAUGCAANN 
                 2272 
                 UUGCAUGGGUAGUUUUAAANN 
                 33 
               
               
                   
               
               
                 1786-1804 
                 UUAAAACUACCCAUGCAAUNN 
                 2273 
                 AUUGCAUGGGUAGUUUUAANN 
                 33 
               
               
                   
               
               
                 1787-1805 
                 UAAAACUACCCAUGCAAUUNN 
                 2274 
                 AAUUGCAUGGGUAGUUUUANN 
                 33 
               
               
                   
               
               
                 1788-1806 
                 AAAACUACCCAUGCAAUUANN 
                 2275 
                 UAAUUGCAUGGGUAGUUUUNN 
                 33 
               
               
                   
               
               
                 1789-1807 
                 AAACUACCCAUGCAAUUAANN 
                 2276 
                 UUAAUUGCAUGGGUAGUUUNN 
                 33 
               
               
                   
               
               
                 1790-1808 
                 AACUACCCAUGCAAUUAAANN 
                 2277 
                 UUUAAUUGCAUGGGUAGUUNN 
                 33 
               
               
                   
               
               
                 1791-1809 
                 ACUACCCAUGCAAUUAAAANN 
                 2278 
                 UUUUAAUUGCAUGGGUAGUNN 
                 33 
               
               
                   
               
               
                 1792-1810 
                 CUACCCAUGCAAUUAAAAGNN 
                 2279 
                 CUUUUAAUUGCAUGGGUAGNN 
                 33 
               
               
                   
               
               
                 1793-1811 
                 UACCCAUGCAAUUAAAAGGNN 
                 2280 
                 CCUUUUAAUUGCAUGGGUANN 
                 33 
               
               
                   
               
               
                 1794-1812 
                 ACCCAUGCAAUUAAAAGGUNN 
                 2281 
                 ACCUUUUAAUUGCAUGGGUNN 
                 33 
               
               
                   
               
               
                 1795-1813 
                 CCCAUGCAAUUAAAAGGUANN 
                 2282 
                 UACCUUUUAAUUGCAUGGGNN 
                 33 
               
               
                   
               
               
                 1796-1814 
                 CCAUGCAAUUAAAAGGUACNN 
                 2283 
                 GUACCUUUUAAUUGCAUGGNN 
                 33 
               
               
                   
               
               
                 1797-1815 
                 CAUGCAAUUAAAAGGUACANN 
                 2284 
                 UGUACCUUUUAAUUGCAUGNN 
                 33 
               
               
                   
               
               
                 1798-1816 
                 AUGCAAUUAAAAGGUACAANN 
                 2285 
                 UUGUACCUUUUAAUUGCAUNN 
                 33 
               
               
                   
               
               
                 1799-1817 
                 UGCAAUUAAAAGGUACAAUNN 
                 2286 
                 AUUGUACCUUUUAAUUGCANN 
                 33 
               
               
                   
               
               
                 1800-1818 
                 GCAAUUAAAAGGUACAAUGNN 
                 2287 
                 CAUUGUACCUUUUAAUUGCNN 
                 33 
               
               
                   
               
               
                 1801-1819 
                 CAAUUAAAAGGUACAAUGCNN 
                 2288 
                 GCAUUGUACCUUUUAAUUGNN 
                 33 
               
               
                   
               
               
                 1802-1820 
                 AAUUAAAAGGUACAAUGCANN 
                 2289 
                 UGCAUUGUACCUUUUAAUUNN 
                 33 
               
               
                   
               
               
                  187-205 
                 AGCCCGGAGGCAGCGAGCGNN 
                 2290 
                 CGCTCGCTGCCTCCGGGCTNN 
                 33 
               
               
                   
               
               
                  188-206 
                 GCCCGGAGGCAGCGAGCGGNN 
                 2291 
                 CCGCTCGCTGCCTCCGGGCNN 
                 33 
               
               
                   
               
               
                  189-207 
                 CCCGGAGGCAGCGAGCGGGNN 
                 2292 
                 CCCGCTCGCTGCCTCCGGGNN 
                 33 
               
               
                   
               
               
                  190-208 
                 CCGGAGGCAGCGAGCGGGGNN 
                 2293 
                 CCCCGCTCGCTGCCTCCGGNN 
                 33 
               
               
                   
               
               
                  191-209 
                 CGGAGGCAGCGAGCGGGGGNN 
                 2294 
                 CCCCCGCTCGCTGCCTCCGNN 
                 33 
               
               
                   
               
               
                  192-210 
                 GGAGGCAGCGAGCGGGGGGNN 
                 2295 
                 CCCCCCGCTCGCTGCCTCCNN 
                 33 
               
               
                   
               
               
                  193-211 
                 GAGGCAGCGAGCGGGGGGCNN 
                 2296 
                 GCCCCCCGCTCGCTGCCTCNN 
                 33 
               
               
                   
               
               
                  194-212 
                 AGGCAGCGAGCGGGGGGCUNN 
                 2297 
                 AGCCCCCCGCUCGCUGCCUNN 
                 33 
               
               
                   
               
               
                  195-213 
                 GGCAGCGAGCGGGGGGCUGNN 
                 2298 
                 CAGCCCCCCGCUCGCUGCCNN 
                 33 
               
               
                   
               
               
                  196-214 
                 GCAGCGAGCGGGGGGCUGCNN 
                 2299 
                 GCAGCCCCCCGCUCGCUGCNN 
                 33 
               
               
                   
               
               
                  197-215 
                 CAGCGAGCGGGGGGCUGCCNN 
                 2300 
                 GGCAGCCCCCCGCUCGCUGNN 
                 33 
               
               
                   
               
               
                  198-216 
                 AGCGAGCGGGGGGCUGCCCNN 
                 2301 
                 GGGCAGCCCCCCGCUCGCUNN 
                 33 
               
               
                   
               
               
                  199-217 
                 GCGAGCGGGGGGCUGCCCCNN 
                 2302 
                 GGGGCAGCCCCCCGCUCGCNN 
                 33 
               
               
                   
               
               
                  200-218 
                 CGAGCGGGGGGCUGCCCCANN 
                 2303 
                 UGGGGCAGCCCCCCGCUCGNN 
                 33 
               
               
                   
               
               
                  201-219 
                 GAGCGGGGGGCUGCCCCAGNN 
                 2304 
                 CUGGGGCAGCCCCCCGCUCNN 
                 33 
               
               
                   
               
               
                  202-220 
                 AGCGGGGGGCUGCCCCAGGNN 
                 2305 
                 CCUGGGGCAGCCCCCCGCUNN 
                 33 
               
               
                   
               
               
                  203-221 
                 GCGGGGGGCUGCCCCAGGCNN 
                 2306 
                 GCCUGGGGCAGCCCCCCGCNN 
                 33 
               
               
                   
               
               
                  204-222 
                 CGGGGGGCUGCCCCAGGCGNN 
                 2307 
                 CGCCUGGGGCAGCCCCCCGNN 
                 33 
               
               
                   
               
               
                  205-223 
                 GGGGGGCUGCCCCAGGCGCNN 
                 2308 
                 GCGCCUGGGGCAGCCCCCCNN 
                 33 
               
               
                   
               
               
                  206-224 
                 GGGGGCUGCCCCAGGCGCGNN 
                 2309 
                 CGCGCCUGGGGCAGCCCCCNN 
                 33 
               
               
                   
               
               
                  207-225 
                 GGGGCUGCCCCAGGCGCGCNN 
                 2310 
                 GCGCGCCUGGGGCAGCCCCNN 
                 33 
               
               
                   
               
               
                  208-226 
                 GGGCUGCCCCAGGCGCGCANN 
                 2311 
                 UGCGCGCCUGGGGCAGCCCNN 
                 33 
               
               
                   
               
               
                  209-227 
                 GGCUGCCCCAGGCGCGCAANN 
                 2312 
                 UUGCGCGCCUGGGGCAGCCNN 
                 33 
               
               
                   
               
               
                  210-228 
                 GCUGCCCCAGGCGCGCAAGNN 
                 2313 
                 CUUGCGCGCCUGGGGCAGCNN 
                 33 
               
               
                   
               
               
                  211-229 
                 CUGCCCCAGGCGCGCAAGCNN 
                 2314 
                 GCUUGCGCGCCUGGGGCAGNN 
                 33 
               
               
                   
               
               
                  212-230 
                 UGCCCCAGGCGCGCAAGCGNN 
                 2315 
                 CGCUUGCGCGCCUGGGGCANN 
                 33 
               
               
                   
               
               
                  247-265 
                 CUGAGCCCCGAGGAGAAGGNN 
                 2316 
                 CCUUCUCCUCGGGGCUCAGNN 
                 33 
               
               
                   
               
               
                  248-266 
                 UGAGCCCCGAGGAGAAGGCNN 
                 2317 
                 GCCUUCUCCUCGGGGCUCANN 
                 33 
               
               
                   
               
               
                  249-267 
                 GAGCCCCGAGGAGAAGGCGNN 
                 2318 
                 CGCCTTCTCCTCGGGGCTCNN 
                 33 
               
               
                   
               
               
                  250-268 
                 AGCCCCGAGGAGAAGGCGCNN 
                 2319 
                 GCGCCTTCTCCTCGGGGCTNN 
                 33 
               
               
                   
               
               
                  251-269 
                 GCCCCGAGGAGAAGGCGCUNN 
                 2320 
                 AGCGCCUUCUCCUCGGGGCNN 
                 33 
               
               
                   
               
               
                  252-270 
                 CCCCGAGGAGAAGGCGCUGNN 
                 2321 
                 CAGCGCCUUCUCCUCGGGGNN 
                 33 
               
               
                   
               
               
                  253-271 
                 CCCGAGGAGAAGGCGCUGANN 
                 2322 
                 UCAGCGCCUUCUCCUCGGGNN 
                 33 
               
               
                   
               
               
                  254-272 
                 CCGAGGAGAAGGCGCUGAGNN 
                 2323 
                 CUCAGCGCCUUCUCCUCGGNN 
                 33 
               
               
                   
               
               
                  255-273 
                 CGAGGAGAAGGCGCUGAGGNN 
                 2324 
                 CCUCAGCGCCUUCUCCUCGNN 
                 33 
               
               
                   
               
               
                  256-274 
                 GAGGAGAAGGCGCUGAGGANN 
                 2325 
                 UCCUCAGCGCCUUCUCCUCNN 
                 33 
               
               
                   
               
               
                  257-275 
                 AGGAGAAGGCGCUGAGGAGNN 
                 2326 
                 CUCCUCAGCGCCUUCUCCUNN 
                 33 
               
               
                   
               
               
                  258-276 
                 GGAGAAGGCGCUGAGGAGGNN 
                 2327 
                 CCUCCUCAGCGCCUUCUCCNN 
                 33 
               
               
                   
               
               
                  259-277 
                 GAGAAGGCGCUGAGGAGGANN 
                 2328 
                 UCCUCCUCAGCGCCUUCUCNN 
                 33 
               
               
                   
               
               
                  260-278 
                 AGAAGGCGCUGAGGAGGAANN 
                 2329 
                 UUCCUCCUCAGCGCCUUCUNN 
                 33 
               
               
                   
               
               
                  261-279 
                 GAAGGCGCUGAGGAGGAAANN 
                 2330 
                 UUUCCUCCUCAGCGCCUUCNN 
                 33 
               
               
                   
               
               
                  262-280 
                 AAGGCGCUGAGGAGGAAACNN 
                 2331 
                 GUUUCCUCCUCAGCGCCUUNN 
                 33 
               
               
                   
               
               
                  263-281 
                 AGGCGCUGAGGAGGAAACUNN 
                 2332 
                 AGUUUCCUCCUCAGCGCCUNN 
                 33 
               
               
                   
               
               
                  264-282 
                 GGCGCUGAGGAGGAAACUGNN 
                 2333 
                 CAGUUUCCUCCUCAGCGCCNN 
                 33 
               
               
                   
               
               
                  265-283 
                 GCGCUGAGGAGGAAACUGANN 
                 2334 
                 UCAGUUUCCUCCUCAGCGCNN 
                 33 
               
               
                   
               
               
                  266-284 
                 CGCUGAGGAGGAAACUGAANN 
                 2335 
                 UUCAGUUUCCUCCUCAGCGNN 
                 33 
               
               
                   
               
               
                  267-285 
                 GCUGAGGAGGAAACUGAAANN 
                 2336 
                 UUUCAGUUUCCUCCUCAGCNN 
                 33 
               
               
                   
               
               
                  268-286 
                 CUGAGGAGGAAACUGAAAANN 
                 2337 
                 UUUUCAGUUUCCUCCUCAGNN 
                 33 
               
               
                   
               
               
                  269-287 
                 UGAGGAGGAAACUGAAAAANN 
                 2338 
                 UUUUUCAGUUUCCUCCUCANN 
                 33 
               
               
                   
               
               
                  270-288 
                 GAGGAGGAAACUGAAAAACNN 
                 2339 
                 GUUUUUCAGUUUCCUCCUCNN 
                 33 
               
               
                   
               
               
                  271-289 
                 AGGAGGAAACUGAAAAACANN 
                 2340 
                 UGUUUUUCAGUUUCCUCCUNN 
                 33 
               
               
                   
               
               
                  272-290 
                 GGAGGAAACUGAAAAACAGNN 
                 2341 
                 CUGUUUUUCAGUUUCCUCCNN 
                 34 
               
               
                   
               
               
                  273-291 
                 GAGGAAACUGAAAAACAGANN 
                 2342 
                 UCUGUUUUUCAGUUUCCUCNN 
                 34 
               
               
                   
               
               
                  274-292 
                 AGGAAACUGAAAAACAGAGNN 
                 2343 
                 CUCUGUUUUUCAGUUUCCUNN 
                 34 
               
               
                   
               
               
                  275-293 
                 GGAAACUGAAAAACAGAGUNN 
                 2344 
                 ACUCUGUUUUUCAGUUUCCNN 
                 34 
               
               
                   
               
               
                  276-294 
                 GAAACUGAAAAACAGAGUANN 
                 2345 
                 UACUCUGUUUUUCAGUUUCNN 
                 34 
               
               
                   
               
               
                  277-295 
                 AAACUGAAAAACAGAGUAGNN 
                 2346 
                 CUACUCUGUUUUUCAGUUUNN 
                 34 
               
               
                   
               
               
                  278-296 
                 AACUGAAAAACAGAGUAGCNN 
                 2347 
                 GCUACUCUGUUUUUCAGUUNN 
                 34 
               
               
                   
               
               
                  279-297 
                 ACUGAAAAACAGAGUAGCANN 
                 2348 
                 UGCUACUCUGUUUUUCAGUNN 
                 34 
               
               
                   
               
               
                  280-298 
                 CUGAAAAACAGAGUAGCAGNN 
                 2349 
                 CUGCUACUCUGUUUUUCAGNN 
                 34 
               
               
                   
               
               
                  281-299 
                 UGAAAAACAGAGUAGCAGCNN 
                 2350 
                 GCUGCUACUCUGUUUUUCANN 
                 34 
               
               
                   
               
               
                  282-300 
                 GAAAAACAGAGUAGCAGCUNN 
                 2351 
                 AGCUGCUACUCUGUUUUUCNN 
                 34 
               
               
                   
               
               
                  283-301 
                 AAAAACAGAGUAGCAGCUCNN 
                 2352 
                 GAGCUGCUACUCUGUUUUUNN 
                 34 
               
               
                   
               
               
                  284-302 
                 AAAACAGAGUAGCAGCUCANN 
                 2353 
                 UGAGCUGCUACUCUGUUUUNN 
                 34 
               
               
                   
               
               
                  285-303 
                 AAACAGAGUAGCAGCUCAGNN 
                 2354 
                 CUGAGCUGCUACUCUGUUUNN 
                 34 
               
               
                   
               
               
                  286-304 
                 AACAGAGUAGCAGCUCAGANN 
                 2355 
                 UCUGAGCUGCUACUCUGUUNN 
                 34 
               
               
                   
               
               
                  287-305 
                 ACAGAGUAGCAGCUCAGACNN 
                 2356 
                 GUCUGAGCUGCUACUCUGUNN 
                 34 
               
               
                   
               
               
                  288-306 
                 CAGAGUAGCAGCUCAGACUNN 
                 2357 
                 AGUCUGAGCUGCUACUCUGNN 
                 34 
               
               
                   
               
               
                  289-307 
                 AGAGUAGCAGCUCAGACUGNN 
                 2358 
                 CAGUCUGAGCUGCUACUCUNN 
                 34 
               
               
                   
               
               
                  290-308 
                 GAGUAGCAGCUCAGACUGCNN 
                 2359 
                 GCAGUCUGAGCUGCUACUCNN 
                 34 
               
               
                   
               
               
                  291-309 
                 AGUAGCAGCUCAGACUGCCNN 
                 2360 
                 GGCAGUCUGAGCUGCUACUNN 
                 34 
               
               
                   
               
               
                  292-310 
                 GUAGCAGCUCAGACUGCCANN 
                 2361 
                 UGGCAGUCUGAGCUGCUACNN 
                 34 
               
               
                   
               
               
                  293-311 
                 UAGCAGCUCAGACUGCCAGNN 
                 2362 
                 CUGGCAGUCUGAGCUGCUANN 
                 34 
               
               
                   
               
               
                  294-312 
                 AGCAGCUCAGACUGCCAGANN 
                 2363 
                 UCUGGCAGUCUGAGCUGCUNN 
                 34 
               
               
                   
               
               
                  295-313 
                 GCAGCUCAGACUGCCAGAGNN 
                 2364 
                 CUCUGGCAGUCUGAGCUGCNN 
                 34 
               
               
                   
               
               
                  296-314 
                 CAGCUCAGACUGCCAGAGANN 
                 2365 
                 UCUCUGGCAGUCUGAGCUGNN 
                 34 
               
               
                   
               
               
                  297-315 
                 AGCUCAGACUGCCAGAGAUNN 
                 2366 
                 AUCUCUGGCAGUCUGAGCUNN 
                 34 
               
               
                   
               
               
                  298-316 
                 GCUCAGACUGCCAGAGAUCNN 
                 2367 
                 GAUCUCUGGCAGUCUGAGCNN 
                 34 
               
               
                   
               
               
                  299-317 
                 CUCAGACUGCCAGAGAUCGNN 
                 2368 
                 CGAUCUCUGGCAGUCUGAGNN 
                 34 
               
               
                   
               
               
                  300-318 
                 UCAGACUGCCAGAGAUCGANN 
                 2369 
                 UCGAUCUCUGGCAGUCUGANN 
                 34 
               
               
                   
               
               
                  301-319 
                 CAGACUGCCAGAGAUCGAANN 
                 2370 
                 UUCGAUCUCUGGCAGUCUGNN 
                 34 
               
               
                   
               
               
                  302-320 
                 AGACUGCCAGAGAUCGAAANN 
                 2371 
                 UUUCGAUCUCUGGCAGUCUNN 
                 34 
               
               
                   
               
               
                  303-321 
                 GACUGCCAGAGAUCGAAAGNN 
                 2372 
                 CUUUCGAUCUCUGGCAGUCNN 
                 34 
               
               
                   
               
               
                  304-322 
                 ACUGCCAGAGAUCGAAAGANN 
                 2373 
                 UCUUUCGAUCUCUGGCAGUNN 
                 34 
               
               
                   
               
               
                  305-323 
                 CUGCCAGAGAUCGAAAGAANN 
                 2374 
                 UUCUUUCGAUCUCUGGCAGNN 
                 34 
               
               
                   
               
               
                  325-343 
                 GCUCGAAUGAGUGAGCUGGNN 
                 2375 
                 CCAGCUCACUCAUUCGAGCNN 
                 34 
               
               
                   
               
               
                  326-344 
                 CUCGAAUGAGUGAGCUGGANN 
                 2376 
                 UCCAGCUCACUCAUUCGAGNN 
                 34 
               
               
                   
               
               
                  327-345 
                 UCGAAUGAGUGAGCUGGAANN 
                 2377 
                 UUCCAGCUCACUCAUUCGANN 
                 34 
               
               
                   
               
               
                  328-346 
                 CGAAUGAGUGAGCUGGAACNN 
                 2378 
                 GUUCCAGCUCACUCAUUCGNN 
                 34 
               
               
                   
               
               
                  329-347 
                 GAAUGAGUGAGCUGGAACANN 
                 2379 
                 UGUUCCAGCUCACUCAUUCNN 
                 34 
               
               
                   
               
               
                  330-348 
                 AAUGAGUGAGCUGGAACAGNN 
                 2380 
                 CUGUUCCAGCUCACUCAUUNN 
                 34 
               
               
                   
               
               
                  331-349 
                 AUGAGUGAGCUGGAACAGCNN 
                 2381 
                 GCUGUUCCAGCUCACUCAUNN 
                 34 
               
               
                   
               
               
                  332-350 
                 UGAGUGAGCUGGAACAGCANN 
                 2382 
                 UGCUGUUCCAGCUCACUCANN 
                 34 
               
               
                   
               
               
                  333-351 
                 GAGUGAGCUGGAACAGCAANN 
                 2383 
                 UUGCUGUUCCAGCUCACUCNN 
                 34 
               
               
                   
               
               
                  334-352 
                 AGUGAGCUGGAACAGCAAGNN 
                 2384 
                 CUUGCUGUUCCAGCUCACUNN 
                 34 
               
               
                   
               
               
                  335-353 
                 GUGAGCUGGAACAGCAAGUNN 
                 2385 
                 ACUUGCUGUUCCAGCUCACNN 
                 34 
               
               
                   
               
               
                  336-354 
                 UGAGCUGGAACAGCAAGUGNN 
                 2386 
                 CACUUGCUGUUCCAGCUCANN 
                 34 
               
               
                   
               
               
                  337-355 
                 GAGCUGGAACAGCAAGUGGNN 
                 2387 
                 CCACUUGCUGUUCCAGCUCNN 
                 34 
               
               
                   
               
               
                  338-356 
                 AGCUGGAACAGCAAGUGGUNN 
                 2388 
                 ACCACUUGCUGUUCCAGCUNN 
                 34 
               
               
                   
               
               
                  339-357 
                 GCUGGAACAGCAAGUGGUANN 
                 2389 
                 UACCACUUGCUGUUCCAGCNN 
                 34 
               
               
                   
               
               
                  340-358 
                 CUGGAACAGCAAGUGGUAGNN 
                 2390 
                 CUACCACUUGCUGUUCCAGNN 
                 34 
               
               
                   
               
               
                  341-359 
                 UGGAACAGCAAGUGGUAGANN 
                 2391 
                 UCUACCACUUGCUGUUCCANN 
                 34 
               
               
                   
               
               
                  342-360 
                 GGAACAGCAAGUGGUAGAUNN 
                 2392 
                 AUCUACCACUUGCUGUUCCNN 
                 34 
               
               
                   
               
               
                  343-361 
                 GAACAGCAAGUGGUAGAUUNN 
                 2393 
                 AAUCUACCACUUGCUGUUCNN 
                 34 
               
               
                   
               
               
                  344-362 
                 AACAGCAAGUGGUAGAUUUNN 
                 2394 
                 AAAUCUACCACUUGCUGUUNN 
                 34 
               
               
                   
               
               
                  345-363 
                 ACAGCAAGUGGUAGAUUUANN 
                 2395 
                 UAAAUCUACCACUUGCUGUNN 
                 34 
               
               
                   
               
               
                  346-364 
                 CAGCAAGUGGUAGAUUUAGNN 
                 2396 
                 CUAAAUCUACCACUUGCUGNN 
                 34 
               
               
                   
               
               
                  347-365 
                 AGCAAGUGGUAGAUUUAGANN 
                 2397 
                 UCUAAAUCUACCACUUGCUNN 
                 34 
               
               
                   
               
               
                  348-366 
                 GCAAGUGGUAGAUUUAGAANN 
                 2398 
                 UUCUAAAUCUACCACUUGCNN 
                 34 
               
               
                   
               
               
                  349-367 
                 CAAGUGGUAGAUUUAGAAGNN 
                 2399 
                 CUUCUAAAUCUACCACUUGNN 
                 34 
               
               
                   
               
               
                  350-368 
                 AAGUGGUAGAUUUAGAAGANN 
                 2400 
                 UCUUCUAAAUCUACCACUUNN 
                 34 
               
               
                   
               
               
                  351-369 
                 AGUGGUAGAUUUAGAAGAANN 
                 2401 
                 UUCUUCUAAAUCUACCACUNN 
                 34 
               
               
                   
               
               
                  352-370 
                 GUGGUAGAUUUAGAAGAAGNN 
                 2402 
                 CUUCUUCUAAAUCUACCACNN 
                 34 
               
               
                   
               
               
                  353-371 
                 UGGUAGAUUUAGAAGAAGANN 
                 2403 
                 UCUUCUUCUAAAUCUACCANN 
                 34 
               
               
                   
               
               
                  354-372 
                 GGUAGAUUUAGAAGAAGAGNN 
                 2404 
                 CUCUUCUUCUAAAUCUACCNN 
                 34 
               
               
                   
               
               
                  355-373 
                 GUAGAUUUAGAAGAAGAGANN 
                 2405 
                 UCUCUUCUUCUAAAUCUACNN 
                 34 
               
               
                   
               
               
                  356-374 
                 UAGAUUUAGAAGAAGAGAANN 
                 2406 
                 UUCUCUUCUUCUAAAUCUANN 
                 34 
               
               
                   
               
               
                  357-375 
                 AGAUUUAGAAGAAGAGAACNN 
                 2407 
                 GUUCUCUUCUUCUAAAUCUNN 
                 34 
               
               
                   
               
               
                  358-376 
                 GAUUUAGAAGAAGAGAACCNN 
                 2408 
                 GGUUCUCUUCUUCUAAAUCNN 
                 34 
               
               
                   
               
               
                  359-377 
                 AUUUAGAAGAAGAGAACCANN 
                 2409 
                 UGGUUCUCUUCUUCUAAAUNN 
                 34 
               
               
                   
               
               
                  360-378 
                 UUUAGAAGAAGAGAACCAANN 
                 2410 
                 UUGGUUCUCUUCUUCUAAANN 
                 34 
               
               
                   
               
               
                  361-379 
                 UUAGAAGAAGAGAACCAAANN 
                 2411 
                 UUUGGUUCUCUUCUUCUAANN 
                 34 
               
               
                   
               
               
                  362-380 
                 UAGAAGAAGAGAACCAAAANN 
                 2412 
                 UUUUGGUUCUCUUCUUCUANN 
                 34 
               
               
                   
               
               
                  363-381 
                 AGAAGAAGAGAACCAAAAANN 
                 2413 
                 TTTTTGGTTCTCTTCTTCTNN 
                 34 
               
               
                   
               
               
                  364-382 
                 GAAGAAGAGAACCAAAAACNN 
                 2414 
                 GTTTTTGGTTCTCTTCTTCNN 
                 34 
               
               
                   
               
               
                  365-383 
                 AAGAAGAGAACCAAAAACUNN 
                 2415 
                 AGUUUUUGGUUCUCUUCUUNN 
                 34 
               
               
                   
               
               
                  366-384 
                 AGAAGAGAACCAAAAACUUNN 
                 2416 
                 AAGUUUUUGGUUCUCUUCUNN 
                 34 
               
               
                   
               
               
                  367-385 
                 GAAGAGAACCAAAAACUUUNN 
                 2417 
                 AAAGUUUUUGGUUCUCUUCNN 
                 34 
               
               
                   
               
               
                  368-386 
                 AAGAGAACCAAAAACUUUUNN 
                 2418 
                 AAAAGUUUUUGGUUCUCUUNN 
                 34 
               
               
                   
               
               
                  369-387 
                 AGAGAACCAAAAACUUUUGNN 
                 2419 
                 CAAAAGUUUUUGGUUCUCUNN 
                 34 
               
               
                   
               
               
                  370-388 
                 GAGAACCAAAAACUUUUGCNN 
                 2420 
                 GCAAAAGUUUUUGGUUCUCNN 
                 34 
               
               
                   
               
               
                  371-389 
                 AGAACCAAAAACUUUUGCUNN 
                 2421 
                 AGCAAAAGUUUUUGGUUCUNN 
                 34 
               
               
                   
               
               
                  372-390 
                 GAACCAAAAACUUUUGCUANN 
                 2422 
                 UAGCAAAAGUUUUUGGUUCNN 
                 34 
               
               
                   
               
               
                  373-391 
                 AACCAAAAACUUUUGCUAGNN 
                 2423 
                 CUAGCAAAAGUUUUUGGUUNN 
                 34 
               
               
                   
               
               
                  374-392 
                 ACCAAAAACUUUUGCUAGANN 
                 2424 
                 UCUAGCAAAAGUUUUUGGUNN 
                 34 
               
               
                   
               
               
                  375-393 
                 CCAAAAACUUUUGCUAGAANN 
                 2425 
                 UUCUAGCAAAAGUUUUUGGNN 
                 34 
               
               
                   
               
               
                  376-394 
                 CAAAAACUUUUGCUAGAAANN 
                 2426 
                 UUUCUAGCAAAAGUUUUUGNN 
                 34 
               
               
                   
               
               
                  377-395 
                 AAAAACUUUUGCUAGAAAANN 
                 2427 
                 UUUUCUAGCAAAAGUUUUUNN 
                 34 
               
               
                   
               
               
                  378-396 
                 AAAACUUUUGCUAGAAAAUNN 
                 2428 
                 AUUUUCUAGCAAAAGUUUUNN 
                 34 
               
               
                   
               
               
                  379-397 
                 AAACUUUUGCUAGAAAAUCNN 
                 2429 
                 GAUUUUCUAGCAAAAGUUUNN 
                 34 
               
               
                   
               
               
                  380-398 
                 AACUUUUGCUAGAAAAUCANN 
                 2430 
                 UGAUUUUCUAGCAAAAGUUNN 
                 34 
               
               
                   
               
               
                  381-399 
                 ACUUUUGCUAGAAAAUCAGNN 
                 2431 
                 CUGAUUUUCUAGCAAAAGUNN 
                 34 
               
               
                   
               
               
                  382-400 
                 CUUUUGCUAGAAAAUCAGCNN 
                 2432 
                 GCUGAUUUUCUAGCAAAAGNN 
                 34 
               
               
                   
               
               
                  383-401 
                 UUUUGCUAGAAAAUCAGCUNN 
                 2433 
                 AGCUGAUUUUCUAGCAAAANN 
                 34 
               
               
                   
               
               
                  384-402 
                 UUUGCUAGAAAAUCAGCUUNN 
                 2434 
                 AAGCUGAUUUUCUAGCAAANN 
                 34 
               
               
                   
               
               
                  385-403 
                 UUGCUAGAAAAUCAGCUUUNN 
                 2435 
                 AAAGCUGAUUUUCUAGCAANN 
                 34 
               
               
                   
               
               
                  386-404 
                 UGCUAGAAAAUCAGCUUUUNN 
                 2436 
                 AAAAGCUGAUUUUCUAGCANN 
                 34 
               
               
                   
               
               
                  387-405 
                 GCUAGAAAAUCAGCUUUUANN 
                 2437 
                 UAAAAGCUGAUUUUCUAGCNN 
                 34 
               
               
                   
               
               
                  388-406 
                 CUAGAAAAUCAGCUUUUACNN 
                 2438 
                 GUAAAAGCUGAUUUUCUAGNN 
                 34 
               
               
                   
               
               
                  389-407 
                 UAGAAAAUCAGCUUUUACGNN 
                 2439 
                 CGUAAAAGCUGAUUUUCUANN 
                 34 
               
               
                   
               
               
                  390-408 
                 AGAAAAUCAGCUUUUACGANN 
                 2440 
                 UCGUAAAAGCUGAUUUUCUNN 
                 34 
               
               
                   
               
               
                  391-409 
                 GAAAAUCAGCUUUUACGAGNN 
                 2441 
                 CUCGUAAAAGCUGAUUUUCNN 
                 35 
               
               
                   
               
               
                  392-410 
                 AAAAUCAGCUUUUACGAGANN 
                 2442 
                 UCUCGUAAAAGCUGAUUUUNN 
                 35 
               
               
                   
               
               
                  393-411 
                 AAAUCAGCUUUUACGAGAGNN 
                 2443 
                 CUCUCGUAAAAGCUGAUUUNN 
                 35 
               
               
                   
               
               
                  394-412 
                 AAUCAGCUUUUACGAGAGANN 
                 2444 
                 UCUCUCGUAAAAGCUGAUUNN 
                 35 
               
               
                   
               
               
                  395-413 
                 AUCAGCUUUUACGAGAGAANN 
                 2445 
                 UUCUCUCGUAAAAGCUGAUNN 
                 35 
               
               
                   
               
               
                  396-414 
                 UCAGCUUUUACGAGAGAAANN 
                 2446 
                 UUUCUCUCGUAAAAGCUGANN 
                 35 
               
               
                   
               
               
                  397-415 
                 CAGCUUUUACGAGAGAAAANN 
                 2447 
                 UUUUCUCUCGUAAAAGCUGNN 
                 35 
               
               
                   
               
               
                  398-416 
                 AGCUUUUACGAGAGAAAACNN 
                 2448 
                 GUUUUCUCUCGUAAAAGCUNN 
                 35 
               
               
                   
               
               
                  399-417 
                 GCUUUUACGAGAGAAAACUNN 
                 2449 
                 AGUUUUCUCUCGUAAAAGCNN 
                 35 
               
               
                   
               
               
                  400-418 
                 CUUUUACGAGAGAAAACUCNN 
                 2450 
                 GAGUUUUCUCUCGUAAAAGNN 
                 35 
               
               
                   
               
               
                  401-419 
                 UUUUACGAGAGAAAACUCANN 
                 2451 
                 UGAGUUUUCUCUCGUAAAANN 
                 35 
               
               
                   
               
               
                  421-439 
                 GGCCUUGUAGUUGAGAACCNN 
                 2452 
                 GGUUCUCAACUACAAGGCCNN 
                 35 
               
               
                   
               
               
                  422-440 
                 GCCUUGUAGUUGAGAACCANN 
                 2453 
                 UGGUUCUCAACUACAAGGCNN 
                 35 
               
               
                   
               
               
                  423-441 
                 CCUUGUAGUUGAGAACCAGNN 
                 2454 
                 CUGGUUCUCAACUACAAGGNN 
                 35 
               
               
                   
               
               
                  424-442 
                 CUUGUAGUUGAGAACCAGGNN 
                 2455 
                 CCUGGUUCUCAACUACAAGNN 
                 35 
               
               
                   
               
               
                  425-443 
                 UUGUAGUUGAGAACCAGGANN 
                 2456 
                 UCCUGGUUCUCAACUACAANN 
                 35 
               
               
                   
               
               
                  426-444 
                 UGUAGUUGAGAACCAGGAGNN 
                 2457 
                 CUCCUGGUUCUCAACUACANN 
                 35 
               
               
                   
               
               
                  427-445 
                 GUAGUUGAGAACCAGGAGUNN 
                 2458 
                 ACUCCUGGUUCUCAACUACNN 
                 35 
               
               
                   
               
               
                  428-446 
                 UAGUUGAGAACCAGGAGUUNN 
                 2459 
                 AACUCCUGGUUCUCAACUANN 
                 35 
               
               
                   
               
               
                  429-447 
                 AGUUGAGAACCAGGAGUUANN 
                 2460 
                 UAACUCCUGGUUCUCAACUNN 
                 35 
               
               
                   
               
               
                  430-448 
                 GUUGAGAACCAGGAGUUAANN 
                 2461 
                 UUAACUCCUGGUUCUCAACNN 
                 35 
               
               
                   
               
               
                  431-449 
                 UUGAGAACCAGGAGUUAAGNN 
                 2462 
                 CUUAACUCCUGGUUCUCAANN 
                 35 
               
               
                   
               
               
                  432-450 
                 UGAGAACCAGGAGUUAAGANN 
                 2463 
                 UCUUAACUCCUGGUUCUCANN 
                 35 
               
               
                   
               
               
                  433-451 
                 GAGAACCAGGAGUUAAGACNN 
                 2464 
                 GUCUUAACUCCUGGUUCUCNN 
                 35 
               
               
                   
               
               
                  434-452 
                 AGAACCAGGAGUUAAGACANN 
                 2465 
                 UGUCUUAACUCCUGGUUCUNN 
                 35 
               
               
                   
               
               
                  435-453 
                 GAACCAGGAGUUAAGACAGNN 
                 2466 
                 CUGUCUUAACUCCUGGUUCNN 
                 35 
               
               
                   
               
               
                  436-454 
                 AACCAGGAGUUAAGACAGCNN 
                 2467 
                 GCUGUCUUAACUCCUGGUUNN 
                 35 
               
               
                   
               
               
                  437-455 
                 ACCAGGAGUUAAGACAGCGNN 
                 2468 
                 CGCUGUCUUAACUCCUGGUNN 
                 35 
               
               
                   
               
               
                  438-456 
                 CCAGGAGUUAAGACAGCGCNN 
                 2469 
                 GCGCUGUCUUAACUCCUGGNN 
                 35 
               
               
                   
               
               
                   44-62 
                 GAGCUAUGGUGGUGGUGGCNN 
                 2470 
                 GCCACCACCACCAUAGCUCNN 
                 35 
               
               
                   
               
               
                   45-63 
                 AGCUAUGGUGGUGGUGGCANN 
                 2471 
                 UGCCACCACCACCAUAGCUNN 
                 35 
               
               
                   
               
               
                  458-476 
                 UGGGGAUGGAUGCCCUGGUNN 
                 2472 
                 ACCAGGGCAUCCAUCCCCANN 
                 35 
               
               
                   
               
               
                  459-477 
                 GGGGAUGGAUGCCCUGGUUNN 
                 2473 
                 AACCAGGGCAUCCAUCCCCNN 
                 35 
               
               
                   
               
               
                  460-478 
                 GGGAUGGAUGCCCUGGUUGNN 
                 2474 
                 CAACCAGGGCAUCCAUCCCNN 
                 35 
               
               
                   
               
               
                  461-479 
                 GGAUGGAUGCCCUGGUUGCNN 
                 2475 
                 GCAACCAGGGCAUCCAUCCNN 
                 35 
               
               
                   
               
               
                  462-480 
                 GAUGGAUGCCCUGGUUGCUNN 
                 2476 
                 AGCAACCAGGGCAUCCAUCNN 
                 35 
               
               
                   
               
               
                   46-64 
                 GCUAUGGUGGUGGUGGCAGNN 
                 2477 
                 CUGCCACCACCACCAUAGCNN 
                 35 
               
               
                   
               
               
                   47-65 
                 CUAUGGUGGUGGUGGCAGCNN 
                 2478 
                 GCUGCCACCACCACCAUAGNN 
                 35 
               
               
                   
               
               
                  482-500 
                 AAGAGGAGGCGGAAGCCAANN 
                 2479 
                 TTGGCTTCCGCCTCCTCTTNN 
                 35 
               
               
                   
               
               
                  483-501 
                 AGAGGAGGCGGAAGCCAAGNN 
                 2480 
                 CTTGGCTTCCGCCTCCTCTNN 
                 35 
               
               
                   
               
               
                  484-502 
                 GAGGAGGCGGAAGCCAAGGNN 
                 2481 
                 CCTTGGCTTCCGCCTCCTCNN 
                 35 
               
               
                   
               
               
                  485-503 
                 AGGAGGCGGAAGCCAAGGGNN 
                 2482 
                 CCCTTGGCTTCCGCCTCCTNN 
                 35 
               
               
                   
               
               
                  486-504 
                 GGAGGCGGAAGCCAAGGGGNN 
                 2483 
                 CCCCTTGGCTTCCGCCTCCNN 
                 35 
               
               
                   
               
               
                   48-66 
                 UAUGGUGGUGGUGGCAGCCNN 
                 2484 
                 GGCUGCCACCACCACCAUANN 
                 35 
               
               
                   
               
               
                  487-505 
                 GAGGCGGAAGCCAAGGGGANN 
                 2485 
                 TCCCCTTGGCTTCCGCCTCNN 
                 35 
               
               
                   
               
               
                  488-506 
                 AGGCGGAAGCCAAGGGGAANN 
                 2486 
                 TTCCCCTTGGCTTCCGCCTNN 
                 35 
               
               
                   
               
               
                  489-507 
                 GGCGGAAGCCAAGGGGAAUNN 
                 2487 
                 AUUCCCCUUGGCUUCCGCCNN 
                 35 
               
               
                   
               
               
                  490-508 
                 GCGGAAGCCAAGGGGAAUGNN 
                 2488 
                 CAUUCCCCUUGGCUUCCGCNN 
                 35 
               
               
                   
               
               
                   49-67 
                 AUGGUGGUGGUGGCAGCCGNN 
                 2489 
                 CGGCUGCCACCACCACCAUNN 
                 35 
               
               
                   
               
               
                   50-68 
                 UGGUGGUGGUGGCAGCCGCNN 
                 2490 
                 GCGGCUGCCACCACCACCANN 
                 35 
               
               
                   
               
               
                  510-528 
                 AGUGAGGCCAGUGGCCGGGNN 
                 2491 
                 CCCGGCCACUGGCCUCACUNN 
                 35 
               
               
                   
               
               
                  511-529 
                 GUGAGGCCAGUGGCCGGGUNN 
                 2492 
                 ACCCGGCCACUGGCCUCACNN 
                 35 
               
               
                   
               
               
                  512-530 
                 UGAGGCCAGUGGCCGGGUCNN 
                 2493 
                 GACCCGGCCACUGGCCUCANN 
                 35 
               
               
                   
               
               
                  513-531 
                 GAGGCCAGUGGCCGGGUCUNN 
                 2494 
                 AGACCCGGCCACUGGCCUCNN 
                 35 
               
               
                   
               
               
                  514-532 
                 AGGCCAGUGGCCGGGUCUGNN 
                 2495 
                 CAGACCCGGCCACUGGCCUNN 
                 35 
               
               
                   
               
               
                  515-533 
                 GGCCAGUGGCCGGGUCUGCNN 
                 2496 
                 GCAGACCCGGCCACUGGCCNN 
                 35 
               
               
                   
               
               
                  516-534 
                 GCCAGUGGCCGGGUCUGCUNN 
                 2497 
                 AGCAGACCCGGCCACUGGCNN 
                 35 
               
               
                   
               
               
                  517-535 
                 CCAGUGGCCGGGUCUGCUGNN 
                 2498 
                 CAGCAGACCCGGCCACUGGNN 
                 35 
               
               
                   
               
               
                  518-536 
                 CAGUGGCCGGGUCUGCUGANN 
                 2499 
                 UCAGCAGACCCGGCCACUGNN 
                 35 
               
               
                   
               
               
                  519-537 
                 AGUGGCCGGGUCUGCUGAGNN 
                 2500 
                 CUCAGCAGACCCGGCCACUNN 
                 35 
               
               
                   
               
               
                  520-538 
                 GUGGCCGGGUCUGCUGAGUNN 
                 2501 
                 ACUCAGCAGACCCGGCCACNN 
                 35 
               
               
                   
               
               
                  521-539 
                 UGGCCGGGUCUGCUGAGUCNN 
                 2502 
                 GACUCAGCAGACCCGGCCANN 
                 35 
               
               
                   
               
               
                  522-540 
                 GGCCGGGUCUGCUGAGUCCNN 
                 2503 
                 GGACUCAGCAGACCCGGCCNN 
                 35 
               
               
                   
               
               
                  523-541 
                 GCCGGGUCUGCUGAGUCCGNN 
                 2504 
                 CGGACUCAGCAGACCCGGCNN 
                 35 
               
               
                   
               
               
                  524-542 
                 CCGGGUCUGCUGAGUCCGCNN 
                 2505 
                 GCGGACUCAGCAGACCCGGNN 
                 35 
               
               
                   
               
               
                  525-543 
                 CGGGUCUGCUGAGUCCGCANN 
                 2506 
                 UGCGGACUCAGCAGACCCGNN 
                 35 
               
               
                   
               
               
                  526-544 
                 GGGUCUGCUGAGUCCGCAGNN 
                 2507 
                 CUGCGGACUCAGCAGACCCNN 
                 35 
               
               
                   
               
               
                  574-592 
                 GUGCAGGCCCAGUUGUCACNN 
                 2508 
                 GUGACAACUGGGCCUGCACNN 
                 35 
               
               
                   
               
               
                  575-593 
                 UGCAGGCCCAGUUGUCACCNN 
                 2509 
                 GGUGACAACUGGGCCUGCANN 
                 35 
               
               
                   
               
               
                  576-594 
                 GCAGGCCCAGUUGUCACCCNN 
                 2510 
                 GGGUGACAACUGGGCCUGCNN 
                 35 
               
               
                   
               
               
                  577-595 
                 CAGGCCCAGUUGUCACCCCNN 
                 2511 
                 GGGGUGACAACUGGGCCUGNN 
                 35 
               
               
                   
               
               
                  578-596 
                 AGGCCCAGUUGUCACCCCUNN 
                 2512 
                 AGGGGUGACAACUGGGCCUNN 
                 35 
               
               
                   
               
               
                  579-597 
                 GGCCCAGUUGUCACCCCUCNN 
                 2513 
                 GAGGGGUGACAACUGGGCCNN 
                 35 
               
               
                   
               
               
                  580-598 
                 GCCCAGUUGUCACCCCUCCNN 
                 2514 
                 GGAGGGGUGACAACUGGGCNN 
                 35 
               
               
                   
               
               
                  581-599 
                 CCCAGUUGUCACCCCUCCANN 
                 2515 
                 UGGAGGGGUGACAACUGGGNN 
                 35 
               
               
                   
               
               
                  582-600 
                 CCAGUUGUCACCCCUCCAGNN 
                 2516 
                 CUGGAGGGGUGACAACUGGNN 
                 35 
               
               
                   
               
               
                  583-601 
                 CAGUUGUCACCCCUCCAGANN 
                 2517 
                 UCUGGAGGGGUGACAACUGNN 
                 35 
               
               
                   
               
               
                  584-602 
                 AGUUGUCACCCCUCCAGAANN 
                 2518 
                 UUCUGGAGGGGUGACAACUNN 
                 35 
               
               
                   
               
               
                  585-603 
                 GUUGUCACCCCUCCAGAACNN 
                 2519 
                 GUUCUGGAGGGGUGACAACNN 
                 35 
               
               
                   
               
               
                  586-604 
                 UUGUCACCCCUCCAGAACANN 
                 2520 
                 UGUUCUGGAGGGGUGACAANN 
                 35 
               
               
                   
               
               
                  587-605 
                 UGUCACCCCUCCAGAACAUNN 
                 2521 
                 AUGUUCUGGAGGGGUGACANN 
                 35 
               
               
                   
               
               
                  588-606 
                 GUCACCCCUCCAGAACAUCNN 
                 2522 
                 GAUGUUCUGGAGGGGUGACNN 
                 35 
               
               
                   
               
               
                  589-607 
                 UCACCCCUCCAGAACAUCUNN 
                 2523 
                 AGAUGUUCUGGAGGGGUGANN 
                 35 
               
               
                   
               
               
                  590-608 
                 CACCCCUCCAGAACAUCUCNN 
                 2524 
                 GAGAUGUUCUGGAGGGGUGNN 
                 35 
               
               
                   
               
               
                  591-609 
                 ACCCCUCCAGAACAUCUCCNN 
                 2525 
                 GGAGAUGUUCUGGAGGGGUNN 
                 35 
               
               
                   
               
               
                  592-610 
                 CCCCUCCAGAACAUCUCCCNN 
                 2526 
                 GGGAGAUGUUCUGGAGGGGNN 
                 35 
               
               
                   
               
               
                  593-611 
                 CCCUCCAGAACAUCUCCCCNN 
                 2527 
                 GGGGAGAUGUUCUGGAGGGNN 
                 35 
               
               
                   
               
               
                  594-612 
                 CCUCCAGAACAUCUCCCCANN 
                 2528 
                 UGGGGAGAUGUUCUGGAGGNN 
                 35 
               
               
                   
               
               
                  595-613 
                 CUCCAGAACAUCUCCCCAUNN 
                 2529 
                 AUGGGGAGAUGUUCUGGAGNN 
                 35 
               
               
                   
               
               
                  596-614 
                 UCCAGAACAUCUCCCCAUGNN 
                 2530 
                 CAUGGGGAGAUGUUCUGGANN 
                 35 
               
               
                   
               
               
                  597-615 
                 CCAGAACAUCUCCCCAUGGNN 
                 2531 
                 CCAUGGGGAGAUGUUCUGGNN 
                 35 
               
               
                   
               
               
                  598-616 
                 CAGAACAUCUCCCCAUGGANN 
                 2532 
                 UCCAUGGGGAGAUGUUCUGNN 
                 35 
               
               
                   
               
               
                  599-617 
                 AGAACAUCUCCCCAUGGAUNN 
                 2533 
                 AUCCAUGGGGAGAUGUUCUNN 
                 35 
               
               
                   
               
               
                  600-618 
                 GAACAUCUCCCCAUGGAUUNN 
                 2534 
                 AAUCCAUGGGGAGAUGUUCNN 
                 35 
               
               
                   
               
               
                  601-619 
                 AACAUCUCCCCAUGGAUUCNN 
                 2535 
                 GAAUCCAUGGGGAGAUGUUNN 
                 35 
               
               
                   
               
               
                  602-620 
                 ACAUCUCCCCAUGGAUUCUNN 
                 2536 
                 AGAAUCCAUGGGGAGAUGUNN 
                 35 
               
               
                   
               
               
                  603-621 
                 CAUCUCCCCAUGGAUUCUGNN 
                 2537 
                 CAGAAUCCAUGGGGAGAUGNN 
                 35 
               
               
                   
               
               
                  604-622 
                 AUCUCCCCAUGGAUUCUGGNN 
                 2538 
                 CCAGAAUCCAUGGGGAGAUNN 
                 35 
               
               
                   
               
               
                  605-623 
                 UCUCCCCAUGGAUUCUGGCNN 
                 2539 
                 GCCAGAAUCCAUGGGGAGANN 
                 35 
               
               
                   
               
               
                  606-624 
                 CUCCCCAUGGAUUCUGGCGNN 
                 2540 
                 CGCCAGAAUCCAUGGGGAGNN 
                 35 
               
               
                   
               
               
                  607-625 
                 UCCCCAUGGAUUCUGGCGGNN 
                 2541 
                 CCGCCAGAAUCCAUGGGGANN 
                 36 
               
               
                   
               
               
                  608-626 
                 CCCCAUGGAUUCUGGCGGUNN 
                 2542 
                 ACCGCCAGAAUCCAUGGGGNN 
                 36 
               
               
                   
               
               
                  609-627 
                 CCCAUGGAUUCUGGCGGUANN 
                 2543 
                 UACCGCCAGAAUCCAUGGGNN 
                 36 
               
               
                   
               
               
                  610-628 
                 CCAUGGAUUCUGGCGGUAUNN 
                 2544 
                 AUACCGCCAGAAUCCAUGGNN 
                 36 
               
               
                   
               
               
                  611-629 
                 CAUGGAUUCUGGCGGUAUUNN 
                 2545 
                 AAUACCGCCAGAAUCCAUGNN 
                 36 
               
               
                   
               
               
                  612-630 
                 AUGGAUUCUGGCGGUAUUGNN 
                 2546 
                 CAAUACCGCCAGAAUCCAUNN 
                 36 
               
               
                   
               
               
                  613-631 
                 UGGAUUCUGGCGGUAUUGANN 
                 2547 
                 UCAAUACCGCCAGAAUCCANN 
                 36 
               
               
                   
               
               
                  614-632 
                 GGAUUCUGGCGGUAUUGACNN 
                 2548 
                 GUCAAUACCGCCAGAAUCCNN 
                 36 
               
               
                   
               
               
                  615-633 
                 GAUUCUGGCGGUAUUGACUNN 
                 2549 
                 AGUCAAUACCGCCAGAAUCNN 
                 36 
               
               
                   
               
               
                  616-634 
                 AUUCUGGCGGUAUUGACUCNN 
                 2550 
                 GAGUCAAUACCGCCAGAAUNN 
                 36 
               
               
                   
               
               
                  617-635 
                 UUCUGGCGGUAUUGACUCUNN 
                 2551 
                 AGAGUCAAUACCGCCAGAANN 
                 36 
               
               
                   
               
               
                  618-636 
                 UCUGGCGGUAUUGACUCUUNN 
                 2552 
                 AAGAGUCAAUACCGCCAGANN 
                 36 
               
               
                   
               
               
                  619-637 
                 CUGGCGGUAUUGACUCUUCNN 
                 2553 
                 GAAGAGUCAAUACCGCCAGNN 
                 36 
               
               
                   
               
               
                  620-638 
                 UGGCGGUAUUGACUCUUCANN 
                 2554 
                 UGAAGAGUCAAUACCGCCANN 
                 36 
               
               
                   
               
               
                  621-639 
                 GGCGGUAUUGACUCUUCAGNN 
                 2555 
                 CUGAAGAGUCAAUACCGCCNN 
                 36 
               
               
                   
               
               
                  622-640 
                 GCGGUAUUGACUCUUCAGANN 
                 2556 
                 UCUGAAGAGUCAAUACCGCNN 
                 36 
               
               
                   
               
               
                  623-641 
                 CGGUAUUGACUCUUCAGAUNN 
                 2557 
                 AUCUGAAGAGUCAAUACCGNN 
                 36 
               
               
                   
               
               
                  624-642 
                 GGUAUUGACUCUUCAGAUUNN 
                 2558 
                 AAUCUGAAGAGUCAAUACCNN 
                 36 
               
               
                   
               
               
                  625-643 
                 GUAUUGACUCUUCAGAUUCNN 
                 2559 
                 GAAUCUGAAGAGUCAAUACNN 
                 36 
               
               
                   
               
               
                  626-644 
                 UAUUGACUCUUCAGAUUCANN 
                 2560 
                 UGAAUCUGAAGAGUCAAUANN 
                 36 
               
               
                   
               
               
                  627-645 
                 AUUGACUCUUCAGAUUCAGNN 
                 2561 
                 CUGAAUCUGAAGAGUCAAUNN 
                 36 
               
               
                   
               
               
                  628-646 
                 UUGACUCUUCAGAUUCAGANN 
                 2562 
                 UCUGAAUCUGAAGAGUCAANN 
                 36 
               
               
                   
               
               
                  629-647 
                 UGACUCUUCAGAUUCAGAGNN 
                 2563 
                 CUCUGAAUCUGAAGAGUCANN 
                 36 
               
               
                   
               
               
                  630-648 
                 GACUCUUCAGAUUCAGAGUNN 
                 2564 
                 ACUCUGAAUCUGAAGAGUCNN 
                 36 
               
               
                   
               
               
                  631-649 
                 ACUCUUCAGAUUCAGAGUCNN 
                 2565 
                 GACUCUGAAUCUGAAGAGUNN 
                 36 
               
               
                   
               
               
                  632-650 
                 CUCUUCAGAUUCAGAGUCUNN 
                 2566 
                 AGACUCUGAAUCUGAAGAGNN 
                 36 
               
               
                   
               
               
                  633-651 
                 UCUUCAGAUUCAGAGUCUGNN 
                 2567 
                 CAGACUCUGAAUCUGAAGANN 
                 36 
               
               
                   
               
               
                  634-652 
                 CUUCAGAUUCAGAGUCUGANN 
                 2568 
                 UCAGACUCUGAAUCUGAAGNN 
                 36 
               
               
                   
               
               
                  635-653 
                 UUCAGAUUCAGAGUCUGAUNN 
                 2569 
                 AUCAGACUCUGAAUCUGAANN 
                 36 
               
               
                   
               
               
                  636-654 
                 UCAGAUUCAGAGUCUGAUANN 
                 2570 
                 UAUCAGACUCUGAAUCUGANN 
                 36 
               
               
                   
               
               
                  637-655 
                 CAGAUUCAGAGUCUGAUAUNN 
                 2571 
                 AUAUCAGACUCUGAAUCUGNN 
                 36 
               
               
                   
               
               
                  638-656 
                 AGAUUCAGAGUCUGAUAUCNN 
                 2572 
                 GAUAUCAGACUCUGAAUCUNN 
                 36 
               
               
                   
               
               
                  639-657 
                 GAUUCAGAGUCUGAUAUCCNN 
                 2573 
                 GGAUAUCAGACUCUGAAUCNN 
                 36 
               
               
                   
               
               
                  640-658 
                 AUUCAGAGUCUGAUAUCCUNN 
                 2574 
                 AGGAUAUCAGACUCUGAAUNN 
                 36 
               
               
                   
               
               
                  641-659 
                 UUCAGAGUCUGAUAUCCUGNN 
                 2575 
                 CAGGAUAUCAGACUCUGAANN 
                 36 
               
               
                   
               
               
                  642-660 
                 UCAGAGUCUGAUAUCCUGUNN 
                 2576 
                 ACAGGAUAUCAGACUCUGANN 
                 36 
               
               
                   
               
               
                  643-661 
                 CAGAGUCUGAUAUCCUGUUNN 
                 2577 
                 AACAGGAUAUCAGACUCUGNN 
                 36 
               
               
                   
               
               
                  644-662 
                 AGAGUCUGAUAUCCUGUUGNN 
                 2578 
                 CAACAGGAUAUCAGACUCUNN 
                 36 
               
               
                   
               
               
                  645-663 
                 GAGUCUGAUAUCCUGUUGGNN 
                 2579 
                 CCAACAGGAUAUCAGACUCNN 
                 36 
               
               
                   
               
               
                  646-664 
                 AGUCUGAUAUCCUGUUGGGNN 
                 2580 
                 CCCAACAGGAUAUCAGACUNN 
                 36 
               
               
                   
               
               
                  647-665 
                 GUCUGAUAUCCUGUUGGGCNN 
                 2581 
                 GCCCAACAGGAUAUCAGACNN 
                 36 
               
               
                   
               
               
                  648-666 
                 UCUGAUAUCCUGUUGGGCANN 
                 2582 
                 UGCCCAACAGGAUAUCAGANN 
                 36 
               
               
                   
               
               
                  649-667 
                 CUGAUAUCCUGUUGGGCAUNN 
                 2583 
                 AUGCCCAACAGGAUAUCAGNN 
                 36 
               
               
                   
               
               
                  650-668 
                 UGAUAUCCUGUUGGGCAUUNN 
                 2584 
                 AAUGCCCAACAGGAUAUCANN 
                 36 
               
               
                   
               
               
                  651-669 
                 GAUAUCCUGUUGGGCAUUCNN 
                 2585 
                 GAAUGCCCAACAGGAUAUCNN 
                 36 
               
               
                   
               
               
                  652-670 
                 AUAUCCUGUUGGGCAUUCUNN 
                 2586 
                 AGAAUGCCCAACAGGAUAUNN 
                 36 
               
               
                   
               
               
                  653-671 
                 UAUCCUGUUGGGCAUUCUGNN 
                 2587 
                 CAGAAUGCCCAACAGGAUANN 
                 36 
               
               
                   
               
               
                  654-672 
                 AUCCUGUUGGGCAUUCUGGNN 
                 2588 
                 CCAGAAUGCCCAACAGGAUNN 
                 36 
               
               
                   
               
               
                  655-673 
                 UCCUGUUGGGCAUUCUGGANN 
                 2589 
                 UCCAGAAUGCCCAACAGGANN 
                 36 
               
               
                   
               
               
                  656-674 
                 CCUGUUGGGCAUUCUGGACNN 
                 2590 
                 GUCCAGAAUGCCCAACAGGNN 
                 36 
               
               
                   
               
               
                  657-675 
                 CUGUUGGGCAUUCUGGACANN 
                 2591 
                 UGUCCAGAAUGCCCAACAGNN 
                 36 
               
               
                   
               
               
                  658-676 
                 UGUUGGGCAUUCUGGACAANN 
                 2592 
                 UUGUCCAGAAUGCCCAACANN 
                 36 
               
               
                   
               
               
                  659-677 
                 GUUGGGCAUUCUGGACAACNN 
                 2593 
                 GUUGUCCAGAAUGCCCAACNN 
                 36 
               
               
                   
               
               
                  660-678 
                 UUGGGCAUUCUGGACAACUNN 
                 2594 
                 AGUUGUCCAGAAUGCCCAANN 
                 36 
               
               
                   
               
               
                  661-679 
                 UGGGCAUUCUGGACAACUUNN 
                 2595 
                 AAGUUGUCCAGAAUGCCCANN 
                 36 
               
               
                   
               
               
                  662-680 
                 GGGCAUUCUGGACAACUUGNN 
                 2596 
                 CAAGUUGUCCAGAAUGCCCNN 
                 36 
               
               
                   
               
               
                  663-681 
                 GGCAUUCUGGACAACUUGGNN 
                 2597 
                 CCAAGUUGUCCAGAAUGCCNN 
                 36 
               
               
                   
               
               
                  664-682 
                 GCAUUCUGGACAACUUGGANN 
                 2598 
                 UCCAAGUUGUCCAGAAUGCNN 
                 36 
               
               
                   
               
               
                  665-683 
                 CAUUCUGGACAACUUGGACNN 
                 2599 
                 GUCCAAGUUGUCCAGAAUGNN 
                 36 
               
               
                   
               
               
                  666-684 
                 AUUCUGGACAACUUGGACCNN 
                 2600 
                 GGUCCAAGUUGUCCAGAAUNN 
                 36 
               
               
                   
               
               
                  667-685 
                 UUCUGGACAACUUGGACCCNN 
                 2601 
                 GGGUCCAAGUUGUCCAGAANN 
                 36 
               
               
                   
               
               
                  668-686 
                 UCUGGACAACUUGGACCCANN 
                 2602 
                 UGGGUCCAAGUUGUCCAGANN 
                 36 
               
               
                   
               
               
                  669-687 
                 CUGGACAACUUGGACCCAGNN 
                 2603 
                 CUGGGUCCAAGUUGUCCAGNN 
                 36 
               
               
                   
               
               
                  670-688 
                 UGGACAACUUGGACCCAGUNN 
                 2604 
                 ACUGGGUCCAAGUUGUCCANN 
                 36 
               
               
                   
               
               
                  671-689 
                 GGACAACUUGGACCCAGUCNN 
                 2605 
                 GACUGGGUCCAAGUUGUCCNN 
                 36 
               
               
                   
               
               
                  672-690 
                 GACAACUUGGACCCAGUCANN 
                 2606 
                 UGACUGGGUCCAAGUUGUCNN 
                 36 
               
               
                   
               
               
                  673-691 
                 ACAACUUGGACCCAGUCAUNN 
                 2607 
                 AUGACUGGGUCCAAGUUGUNN 
                 36 
               
               
                   
               
               
                  674-692 
                 CAACUUGGACCCAGUCAUGNN 
                 2608 
                 CAUGACUGGGUCCAAGUUGNN 
                 36 
               
               
                   
               
               
                  675-693 
                 AACUUGGACCCAGUCAUGUNN 
                 2609 
                 ACAUGACUGGGUCCAAGUUNN 
                 36 
               
               
                   
               
               
                  676-694 
                 ACUUGGACCCAGUCAUGUUNN 
                 2610 
                 AACAUGACUGGGUCCAAGUNN 
                 36 
               
               
                   
               
               
                  677-695 
                 CUUGGACCCAGUCAUGUUCNN 
                 2611 
                 GAACAUGACUGGGUCCAAGNN 
                 36 
               
               
                   
               
               
                  678-696 
                 UUGGACCCAGUCAUGUUCUNN 
                 2612 
                 AGAACAUGACUGGGUCCAANN 
                 36 
               
               
                   
               
               
                  679-697 
                 UGGACCCAGUCAUGUUCUUNN 
                 2613 
                 AAGAACAUGACUGGGUCCANN 
                 36 
               
               
                   
               
               
                  680-698 
                 GGACCCAGUCAUGUUCUUCNN 
                 2614 
                 GAAGAACAUGACUGGGUCCNN 
                 36 
               
               
                   
               
               
                  681-699 
                 GACCCAGUCAUGUUCUUCANN 
                 2615 
                 UGAAGAACAUGACUGGGUCNN 
                 36 
               
               
                   
               
               
                  682-700 
                 ACCCAGUCAUGUUCUUCAANN 
                 2616 
                 UUGAAGAACAUGACUGGGUNN 
                 36 
               
               
                   
               
               
                  683-701 
                 CCCAGUCAUGUUCUUCAAANN 
                 2617 
                 UUUGAAGAACAUGACUGGGNN 
                 36 
               
               
                   
               
               
                  684-702 
                 CCAGUCAUGUUCUUCAAAUNN 
                 2618 
                 AUUUGAAGAACAUGACUGGNN 
                 36 
               
               
                   
               
               
                  685-703 
                 CAGUCAUGUUCUUCAAAUGNN 
                 2619 
                 CAUUUGAAGAACAUGACUGNN 
                 36 
               
               
                   
               
               
                  686-704 
                 AGUCAUGUUCUUCAAAUGCNN 
                 2620 
                 GCAUUUGAAGAACAUGACUNN 
                 36 
               
               
                   
               
               
                  687-705 
                 GUCAUGUUCUUCAAAUGCCNN 
                 2621 
                 GGCAUUUGAAGAACAUGACNN 
                 36 
               
               
                   
               
               
                  688-706 
                 UCAUGUUCUUCAAAUGCCCNN 
                 2622 
                 GGGCAUUUGAAGAACAUGANN 
                 36 
               
               
                   
               
               
                  689-707 
                 CAUGUUCUUCAAAUGCCCUNN 
                 2623 
                 AGGGCAUUUGAAGAACAUGNN 
                 36 
               
               
                   
               
               
                  690-708 
                 AUGUUCUUCAAAUGCCCUUNN 
                 2624 
                 AAGGGCAUUUGAAGAACAUNN 
                 36 
               
               
                   
               
               
                  691-709 
                 UGUUCUUCAAAUGCCCUUCNN 
                 2625 
                 GAAGGGCAUUUGAAGAACANN 
                 36 
               
               
                   
               
               
                  692-710 
                 GUUCUUCAAAUGCCCUUCCNN 
                 2626 
                 GGAAGGGCAUUUGAAGAACNN 
                 36 
               
               
                   
               
               
                  693-711 
                 UUCUUCAAAUGCCCUUCCCNN 
                 2627 
                 GGGAAGGGCAUUUGAAGAANN 
                 36 
               
               
                   
               
               
                  694-712 
                 UCUUCAAAUGCCCUUCCCCNN 
                 2628 
                 GGGGAAGGGCAUUUGAAGANN 
                 36 
               
               
                   
               
               
                  695-713 
                 CUUCAAAUGCCCUUCCCCANN 
                 2629 
                 UGGGGAAGGGCAUUUGAAGNN 
                 36 
               
               
                   
               
               
                  696-714 
                 UUCAAAUGCCCUUCCCCAGNN 
                 2630 
                 CUGGGGAAGGGCAUUUGAANN 
                 36 
               
               
                   
               
               
                  697-715 
                 UCAAAUGCCCUUCCCCAGANN 
                 2631 
                 UCUGGGGAAGGGCAUUUGANN 
                 36 
               
               
                   
               
               
                  698-716 
                 CAAAUGCCCUUCCCCAGAGNN 
                 2632 
                 CUCUGGGGAAGGGCAUUUGNN 
                 36 
               
               
                   
               
               
                  718-736 
                 CUGCCAGCCUGGAGGAGCUNN 
                 2633 
                 AGCUCCUCCAGGCUGGCAGNN 
                 36 
               
               
                   
               
               
                  719-737 
                 UGCCAGCCUGGAGGAGCUCNN 
                 2634 
                 GAGCUCCUCCAGGCUGGCANN 
                 36 
               
               
                   
               
               
                  720-738 
                 GCCAGCCUGGAGGAGCUCCNN 
                 2635 
                 GGAGCUCCUCCAGGCUGGCNN 
                 36 
               
               
                   
               
               
                  721-739 
                 CCAGCCUGGAGGAGCUCCCNN 
                 2636 
                 GGGAGCUCCUCCAGGCUGGNN 
                 36 
               
               
                   
               
               
                  722-740 
                 CAGCCUGGAGGAGCUCCCANN 
                 2637 
                 UGGGAGCUCCUCCAGGCUGNN 
                 36 
               
               
                   
               
               
                  723-741 
                 AGCCUGGAGGAGCUCCCAGNN 
                 2638 
                 CUGGGAGCUCCUCCAGGCUNN 
                 36 
               
               
                   
               
               
                  724-742 
                 GCCUGGAGGAGCUCCCAGANN 
                 2639 
                 UCUGGGAGCUCCUCCAGGCNN 
                 36 
               
               
                   
               
               
                  725-743 
                 CCUGGAGGAGCUCCCAGAGNN 
                 2640 
                 CUCUGGGAGCUCCUCCAGGNN 
                 36 
               
               
                   
               
               
                  726-744 
                 CUGGAGGAGCUCCCAGAGGNN 
                 2641 
                 CCUCUGGGAGCUCCUCCAGNN 
                 37 
               
               
                   
               
               
                  727-745 
                 UGGAGGAGCUCCCAGAGGUNN 
                 2642 
                 ACCUCUGGGAGCUCCUCCANN 
                 37 
               
               
                   
               
               
                  728-746 
                 GGAGGAGCUCCCAGAGGUCNN 
                 2643 
                 GACCUCUGGGAGCUCCUCCNN 
                 37 
               
               
                   
               
               
                  729-747 
                 GAGGAGCUCCCAGAGGUCUNN 
                 2644 
                 AGACCUCUGGGAGCUCCUCNN 
                 37 
               
               
                   
               
               
                  730-748 
                 AGGAGCUCCCAGAGGUCUANN 
                 2645 
                 UAGACCUCUGGGAGCUCCUNN 
                 37 
               
               
                   
               
               
                  731-749 
                 GGAGCUCCCAGAGGUCUACNN 
                 2646 
                 GUAGACCUCUGGGAGCUCCNN 
                 37 
               
               
                   
               
               
                  732-750 
                 GAGCUCCCAGAGGUCUACCNN 
                 2647 
                 GGUAGACCUCUGGGAGCUCNN 
                 37 
               
               
                   
               
               
                  733-751 
                 AGCUCCCAGAGGUCUACCCNN 
                 2648 
                 GGGUAGACCUCUGGGAGCUNN 
                 37 
               
               
                   
               
               
                  734-752 
                 GCUCCCAGAGGUCUACCCANN 
                 2649 
                 UGGGUAGACCUCUGGGAGCNN 
                 37 
               
               
                   
               
               
                  735-753 
                 CUCCCAGAGGUCUACCCAGNN 
                 2650 
                 CUGGGUAGACCUCUGGGAGNN 
                 37 
               
               
                   
               
               
                  736-754 
                 UCCCAGAGGUCUACCCAGANN 
                 2651 
                 UCUGGGUAGACCUCUGGGANN 
                 37 
               
               
                   
               
               
                  737-755 
                 CCCAGAGGUCUACCCAGAANN 
                 2652 
                 UUCUGGGUAGACCUCUGGGNN 
                 37 
               
               
                   
               
               
                  738-756 
                 CCAGAGGUCUACCCAGAAGNN 
                 2653 
                 CUUCUGGGUAGACCUCUGGNN 
                 37 
               
               
                   
               
               
                  739-757 
                 CAGAGGUCUACCCAGAAGGNN 
                 2654 
                 CCUUCUGGGUAGACCUCUGNN 
                 37 
               
               
                   
               
               
                  740-758 
                 AGAGGUCUACCCAGAAGGANN 
                 2655 
                 UCCUUCUGGGUAGACCUCUNN 
                 37 
               
               
                   
               
               
                  741-759 
                 GAGGUCUACCCAGAAGGACNN 
                 2656 
                 GUCCUUCUGGGUAGACCUCNN 
                 37 
               
               
                   
               
               
                  742-760 
                 AGGUCUACCCAGAAGGACCNN 
                 2657 
                 GGUCCUUCUGGGUAGACCUNN 
                 37 
               
               
                   
               
               
                  743-761 
                 GGUCUACCCAGAAGGACCCNN 
                 2658 
                 GGGUCCUUCUGGGUAGACCNN 
                 37 
               
               
                   
               
               
                  744-762 
                 GUCUACCCAGAAGGACCCANN 
                 2659 
                 UGGGUCCUUCUGGGUAGACNN 
                 37 
               
               
                   
               
               
                  745-763 
                 UCUACCCAGAAGGACCCAGNN 
                 2660 
                 CUGGGUCCUUCUGGGUAGANN 
                 37 
               
               
                   
               
               
                  746-764 
                 CUACCCAGAAGGACCCAGUNN 
                 2661 
                 ACUGGGUCCUUCUGGGUAGNN 
                 37 
               
               
                   
               
               
                  747-765 
                 UACCCAGAAGGACCCAGUUNN 
                 2662 
                 AACUGGGUCCUUCUGGGUANN 
                 37 
               
               
                   
               
               
                  748-766 
                 ACCCAGAAGGACCCAGUUCNN 
                 2663 
                 GAACUGGGUCCUUCUGGGUNN 
                 37 
               
               
                   
               
               
                  749-767 
                 CCCAGAAGGACCCAGUUCCNN 
                 2664 
                 GGAACUGGGUCCUUCUGGGNN 
                 37 
               
               
                   
               
               
                  750-768 
                 CCAGAAGGACCCAGUUCCUNN 
                 2665 
                 AGGAACUGGGUCCUUCUGGNN 
                 37 
               
               
                   
               
               
                  751-769 
                 CAGAAGGACCCAGUUCCUUNN 
                 2666 
                 AAGGAACUGGGUCCUUCUGNN 
                 37 
               
               
                   
               
               
                  752-770 
                 AGAAGGACCCAGUUCCUUANN 
                 2667 
                 UAAGGAACUGGGUCCUUCUNN 
                 37 
               
               
                   
               
               
                  753-771 
                 GAAGGACCCAGUUCCUUACNN 
                 2668 
                 GUAAGGAACUGGGUCCUUCNN 
                 37 
               
               
                   
               
               
                  754-772 
                 AAGGACCCAGUUCCUUACCNN 
                 2669 
                 GGUAAGGAACUGGGUCCUUNN 
                 37 
               
               
                   
               
               
                  755-773 
                 AGGACCCAGUUCCUUACCANN 
                 2670 
                 UGGUAAGGAACUGGGUCCUNN 
                 37 
               
               
                   
               
               
                  756-774 
                 GGACCCAGUUCCUUACCAGNN 
                 2671 
                 CUGGUAAGGAACUGGGUCCNN 
                 37 
               
               
                   
               
               
                  757-775 
                 GACCCAGUUCCUUACCAGCNN 
                 2672 
                 GCUGGUAAGGAACUGGGUCNN 
                 37 
               
               
                   
               
               
                  758-776 
                 ACCCAGUUCCUUACCAGCCNN 
                 2673 
                 GGCUGGUAAGGAACUGGGUNN 
                 37 
               
               
                   
               
               
                  759-777 
                 CCCAGUUCCUUACCAGCCUNN 
                 2674 
                 AGGCUGGUAAGGAACUGGGNN 
                 37 
               
               
                   
               
               
                  760-778 
                 CCAGUUCCUUACCAGCCUCNN 
                 2675 
                 GAGGCUGGUAAGGAACUGGNN 
                 37 
               
               
                   
               
               
                  761-779 
                 CAGUUCCUUACCAGCCUCCNN 
                 2676 
                 GGAGGCUGGUAAGGAACUGNN 
                 37 
               
               
                   
               
               
                  762-780 
                 AGUUCCUUACCAGCCUCCCNN 
                 2677 
                 GGGAGGCUGGUAAGGAACUNN 
                 37 
               
               
                   
               
               
                  763-781 
                 GUUCCUUACCAGCCUCCCUNN 
                 2678 
                 AGGGAGGCUGGUAAGGAACNN 
                 37 
               
               
                   
               
               
                  764-782 
                 UUCCUUACCAGCCUCCCUUNN 
                 2679 
                 AAGGGAGGCUGGUAAGGAANN 
                 37 
               
               
                   
               
               
                  765-783 
                 UCCUUACCAGCCUCCCUUUNN 
                 2680 
                 AAAGGGAGGCUGGUAAGGANN 
                 37 
               
               
                   
               
               
                  766-784 
                 CCUUACCAGCCUCCCUUUCNN 
                 2681 
                 GAAAGGGAGGCUGGUAAGGNN 
                 37 
               
               
                   
               
               
                  767-785 
                 CUUACCAGCCUCCCUUUCUNN 
                 2682 
                 AGAAAGGGAGGCUGGUAAGNN 
                 37 
               
               
                   
               
               
                  768-786 
                 UUACCAGCCUCCCUUUCUCNN 
                 2683 
                 GAGAAAGGGAGGCUGGUAANN 
                 37 
               
               
                   
               
               
                  769-787 
                 UACCAGCCUCCCUUUCUCUNN 
                 2684 
                 AGAGAAAGGGAGGCUGGUANN 
                 37 
               
               
                   
               
               
                  770-788 
                 ACCAGCCUCCCUUUCUCUGNN 
                 2685 
                 CAGAGAAAGGGAGGCUGGUNN 
                 37 
               
               
                   
               
               
                  771-789 
                 CCAGCCUCCCUUUCUCUGUNN 
                 2686 
                 ACAGAGAAAGGGAGGCUGGNN 
                 37 
               
               
                   
               
               
                  772-790 
                 CAGCCUCCCUUUCUCUGUCNN 
                 2687 
                 GACAGAGAAAGGGAGGCUGNN 
                 37 
               
               
                   
               
               
                  773-791 
                 AGCCUCCCUUUCUCUGUCANN 
                 2688 
                 UGACAGAGAAAGGGAGGCUNN 
                 37 
               
               
                   
               
               
                  774-792 
                 GCCUCCCUUUCUCUGUCAGNN 
                 2689 
                 CUGACAGAGAAAGGGAGGCNN 
                 37 
               
               
                   
               
               
                  775-793 
                 CCUCCCUUUCUCUGUCAGUNN 
                 2690 
                 ACUGACAGAGAAAGGGAGGNN 
                 37 
               
               
                   
               
               
                  776-794 
                 CUCCCUUUCUCUGUCAGUGNN 
                 2691 
                 CACUGACAGAGAAAGGGAGNN 
                 37 
               
               
                   
               
               
                  777-795 
                 UCCCUUUCUCUGUCAGUGGNN 
                 2692 
                 CCACUGACAGAGAAAGGGANN 
                 37 
               
               
                   
               
               
                  778-796 
                 CCCUUUCUCUGUCAGUGGGNN 
                 2693 
                 CCCACUGACAGAGAAAGGGNN 
                 37 
               
               
                   
               
               
                  779-797 
                 CCUUUCUCUGUCAGUGGGGNN 
                 2694 
                 CCCCACUGACAGAGAAAGGNN 
                 37 
               
               
                   
               
               
                  780-798 
                 CUUUCUCUGUCAGUGGGGANN 
                 2695 
                 UCCCCACUGACAGAGAAAGNN 
                 37 
               
               
                   
               
               
                  781-799 
                 UUUCUCUGUCAGUGGGGACNN 
                 2696 
                 GUCCCCACUGACAGAGAAANN 
                 37 
               
               
                   
               
               
                  782-800 
                 UUCUCUGUCAGUGGGGACGNN 
                 2697 
                 CGUCCCCACUGACAGAGAANN 
                 37 
               
               
                   
               
               
                  783-801 
                 UCUCUGUCAGUGGGGACGUNN 
                 2698 
                 ACGUCCCCACUGACAGAGANN 
                 37 
               
               
                   
               
               
                  784-802 
                 CUCUGUCAGUGGGGACGUCNN 
                 2699 
                 GACGUCCCCACUGACAGAGNN 
                 37 
               
               
                   
               
               
                  785-803 
                 UCUGUCAGUGGGGACGUCANN 
                 2700 
                 UGACGUCCCCACUGACAGANN 
                 37 
               
               
                   
               
               
                  786-804 
                 CUGUCAGUGGGGACGUCAUNN 
                 2701 
                 AUGACGUCCCCACUGACAGNN 
                 37 
               
               
                   
               
               
                  787-805 
                 UGUCAGUGGGGACGUCAUCNN 
                 2702 
                 GAUGACGUCCCCACUGACANN 
                 37 
               
               
                   
               
               
                  788-806 
                 GUCAGUGGGGACGUCAUCANN 
                 2703 
                 UGAUGACGUCCCCACUGACNN 
                 37 
               
               
                   
               
               
                  789-807 
                 UCAGUGGGGACGUCAUCAGNN 
                 2704 
                 CUGAUGACGUCCCCACUGANN 
                 37 
               
               
                   
               
               
                  790-808 
                 CAGUGGGGACGUCAUCAGCNN 
                 2705 
                 GCUGAUGACGUCCCCACUGNN 
                 37 
               
               
                   
               
               
                  791-809 
                 AGUGGGGACGUCAUCAGCCNN 
                 2706 
                 GGCUGAUGACGUCCCCACUNN 
                 37 
               
               
                   
               
               
                  792-810 
                 GUGGGGACGUCAUCAGCCANN 
                 2707 
                 UGGCUGAUGACGUCCCCACNN 
                 37 
               
               
                   
               
               
                  793-811 
                 UGGGGACGUCAUCAGCCAANN 
                 2708 
                 UUGGCUGAUGACGUCCCCANN 
                 37 
               
               
                   
               
               
                  794-812 
                 GGGGACGUCAUCAGCCAAGNN 
                 2709 
                 CUUGGCUGAUGACGUCCCCNN 
                 37 
               
               
                   
               
               
                  795-813 
                 GGGACGUCAUCAGCCAAGCNN 
                 2710 
                 GCUUGGCUGAUGACGUCCCNN 
                 37 
               
               
                   
               
               
                  796-814 
                 GGACGUCAUCAGCCAAGCUNN 
                 2711 
                 AGCUUGGCUGAUGACGUCCNN 
                 37 
               
               
                   
               
               
                  797-815 
                 GACGUCAUCAGCCAAGCUGNN 
                 2712 
                 CAGCUUGGCUGAUGACGUCNN 
                 37 
               
               
                   
               
               
                  798-816 
                 ACGUCAUCAGCCAAGCUGGNN 
                 2713 
                 CCAGCUUGGCUGAUGACGUNN 
                 37 
               
               
                   
               
               
                  799-817 
                 CGUCAUCAGCCAAGCUGGANN 
                 2714 
                 UCCAGCUUGGCUGAUGACGNN 
                 37 
               
               
                   
               
               
                  800-818 
                 GUCAUCAGCCAAGCUGGAANN 
                 2715 
                 UUCCAGCUUGGCUGAUGACNN 
                 37 
               
               
                   
               
               
                  801-819 
                 UCAUCAGCCAAGCUGGAAGNN 
                 2716 
                 CUUCCAGCUUGGCUGAUGANN 
                 37 
               
               
                   
               
               
                  802-820 
                 CAUCAGCCAAGCUGGAAGCNN 
                 2717 
                 GCUUCCAGCUUGGCUGAUGNN 
                 37 
               
               
                   
               
               
                  803-821 
                 AUCAGCCAAGCUGGAAGCCNN 
                 2718 
                 GGCUUCCAGCUUGGCUGAUNN 
                 37 
               
               
                   
               
               
                  804-822 
                 UCAGCCAAGCUGGAAGCCANN 
                 2719 
                 UGGCUUCCAGCUUGGCUGANN 
                 37 
               
               
                   
               
               
                  805-823 
                 CAGCCAAGCUGGAAGCCAUNN 
                 2720 
                 AUGGCUUCCAGCUUGGCUGNN 
                 37 
               
               
                   
               
               
                  806-824 
                 AGCCAAGCUGGAAGCCAUUNN 
                 2721 
                 AAUGGCUUCCAGCUUGGCUNN 
                 37 
               
               
                   
               
               
                  807-825 
                 GCCAAGCUGGAAGCCAUUANN 
                 2722 
                 UAAUGGCUUCCAGCUUGGCNN 
                 37 
               
               
                   
               
               
                  808-826 
                 CCAAGCUGGAAGCCAUUAANN 
                 2723 
                 UUAAUGGCUUCCAGCUUGGNN 
                 37 
               
               
                   
               
               
                  809-827 
                 CAAGCUGGAAGCCAUUAAUNN 
                 2724 
                 AUUAAUGGCUUCCAGCUUGNN 
                 37 
               
               
                   
               
               
                  810-828 
                 AAGCUGGAAGCCAUUAAUGNN 
                 2725 
                 CAUUAAUGGCUUCCAGCUUNN 
                 37 
               
               
                   
               
               
                  811-829 
                 AGCUGGAAGCCAUUAAUGANN 
                 2726 
                 UCAUUAAUGGCUUCCAGCUNN 
                 37 
               
               
                   
               
               
                  812-830 
                 GCUGGAAGCCAUUAAUGAANN 
                 2727 
                 UUCAUUAAUGGCUUCCAGCNN 
                 37 
               
               
                   
               
               
                  813-831 
                 CUGGAAGCCAUUAAUGAACNN 
                 2728 
                 GUUCAUUAAUGGCUUCCAGNN 
                 37 
               
               
                   
               
               
                  814-832 
                 UGGAAGCCAUUAAUGAACUNN 
                 2729 
                 AGUUCAUUAAUGGCUUCCANN 
                 37 
               
               
                   
               
               
                  815-833 
                 GGAAGCCAUUAAUGAACUANN 
                 2730 
                 UAGUUCAUUAAUGGCUUCCNN 
                 37 
               
               
                   
               
               
                  816-834 
                 GAAGCCAUUAAUGAACUAANN 
                 2731 
                 UUAGUUCAUUAAUGGCUUCNN 
                 37 
               
               
                   
               
               
                  817-835 
                 AAGCCAUUAAUGAACUAAUNN 
                 2732 
                 AUUAGUUCAUUAAUGGCUUNN 
                 37 
               
               
                   
               
               
                  818-836 
                 AGCCAUUAAUGAACUAAUUNN 
                 2733 
                 AAUUAGUUCAUUAAUGGCUNN 
                 37 
               
               
                   
               
               
                  819-837 
                 GCCAUUAAUGAACUAAUUCNN 
                 2734 
                 GAAUUAGUUCAUUAAUGGCNN 
                 37 
               
               
                   
               
               
                  820-838 
                 CCAUUAAUGAACUAAUUCGNN 
                 2735 
                 CGAAUUAGUUCAUUAAUGGNN 
                 37 
               
               
                   
               
               
                  821-839 
                 CAUUAAUGAACUAAUUCGUNN 
                 2736 
                 ACGAAUUAGUUCAUUAAUGNN 
                 37 
               
               
                   
               
               
                  822-840 
                 AUUAAUGAACUAAUUCGUUNN 
                 2737 
                 AACGAAUUAGUUCAUUAAUNN 
                 37 
               
               
                   
               
               
                  823-841 
                 UUAAUGAACUAAUUCGUUUNN 
                 2738 
                 AAACGAAUUAGUUCAUUAANN 
                 37 
               
               
                   
               
               
                  824-842 
                 UAAUGAACUAAUUCGUUUUNN 
                 2739 
                 AAAACGAAUUAGUUCAUUANN 
                 37 
               
               
                   
               
               
                  825-843 
                 AAUGAACUAAUUCGUUUUGNN 
                 2740 
                 CAAAACGAAUUAGUUCAUUNN 
                 37 
               
               
                   
               
               
                  826-844 
                 AUGAACUAAUUCGUUUUGANN 
                 2741 
                 UCAAAACGAAUUAGUUCAUNN 
                 38 
               
               
                   
               
               
                  827-845 
                 UGAACUAAUUCGUUUUGACNN 
                 2742 
                 GUCAAAACGAAUUAGUUCANN 
                 38 
               
               
                   
               
               
                  828-846 
                 GAACUAAUUCGUUUUGACCNN 
                 2743 
                 GGUCAAAACGAAUUAGUUCNN 
                 38 
               
               
                   
               
               
                  829-847 
                 AACUAAUUCGUUUUGACCANN 
                 2744 
                 UGGUCAAAACGAAUUAGUUNN 
                 38 
               
               
                   
               
               
                  830-848 
                 ACUAAUUCGUUUUGACCACNN 
                 2745 
                 GUGGUCAAAACGAAUUAGUNN 
                 38 
               
               
                   
               
               
                  831-849 
                 CUAAUUCGUUUUGACCACANN 
                 2746 
                 UGUGGUCAAAACGAAUUAGNN 
                 38 
               
               
                   
               
               
                  832-850 
                 UAAUUCGUUUUGACCACAUNN 
                 2747 
                 AUGUGGUCAAAACGAAUUANN 
                 38 
               
               
                   
               
               
                  833-851 
                 AAUUCGUUUUGACCACAUANN 
                 2748 
                 UAUGUGGUCAAAACGAAUUNN 
                 38 
               
               
                   
               
               
                  834-852 
                 AUUCGUUUUGACCACAUAUNN 
                 2749 
                 AUAUGUGGUCAAAACGAAUNN 
                 38 
               
               
                   
               
               
                  835-853 
                 UUCGUUUUGACCACAUAUANN 
                 2750 
                 UAUAUGUGGUCAAAACGAANN 
                 38 
               
               
                   
               
               
                  836-854 
                 UCGUUUUGACCACAUAUAUNN 
                 2751 
                 AUAUAUGUGGUCAAAACGANN 
                 38 
               
               
                   
               
               
                  837-855 
                 CGUUUUGACCACAUAUAUANN 
                 2752 
                 UAUAUAUGUGGUCAAAACGNN 
                 38 
               
               
                   
               
               
                  838-856 
                 GUUUUGACCACAUAUAUACNN 
                 2753 
                 GUAUAUAUGUGGUCAAAACNN 
                 38 
               
               
                   
               
               
                  839-857 
                 UUUUGACCACAUAUAUACCNN 
                 2754 
                 GGUAUAUAUGUGGUCAAAANN 
                 38 
               
               
                   
               
               
                  840-858 
                 UUUGACCACAUAUAUACCANN 
                 2755 
                 UGGUAUAUAUGUGGUCAAANN 
                 38 
               
               
                   
               
               
                  841-859 
                 UUGACCACAUAUAUACCAANN 
                 2756 
                 UUGGUAUAUAUGUGGUCAANN 
                 38 
               
               
                   
               
               
                  842-860 
                 UGACCACAUAUAUACCAAGNN 
                 2757 
                 CUUGGUAUAUAUGUGGUCANN 
                 38 
               
               
                   
               
               
                  843-861 
                 GACCACAUAUAUACCAAGCNN 
                 2758 
                 GCUUGGUAUAUAUGUGGUCNN 
                 38 
               
               
                   
               
               
                  844-862 
                 ACCACAUAUAUACCAAGCCNN 
                 2759 
                 GGCUUGGUAUAUAUGUGGUNN 
                 38 
               
               
                   
               
               
                  845-863 
                 CCACAUAUAUACCAAGCCCNN 
                 2760 
                 GGGCUUGGUAUAUAUGUGGNN 
                 38 
               
               
                   
               
               
                  846-864 
                 CACAUAUAUACCAAGCCCCNN 
                 2761 
                 GGGGCUUGGUAUAUAUGUGNN 
                 38 
               
               
                   
               
               
                  847-865 
                 ACAUAUAUACCAAGCCCCUNN 
                 2762 
                 AGGGGCUUGGUAUAUAUGUNN 
                 38 
               
               
                   
               
               
                  867-885 
                 GUCUUAGAGAUACCCUCUGNN 
                 2763 
                 CAGAGGGUAUCUCUAAGACNN 
                 38 
               
               
                   
               
               
                  868-886 
                 UCUUAGAGAUACCCUCUGANN 
                 2764 
                 UCAGAGGGUAUCUCUAAGANN 
                 38 
               
               
                   
               
               
                  869-887 
                 CUUAGAGAUACCCUCUGAGNN 
                 2765 
                 CUCAGAGGGUAUCUCUAAGNN 
                 38 
               
               
                   
               
               
                  870-888 
                 UUAGAGAUACCCUCUGAGANN 
                 2766 
                 UCUCAGAGGGUAUCUCUAANN 
                 38 
               
               
                   
               
               
                  871-889 
                 UAGAGAUACCCUCUGAGACNN 
                 2767 
                 GUCUCAGAGGGUAUCUCUANN 
                 38 
               
               
                   
               
               
                  872-890 
                 AGAGAUACCCUCUGAGACANN 
                 2768 
                 UGUCUCAGAGGGUAUCUCUNN 
                 38 
               
               
                   
               
               
                  873-891 
                 GAGAUACCCUCUGAGACAGNN 
                 2769 
                 CUGUCUCAGAGGGUAUCUCNN 
                 38 
               
               
                   
               
               
                  874-892 
                 AGAUACCCUCUGAGACAGANN 
                 2770 
                 UCUGUCUCAGAGGGUAUCUNN 
                 38 
               
               
                   
               
               
                  875-893 
                 GAUACCCUCUGAGACAGAGNN 
                 2771 
                 CUCUGUCUCAGAGGGUAUCNN 
                 38 
               
               
                   
               
               
                  876-894 
                 AUACCCUCUGAGACAGAGANN 
                 2772 
                 UCUCUGUCUCAGAGGGUAUNN 
                 38 
               
               
                   
               
               
                  877-895 
                 UACCCUCUGAGACAGAGAGNN 
                 2773 
                 CUCUCUGUCUCAGAGGGUANN 
                 38 
               
               
                   
               
               
                  878-896 
                 ACCCUCUGAGACAGAGAGCNN 
                 2774 
                 GCUCUCUGUCUCAGAGGGUNN 
                 38 
               
               
                   
               
               
                  879-897 
                 CCCUCUGAGACAGAGAGCCNN 
                 2775 
                 GGCUCUCUGUCUCAGAGGGNN 
                 38 
               
               
                   
               
               
                  880-898 
                 CCUCUGAGACAGAGAGCCANN 
                 2776 
                 UGGCUCUCUGUCUCAGAGGNN 
                 38 
               
               
                   
               
               
                  881-899 
                 CUCUGAGACAGAGAGCCAANN 
                 2777 
                 UUGGCUCUCUGUCUCAGAGNN 
                 38 
               
               
                   
               
               
                  882-900 
                 UCUGAGACAGAGAGCCAAGNN 
                 2778 
                 CUUGGCUCUCUGUCUCAGANN 
                 38 
               
               
                   
               
               
                  883-901 
                 CUGAGACAGAGAGCCAAGCNN 
                 2779 
                 GCUUGGCUCUCUGUCUCAGNN 
                 38 
               
               
                   
               
               
                  884-902 
                 UGAGACAGAGAGCCAAGCUNN 
                 2780 
                 AGCUUGGCUCUCUGUCUCANN 
                 38 
               
               
                   
               
               
                  885-903 
                 GAGACAGAGAGCCAAGCUANN 
                 2781 
                 UAGCUUGGCUCUCUGUCUCNN 
                 38 
               
               
                   
               
               
                  886-904 
                 AGACAGAGAGCCAAGCUAANN 
                 2782 
                 UUAGCUUGGCUCUCUGUCUNN 
                 38 
               
               
                   
               
               
                  887-905 
                 GACAGAGAGCCAAGCUAAUNN 
                 2783 
                 AUUAGCUUGGCUCUCUGUCNN 
                 38 
               
               
                   
               
               
                  888-906 
                 ACAGAGAGCCAAGCUAAUGNN 
                 2784 
                 CAUUAGCUUGGCUCUCUGUNN 
                 38 
               
               
                   
               
               
                  889-907 
                 CAGAGAGCCAAGCUAAUGUNN 
                 2785 
                 ACAUUAGCUUGGCUCUCUGNN 
                 38 
               
               
                   
               
               
                  890-908 
                 AGAGAGCCAAGCUAAUGUGNN 
                 2786 
                 CACAUUAGCUUGGCUCUCUNN 
                 38 
               
               
                   
               
               
                  891-909 
                 GAGAGCCAAGCUAAUGUGGNN 
                 2787 
                 CCACAUUAGCUUGGCUCUCNN 
                 38 
               
               
                   
               
               
                  892-910 
                 AGAGCCAAGCUAAUGUGGUNN 
                 2788 
                 ACCACAUUAGCUUGGCUCUNN 
                 38 
               
               
                   
               
               
                  893-911 
                 GAGCCAAGCUAAUGUGGUANN 
                 2789 
                 UACCACAUUAGCUUGGCUCNN 
                 38 
               
               
                   
               
               
                  894-912 
                 AGCCAAGCUAAUGUGGUAGNN 
                 2790 
                 CUACCACAUUAGCUUGGCUNN 
                 38 
               
               
                   
               
               
                  895-913 
                 GCCAAGCUAAUGUGGUAGUNN 
                 2791 
                 ACUACCACAUUAGCUUGGCNN 
                 38 
               
               
                   
               
               
                  896-914 
                 CCAAGCUAAUGUGGUAGUGNN 
                 2792 
                 CACUACCACAUUAGCUUGGNN 
                 38 
               
               
                   
               
               
                  897-915 
                 CAAGCUAAUGUGGUAGUGANN 
                 2793 
                 UCACUACCACAUUAGCUUGNN 
                 38 
               
               
                   
               
               
                  898-916 
                 AAGCUAAUGUGGUAGUGAANN 
                 2794 
                 UUCACUACCACAUUAGCUUNN 
                 38 
               
               
                   
               
               
                  899-917 
                 AGCUAAUGUGGUAGUGAAANN 
                 2795 
                 UUUCACUACCACAUUAGCUNN 
                 38 
               
               
                   
               
               
                  900-918 
                 GCUAAUGUGGUAGUGAAAANN 
                 2796 
                 UUUUCACUACCACAUUAGCNN 
                 38 
               
               
                   
               
               
                  901-919 
                 CUAAUGUGGUAGUGAAAAUNN 
                 2797 
                 AUUUUCACUACCACAUUAGNN 
                 38 
               
               
                   
               
               
                  902-920 
                 UAAUGUGGUAGUGAAAAUCNN 
                 2798 
                 GAUUUUCACUACCACAUUANN 
                 38 
               
               
                   
               
               
                  903-921 
                 AAUGUGGUAGUGAAAAUCGNN 
                 2799 
                 CGAUUUUCACUACCACAUUNN 
                 38 
               
               
                   
               
               
                  904-922 
                 AUGUGGUAGUGAAAAUCGANN 
                 2800 
                 UCGAUUUUCACUACCACAUNN 
                 38 
               
               
                   
               
               
                  905-923 
                 UGUGGUAGUGAAAAUCGAGNN 
                 2801 
                 CUCGAUUUUCACUACCACANN 
                 38 
               
               
                   
               
               
                  906-924 
                 GUGGUAGUGAAAAUCGAGGNN 
                 2802 
                 CCUCGAUUUUCACUACCACNN 
                 38 
               
               
                   
               
               
                  907-925 
                 UGGUAGUGAAAAUCGAGGANN 
                 2803 
                 UCCUCGAUUUUCACUACCANN 
                 38 
               
               
                   
               
               
                  908-926 
                 GGUAGUGAAAAUCGAGGAANN 
                 2804 
                 UUCCUCGAUUUUCACUACCNN 
                 38 
               
               
                   
               
               
                  909-927 
                 GUAGUGAAAAUCGAGGAAGNN 
                 2805 
                 CUUCCUCGAUUUUCACUACNN 
                 38 
               
               
                   
               
               
                  910-928 
                 UAGUGAAAAUCGAGGAAGCNN 
                 2806 
                 GCUUCCUCGAUUUUCACUANN 
                 38 
               
               
                   
               
               
                  911-929 
                 AGUGAAAAUCGAGGAAGCANN 
                 2807 
                 UGCUUCCUCGAUUUUCACUNN 
                 38 
               
               
                   
               
               
                  912-930 
                 GUGAAAAUCGAGGAAGCACNN 
                 2808 
                 GUGCUUCCUCGAUUUUCACNN 
                 38 
               
               
                   
               
               
                  913-931 
                 UGAAAAUCGAGGAAGCACCNN 
                 2809 
                 GGUGCUUCCUCGAUUUUCANN 
                 38 
               
               
                   
               
               
                  914-932 
                 GAAAAUCGAGGAAGCACCUNN 
                 2810 
                 AGGUGCUUCCUCGAUUUUCNN 
                 38 
               
               
                   
               
               
                  915-933 
                 AAAAUCGAGGAAGCACCUCNN 
                 2811 
                 GAGGUGCUUCCUCGAUUUUNN 
                 38 
               
               
                   
               
               
                  916-934 
                 AAAUCGAGGAAGCACCUCUNN 
                 2812 
                 AGAGGUGCUUCCUCGAUUUNN 
                 38 
               
               
                   
               
               
                  917-935 
                 AAUCGAGGAAGCACCUCUCNN 
                 2813 
                 GAGAGGUGCUUCCUCGAUUNN 
                 38 
               
               
                   
               
               
                  918-936 
                 AUCGAGGAAGCACCUCUCANN 
                 2814 
                 UGAGAGGUGCUUCCUCGAUNN 
                 38 
               
               
                   
               
               
                  919-937 
                 UCGAGGAAGCACCUCUCAGNN 
                 2815 
                 CUGAGAGGUGCUUCCUCGANN 
                 38 
               
               
                   
               
               
                  920-938 
                 CGAGGAAGCACCUCUCAGCNN 
                 2816 
                 GCUGAGAGGUGCUUCCUCGNN 
                 38 
               
               
                   
               
               
                  921-939 
                 GAGGAAGCACCUCUCAGCCNN 
                 2817 
                 GGCUGAGAGGUGCUUCCUCNN 
                 38 
               
               
                   
               
               
                  922-940 
                 AGGAAGCACCUCUCAGCCCNN 
                 2818 
                 GGGCUGAGAGGUGCUUCCUNN 
                 38 
               
               
                   
               
               
                  923-941 
                 GGAAGCACCUCUCAGCCCCNN 
                 2819 
                 GGGGCUGAGAGGUGCUUCCNN 
                 38 
               
               
                   
               
               
                  924-942 
                 GAAGCACCUCUCAGCCCCUNN 
                 2820 
                 AGGGGCUGAGAGGUGCUUCNN 
                 38 
               
               
                   
               
               
                  925-943 
                 AAGCACCUCUCAGCCCCUCNN 
                 2821 
                 GAGGGGCUGAGAGGUGCUUNN 
                 38 
               
               
                   
               
               
                  926-944 
                 AGCACCUCUCAGCCCCUCANN 
                 2822 
                 UGAGGGGCUGAGAGGUGCUNN 
                 38 
               
               
                   
               
               
                  927-945 
                 GCACCUCUCAGCCCCUCAGNN 
                 2823 
                 CUGAGGGGCUGAGAGGUGCNN 
                 38 
               
               
                   
               
               
                  928-946 
                 CACCUCUCAGCCCCUCAGANN 
                 2824 
                 UCUGAGGGGCUGAGAGGUGNN 
                 38 
               
               
                   
               
               
                  929-947 
                 ACCUCUCAGCCCCUCAGAGNN 
                 2825 
                 CUCUGAGGGGCUGAGAGGUNN 
                 38 
               
               
                   
               
               
                  930-948 
                 CCUCUCAGCCCCUCAGAGANN 
                 2826 
                 UCUCUGAGGGGCUGAGAGGNN 
                 38 
               
               
                   
               
               
                  931-949 
                 CUCUCAGCCCCUCAGAGAANN 
                 2827 
                 UUCUCUGAGGGGCUGAGAGNN 
                 38 
               
               
                   
               
               
                  932-950 
                 UCUCAGCCCCUCAGAGAAUNN 
                 2828 
                 AUUCUCUGAGGGGCUGAGANN 
                 38 
               
               
                   
               
               
                  933-951 
                 CUCAGCCCCUCAGAGAAUGNN 
                 2829 
                 CAUUCUCUGAGGGGCUGAGNN 
                 38 
               
               
                   
               
               
                  934-952 
                 UCAGCCCCUCAGAGAAUGANN 
                 2830 
                 UCAUUCUCUGAGGGGCUGANN 
                 38 
               
               
                   
               
               
                  935-953 
                 CAGCCCCUCAGAGAAUGAUNN 
                 2831 
                 AUCAUUCUCUGAGGGGCUGNN 
                 38 
               
               
                   
               
               
                  936-954 
                 AGCCCCUCAGAGAAUGAUCNN 
                 2832 
                 GAUCAUUCUCUGAGGGGCUNN 
                 38 
               
               
                   
               
               
                  937-955 
                 GCCCCUCAGAGAAUGAUCANN 
                 2833 
                 UGAUCAUUCUCUGAGGGGCNN 
                 38 
               
               
                   
               
               
                  938-956 
                 CCCCUCAGAGAAUGAUCACNN 
                 2834 
                 GUGAUCAUUCUCUGAGGGGNN 
                 38 
               
               
                   
               
               
                  939-957 
                 CCCUCAGAGAAUGAUCACCNN 
                 2835 
                 GGUGAUCAUUCUCUGAGGGNN 
                 38 
               
               
                   
               
               
                  940-958 
                 CCUCAGAGAAUGAUCACCCNN 
                 2836 
                 GGGUGAUCAUUCUCUGAGGNN 
                 38 
               
               
                   
               
               
                  941-959 
                 CUCAGAGAAUGAUCACCCUNN 
                 2837 
                 AGGGUGAUCAUUCUCUGAGNN 
                 38 
               
               
                   
               
               
                  942-960 
                 UCAGAGAAUGAUCACCCUGNN 
                 2838 
                 CAGGGUGAUCAUUCUCUGANN 
                 38 
               
               
                   
               
               
                  943-961 
                 CAGAGAAUGAUCACCCUGANN 
                 2839 
                 UCAGGGUGAUCAUUCUCUGNN 
                 38 
               
               
                   
               
               
                  944-962 
                 AGAGAAUGAUCACCCUGAANN 
                 2840 
                 UUCAGGGUGAUCAUUCUCUNN 
                 38 
               
               
                   
               
               
                  945-963 
                 GAGAAUGAUCACCCUGAAUNN 
                 2841 
                 AUUCAGGGUGAUCAUUCUCNN 
                 39 
               
               
                   
               
               
                  946-964 
                 AGAAUGAUCACCCUGAAUUNN 
                 2842 
                 AAUUCAGGGUGAUCAUUCUNN 
                 39 
               
               
                   
               
               
                  947-965 
                 GAAUGAUCACCCUGAAUUCNN 
                 2843 
                 GAAUUCAGGGUGAUCAUUCNN 
                 39 
               
               
                   
               
               
                  948-966 
                 AAUGAUCACCCUGAAUUCANN 
                 2844 
                 UGAAUUCAGGGUGAUCAUUNN 
                 39 
               
               
                   
               
               
                  949-967 
                 AUGAUCACCCUGAAUUCAUNN 
                 2845 
                 AUGAAUUCAGGGUGAUCAUNN 
                 39 
               
               
                   
               
               
                  950-968 
                 UGAUCACCCUGAAUUCAUUNN 
                 2846 
                 AAUGAAUUCAGGGUGAUCANN 
                 39 
               
               
                   
               
               
                  951-969 
                 GAUCACCCUGAAUUCAUUGNN 
                 2847 
                 CAAUGAAUUCAGGGUGAUCNN 
                 39 
               
               
                   
               
               
                  952-970 
                 AUCACCCUGAAUUCAUUGUNN 
                 2848 
                 ACAAUGAAUUCAGGGUGAUNN 
                 39 
               
               
                   
               
               
                  953-971 
                 UCACCCUGAAUUCAUUGUCNN 
                 2849 
                 GACAAUGAAUUCAGGGUGANN 
                 39 
               
               
                   
               
               
                  954-972 
                 CACCCUGAAUUCAUUGUCUNN 
                 2850 
                 AGACAAUGAAUUCAGGGUGNN 
                 39 
               
               
                   
               
               
                  955-973 
                 ACCCUGAAUUCAUUGUCUCNN 
                 2851 
                 GAGACAAUGAAUUCAGGGUNN 
                 39 
               
               
                   
               
               
                  956-974 
                 CCCUGAAUUCAUUGUCUCANN 
                 2852 
                 UGAGACAAUGAAUUCAGGGNN 
                 39 
               
               
                   
               
               
                  957-975 
                 CCUGAAUUCAUUGUCUCAGNN 
                 2853 
                 CUGAGACAAUGAAUUCAGGNN 
                 39 
               
               
                   
               
               
                  958-976 
                 CUGAAUUCAUUGUCUCAGUNN 
                 2854 
                 ACUGAGACAAUGAAUUCAGNN 
                 39 
               
               
                   
               
               
                  959-977 
                 UGAAUUCAUUGUCUCAGUGNN 
                 2855 
                 CACUGAGACAAUGAAUUCANN 
                 39 
               
               
                   
               
               
                  960-978 
                 GAAUUCAUUGUCUCAGUGANN 
                 2856 
                 UCACUGAGACAAUGAAUUCNN 
                 39 
               
               
                   
               
               
                  961-979 
                 AAUUCAUUGUCUCAGUGAANN 
                 2857 
                 UUCACUGAGACAAUGAAUUNN 
                 39 
               
               
                   
               
               
                  962-980 
                 AUUCAUUGUCUCAGUGAAGNN 
                 2858 
                 CUUCACUGAGACAAUGAAUNN 
                 39 
               
               
                   
               
               
                  963-981 
                 UUCAUUGUCUCAGUGAAGGNN 
                 2859 
                 CCUUCACUGAGACAAUGAANN 
                 39 
               
               
                   
               
               
                  964-982 
                 UCAUUGUCUCAGUGAAGGANN 
                 2860 
                 UCCUUCACUGAGACAAUGANN 
                 39 
               
               
                   
               
               
                  965-983 
                 CAUUGUCUCAGUGAAGGAANN 
                 2861 
                 UUCCUUCACUGAGACAAUGNN 
                 39 
               
               
                   
               
               
                  966-984 
                 AUUGUCUCAGUGAAGGAAGNN 
                 2862 
                 CUUCCUUCACUGAGACAAUNN 
                 39 
               
               
                   
               
               
                  967-985 
                 UUGUCUCAGUGAAGGAAGANN 
                 2863 
                 UCUUCCUUCACUGAGACAANN 
                 39 
               
               
                   
               
               
                  968-986 
                 UGUCUCAGUGAAGGAAGAANN 
                 2864 
                 UUCUUCCUUCACUGAGACANN 
                 39 
               
               
                   
               
               
                  969-987 
                 GUCUCAGUGAAGGAAGAACNN 
                 2865 
                 GUUCUUCCUUCACUGAGACNN 
                 39 
               
               
                   
               
               
                  970-988 
                 UCUCAGUGAAGGAAGAACCNN 
                 2866 
                 GGUUCUUCCUUCACUGAGANN 
                 39 
               
               
                   
               
               
                  971-989 
                 CUCAGUGAAGGAAGAACCUNN 
                 2867 
                 AGGUUCUUCCUUCACUGAGNN 
                 39 
               
               
                   
               
               
                  972-990 
                 UCAGUGAAGGAAGAACCUGNN 
                 2868 
                 CAGGUUCUUCCUUCACUGANN 
                 39 
               
               
                   
               
               
                  973-991 
                 CAGUGAAGGAAGAACCUGUNN 
                 2869 
                 ACAGGUUCUUCCUUCACUGNN 
                 39 
               
               
                   
               
               
                  974-992 
                 AGUGAAGGAAGAACCUGUANN 
                 2870 
                 UACAGGUUCUUCCUUCACUNN 
                 39 
               
               
                   
               
               
                  975-993 
                 GUGAAGGAAGAACCUGUAGNN 
                 2871 
                 CUACAGGUUCUUCCUUCACNN 
                 39 
               
               
                   
               
               
                  976-994 
                 UGAAGGAAGAACCUGUAGANN 
                 2872 
                 UCUACAGGUUCUUCCUUCANN 
                 39 
               
               
                   
               
               
                  977-995 
                 GAAGGAAGAACCUGUAGAANN 
                 2873 
                 UUCUACAGGUUCUUCCUUCNN 
                 39 
               
               
                   
               
               
                  978-996 
                 AAGGAAGAACCUGUAGAAGNN 
                 2874 
                 CUUCUACAGGUUCUUCCUUNN 
                 39 
               
               
                   
               
               
                  979-997 
                 AGGAAGAACCUGUAGAAGANN 
                 2875 
                 UCUUCUACAGGUUCUUCCUNN 
                 39 
               
               
                   
               
               
                  980-998 
                 GGAAGAACCUGUAGAAGAUNN 
                 2876 
                 AUCUUCUACAGGUUCUUCCNN 
                 39 
               
               
                   
               
               
                  981-999 
                 GAAGAACCUGUAGAAGAUGNN 
                 2877 
                 CAUCUUCUACAGGUUCUUCNN 
                 39 
               
               
                   
               
               
                  982-1000 
                 AAGAACCUGUAGAAGAUGANN 
                 2878 
                 UCAUCUUCUACAGGUUCUUNN 
                 39 
               
               
                   
               
               
                  983-1001 
                 AGAACCUGUAGAAGAUGACNN 
                 2879 
                 GUCAUCUUCUACAGGUUCUNN 
                 39 
               
               
                   
               
               
                  984-1002 
                 GAACCUGUAGAAGAUGACCNN 
                 2880 
                 GGUCAUCUUCUACAGGUUCNN 
                 39 
               
               
                   
               
               
                  985-1003 
                 AACCUGUAGAAGAUGACCUNN 
                 2881 
                 AGGUCAUCUUCUACAGGUUNN 
                 39 
               
               
                   
               
               
                  986-1004 
                 ACCUGUAGAAGAUGACCUCNN 
                 2882 
                 GAGGUCAUCUUCUACAGGUNN 
                 39 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Sequences of dsRNA targeting both mouse and rhesus monkey XBP-1. 
               
               
                 *Target refers location of target sequence in NM_013842 ( Mus   musculis   
               
               
                 XPB1 mRNA). Sense and antisense sequences are described with optional 
               
               
                 dinucleotide (NN) overhangs. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ ID 
                   
                 SEQ ID 
               
               
                 *Target 
                 sense (5′-3′) 
                 NO 
                 antisense (5′-3′) 
                 NO 
               
               
                   
               
               
                  369-387 
                 AGAAAACUCACGGCCUUGUNN 
                 3942 
                 ACAAGGCCGUGAGUUUUCUNN 
                 4042 
               
               
                   
               
               
                  237-255 
                 AACUGAAAAACAGAGUAGCNN 
                 3943 
                 GCUACUCUGUUUUUCAGUUNN 
                 4043 
               
               
                   
               
               
                  491-509 
                 GGGUCUGCUGAGUCCGCAGNN 
                 3944 
                 CUGCGGACUCAGCAGACCCNN 
                 4044 
               
               
                   
               
               
                  917-935 
                 AUCACCCUGAAUUCAUUGUNN 
                 3945 
                 ACAAUGAAUUCAGGGUGAUNN 
                 4045 
               
               
                   
               
               
                  923-941 
                 CUGAAUUCAUUGUCUCAGUNN 
                 3946 
                 ACUGAGACAAUGAAUUCAGNN 
                 4046 
               
               
                   
               
               
                  702-720 
                 CCCAGAGGUCUACCCAGAANN 
                 3947 
                 UUCUGGGUAGACCUCUGGGNN 
                 4047 
               
               
                   
               
               
                  926-944 
                 AAUUCAUUGUCUCAGUGAANN 
                 3948 
                 UUCACUGAGACAAUGAAUUNN 
                 4048 
               
               
                   
               
               
                  391-409 
                 UGAGAACCAGGAGUUAAGANN 
                 3949 
                 UCUUAACUCCUGGUUCUCANN 
                 4049 
               
               
                   
               
               
                  775-793 
                 AAGCUGGAAGCCAUUAAUGNN 
                 3950 
                 CAUUAAUGGCUUCCAGCUUNN 
                 4050 
               
               
                   
               
               
                 1150-1168 
                 CCCCAGCUGAUUAGUGUCUNN 
                 3951 
                 AGACACUAAUCAGCUGGGGNN 
                 4051 
               
               
                   
               
               
                  776-794 
                 AGCUGGAAGCCAUUAAUGANN 
                 3952 
                 UCAUUAAUGGCUUCCAGCUNN 
                 4052 
               
               
                   
               
               
                  921-939 
                 CCCUGAAUUCAUUGUCUCANN 
                 3953 
                 UGAGACAAUGAAUUCAGGGNN 
                 4053 
               
               
                   
               
               
                  777-795 
                 GCUGGAAGCCAUUAAUGAANN 
                 3954 
                 UUCAUUAAUGGCUUCCAGCNN 
                 4054 
               
               
                   
               
               
                  539-557 
                 GUGCAGGCCCAGUUGUCACNN 
                 3955 
                 GUGACAACUGGGCCUGCACNN 
                 4055 
               
               
                   
               
               
                  731-749 
                 CCUUACCAGCCUCCCUUUCNN 
                 3956 
                 GAAAGGGAGGCUGGUAAGGNN 
                 4056 
               
               
                   
               
               
                  924-942 
                 UGAAUUCAUUGUCUCAGUGNN 
                 3957 
                 CACUGAGACAAUGAAUUCANN 
                 4057 
               
               
                   
               
               
                 1151-1169 
                 CCCAGCUGAUUAGUGUCUANN 
                 3958 
                 UAGACACUAAUCAGCUGGGNN 
                 4058 
               
               
                   
               
               
                 1152-1170 
                 CCAGCUGAUUAGUGUCUAANN 
                 3959 
                 UUAGACACUAAUCAGCUGGNN 
                 4059 
               
               
                   
               
               
                 1718-1736 
                 ACUAUGUAAAUGCUUGAUGNN 
                 3960 
                 CAUCAAGCAUUUACAUAGUNN 
                 4060 
               
               
                   
               
               
                  368-386 
                 GAGAAAACUCACGGCCUUGNN 
                 3961 
                 CAAGGCCGUGAGUUUUCUCNN 
                 4061 
               
               
                   
               
               
                  489-507 
                 CCGGGUCUGCUGAGUCCGCNN 
                 3962 
                 GCGGACUCAGCAGACCCGGNN 
                 4062 
               
               
                   
               
               
                  238-256 
                 ACUGAAAAACAGAGUAGCANN 
                 3963 
                 UGCUACUCUGUUUUUCAGUNN 
                 4063 
               
               
                   
               
               
                  240-258 
                 UGAAAAACAGAGUAGCAGCNN 
                 3964 
                 GCUGCUACUCUGUUUUUCANN 
                 4064 
               
               
                   
               
               
                  390-408 
                 UUGAGAACCAGGAGUUAAGNN 
                 3965 
                 CUUAACUCCUGGUUCUCAANN 
                 4065 
               
               
                   
               
               
                  487-505 
                 GGCCGGGUCUGCUGAGUCCNN 
                 3966 
                 GGACUCAGCAGACCCGGCCNN 
                 4066 
               
               
                   
               
               
                  741-759 
                 CUCCCUUUCUCUGUCAGUGNN 
                 3967 
                 CACUGACAGAGAAAGGGAGNN 
                 4067 
               
               
                   
               
               
                  918-936 
                 UCACCCUGAAUUCAUUGUCNN 
                 3968 
                 GACAAUGAAUUCAGGGUGANN 
                 4068 
               
               
                   
               
               
                  919-937 
                 CACCCUGAAUUCAUUGUCUNN 
                 3969 
                 AGACAAUGAAUUCAGGGUGNN 
                 4069 
               
               
                   
               
               
                 1130-1148 
                 CUUUUGCCAAUGAACUUUUNN 
                 3970 
                 AAAAGUUCAUUGGCAAAAGNN 
                 4070 
               
               
                   
               
               
                 1712-1730 
                 AAAUUUACUAUGUAAAUGCNN 
                 3971 
                 GCAUUUACAUAGUAAAUUUNN 
                 4071 
               
               
                   
               
               
                 1714-1732 
                 AUUUACUAUGUAAAUGCUUNN 
                 3972 
                 AAGCAUUUACAUAGUAAAUNN 
                 4072 
               
               
                   
               
               
                 1717-1735 
                 UACUAUGUAAAUGCUUGAUNN 
                 3973 
                 AUCAAGCAUUUACAUAGUANN 
                 4073 
               
               
                   
               
               
                 1719-1737 
                 CUAUGUAAAUGCUUGAUGGNN 
                 3974 
                 CCAUCAAGCAUUUACAUAGNN 
                 4074 
               
               
                   
               
               
                 1775-1793 
                 CCAUUUAUUUAAAACUACCNN 
                 3975 
                 GGUAGUUUUAAAUAAAUGGNN 
                 4075 
               
               
                   
               
               
                 1776-1794 
                 CAUUUAUUUAAAACUACCCNN 
                 3976 
                 GGGUAGUUUUAAAUAAAUGNN 
                 4076 
               
               
                   
               
               
                  239-257 
                 CUGAAAAACAGAGUAGCAGNN 
                 3977 
                 CUGCUACUCUGUUUUUCAGNN 
                 4077 
               
               
                   
               
               
                  347-365 
                 CUAGAAAAUCAGCUUUUACNN 
                 3978 
                 GUAAAAGCUGAUUUUCUAGNN 
                 4078 
               
               
                   
               
               
                  348-366 
                 UAGAAAAUCAGCUUUUACGNN 
                 3979 
                 CGUAAAAGCUGAUUUUCUANN 
                 4079 
               
               
                   
               
               
                  485-503 
                 GUGGCCGGGUCUGCUGAGUNN 
                 3980 
                 ACUCAGCAGACCCGGCCACNN 
                 4080 
               
               
                   
               
               
                  486-504 
                 UGGCCGGGUCUGCUGAGUCNN 
                 3981 
                 GACUCAGCAGACCCGGCCANN 
                 4081 
               
               
                   
               
               
                  488-506 
                 GCCGGGUCUGCUGAGUCCGNN 
                 3982 
                 CGGACUCAGCAGACCCGGCNN 
                 4082 
               
               
                   
               
               
                  540-558 
                 UGCAGGCCCAGUUGUCACCNN 
                 3983 
                 GGUGACAACUGGGCCUGCANN 
                 4083 
               
               
                   
               
               
                  703-721 
                 CCAGAGGUCUACCCAGAAGNN 
                 3984 
                 CUUCUGGGUAGACCUCUGGNN 
                 4084 
               
               
                   
               
               
                  705-723 
                 AGAGGUCUACCCAGAAGGANN 
                 3985 
                 UCCUUCUGGGUAGACCUCUNN 
                 4085 
               
               
                   
               
               
                  730-748 
                 UCCUUACCAGCCUCCCUUUNN 
                 3986 
                 AAAGGGAGGCUGGUAAGGANN 
                 4086 
               
               
                   
               
               
                  742-760 
                 UCCCUUUCUCUGUCAGUGGNN 
                 3987 
                 CCACUGACAGAGAAAGGGANN 
                 4087 
               
               
                   
               
               
                  744-762 
                 CCUUUCUCUGUCAGUGGGGNN 
                 3988 
                 CCCCACUGACAGAGAAAGGNN 
                 4088 
               
               
                   
               
               
                  767-785 
                 CAUCAGCCAAGCUGGAAGCNN 
                 3989 
                 GCUUCCAGCUUGGCUGAUGNN 
                 4089 
               
               
                   
               
               
                  771-789 
                 AGCCAAGCUGGAAGCCAUUNN 
                 3990 
                 AAUGGCUUCCAGCUUGGCUNN 
                 4090 
               
               
                   
               
               
                  916-934 
                 GAUCACCCUGAAUUCAUUGNN 
                 3991 
                 CAAUGAAUUCAGGGUGAUCNN 
                 4091 
               
               
                   
               
               
                  920-938 
                 ACCCUGAAUUCAUUGUCUCNN 
                 3992 
                 GAGACAAUGAAUUCAGGGUNN 
                 4092 
               
               
                   
               
               
                  922-940 
                 CCUGAAUUCAUUGUCUCAGNN 
                 3993 
                 CUGAGACAAUGAAUUCAGGNN 
                 4093 
               
               
                   
               
               
                  925-943 
                 GAAUUCAUUGUCUCAGUGANN 
                 3994 
                 UCACUGAGACAAUGAAUUCNN 
                 4094 
               
               
                   
               
               
                 1720-1738 
                 UAUGUAAAUGCUUGAUGGANN 
                 3995 
                 UCCAUCAAGCAUUUACAUANN 
                 4095 
               
               
                   
               
               
                  232-250 
                 GAGGAAACUGAAAAACAGANN 
                 3996 
                 UCUGUUUUUCAGUUUCCUCNN 
                 4096 
               
               
                   
               
               
                  236-254 
                 AAACUGAAAAACAGAGUAGNN 
                 3997 
                 CUACUCUGUUUUUCAGUUUNN 
                 4097 
               
               
                   
               
               
                  728-746 
                 GUUCCUUACCAGCCUCCCUNN 
                 3998 
                 AGGGAGGCUGGUAAGGAACNN 
                 4098 
               
               
                   
               
               
                  729-747 
                 UUCCUUACCAGCCUCCCUUNN 
                 3999 
                 AAGGGAGGCUGGUAAGGAANN 
                 4099 
               
               
                   
               
               
                  745-763 
                 CUUUCUCUGUCAGUGGGGANN 
                 4000 
                 UCCCCACUGACAGAGAAAGNN 
                 4100 
               
               
                   
               
               
                  766-784 
                 UCAUCAGCCAAGCUGGAAGNN 
                 4001 
                 CUUCCAGCUUGGCUGAUGANN 
                 4101 
               
               
                   
               
               
                  927-945 
                 AUUCAUUGUCUCAGUGAAGNN 
                 4002 
                 CUUCACUGAGACAAUGAAUNN 
                 4102 
               
               
                   
               
               
                  234-252 
                 GGAAACUGAAAAACAGAGUNN 
                 4003 
                 ACUCUGUUUUUCAGUUUCCNN 
                 4103 
               
               
                   
               
               
                  235-253 
                 GAAACUGAAAAACAGAGUANN 
                 4004 
                 UACUCUGUUUUUCAGUUUCNN 
                 4104 
               
               
                   
               
               
                  346-364 
                 GCUAGAAAAUCAGCUUUUANN 
                 4005 
                 UAAAAGCUGAUUUUCUAGCNN 
                 4105 
               
               
                   
               
               
                  490-508 
                 CGGGUCUGCUGAGUCCGCANN 
                 4006 
                 UGCGGACUCAGCAGACCCGNN 
                 4106 
               
               
                   
               
               
                  700-718 
                 CUCCCAGAGGUCUACCCAGNN 
                 4007 
                 CUGGGUAGACCUCUGGGAGNN 
                 4107 
               
               
                   
               
               
                 1715-1733 
                 UUUACUAUGUAAAUGCUUGNN 
                 4008 
                 CAAGCAUUUACAUAGUAAANN 
                 4108 
               
               
                   
               
               
                  734-752 
                 UACCAGCCUCCCUUUCUCUNN 
                 4009 
                 AGAGAAAGGGAGGCUGGUANN 
                 4109 
               
               
                   
               
               
                  773-791 
                 CCAAGCUGGAAGCCAUUAANN 
                 4010 
                 UUAAUGGCUUCCAGCUUGGNN 
                 4110 
               
               
                   
               
               
                  778-796 
                 CUGGAAGCCAUUAAUGAACNN 
                 4011 
                 GUUCAUUAAUGGCUUCCAGNN 
                 4111 
               
               
                   
               
               
                  779-797 
                 UGGAAGCCAUUAAUGAACUNN 
                 4012 
                 AGUUCAUUAAUGGCUUCCANN 
                 4112 
               
               
                   
               
               
                 1774-1792 
                 UCCAUUUAUUUAAAACUACNN 
                 4013 
                 GUAGUUUUAAAUAAAUGGANN 
                 4113 
               
               
                   
               
               
                  704-722 
                 CAGAGGUCUACCCAGAAGGNN 
                 4014 
                 CCUUCUGGGUAGACCUCUGNN 
                 4114 
               
               
                   
               
               
                 1716-1734 
                 UUACUAUGUAAAUGCUUGANN 
                 4015 
                 UCAAGCAUUUACAUAGUAANN 
                 4115 
               
               
                   
               
               
                 1713-1731 
                 AAUUUACUAUGUAAAUGCUNN 
                 4016 
                 AGCAUUUACAUAGUAAAUUNN 
                 4116 
               
               
                   
               
               
                  768-786 
                 AUCAGCCAAGCUGGAAGCCNN 
                 4017 
                 GGCUUCCAGCUUGGCUGAUNN 
                 4117 
               
               
                   
               
               
                 1129-1147 
                 ACUUUUGCCAAUGAACUUUNN 
                 4018 
                 AAAGUUCAUUGGCAAAAGUNN 
                 4118 
               
               
                   
               
               
                  389-407 
                 GUUGAGAACCAGGAGUUAANN 
                 4019 
                 UUAACUCCUGGUUCUCAACNN 
                 4119 
               
               
                   
               
               
                  701-719 
                 UCCCAGAGGUCUACCCAGANN 
                 4020 
                 UCUGGGUAGACCUCUGGGANN 
                 4120 
               
               
                   
               
               
                  706-724 
                 GAGGUCUACCCAGAAGGACNN 
                 4021 
                 GUCCUUCUGGGUAGACCUCNN 
                 4121 
               
               
                   
               
               
                  707-725 
                 AGGUCUACCCAGAAGGACCNN 
                 4022 
                 GGUCCUUCUGGGUAGACCUNN 
                 4122 
               
               
                   
               
               
                  727-745 
                 AGUUCCUUACCAGCCUCCCNN 
                 4023 
                 GGGAGGCUGGUAAGGAACUNN 
                 4123 
               
               
                   
               
               
                  733-751 
                 UUACCAGCCUCCCUUUCUCNN 
                 4024 
                 GAGAAAGGGAGGCUGGUAANN 
                 4124 
               
               
                   
               
               
                  736-754 
                 CCAGCCUCCCUUUCUCUGUNN 
                 4025 
                 ACAGAGAAAGGGAGGCUGGNN 
                 4125 
               
               
                   
               
               
                  738-756 
                 AGCCUCCCUUUCUCUGUCANN 
                 4026 
                 UGACAGAGAAAGGGAGGCUNN 
                 4126 
               
               
                   
               
               
                  743-761 
                 CCCUUUCUCUGUCAGUGGGNN 
                 4027 
                 CCCACUGACAGAGAAAGGGNN 
                 4127 
               
               
                   
               
               
                  769-787 
                 UCAGCCAAGCUGGAAGCCANN 
                 4028 
                 UGGCUUCCAGCUUGGCUGANN 
                 4128 
               
               
                   
               
               
                  772-790 
                 GCCAAGCUGGAAGCCAUUANN 
                 4029 
                 UAAUGGCUUCCAGCUUGGCNN 
                 4129 
               
               
                   
               
               
                  774-792 
                 CAAGCUGGAAGCCAUUAAUNN 
                 4030 
                 AUUAAUGGCUUCCAGCUUGNN 
                 4130 
               
               
                   
               
               
                  231-249 
                 GGAGGAAACUGAAAAACAGNN 
                 4031 
                 CUGUUUUUCAGUUUCCUCCNN 
                 4131 
               
               
                   
               
               
                  233-251 
                 AGGAAACUGAAAAACAGAGNN 
                 4032 
                 CUCUGUUUUUCAGUUUCCUNN 
                 4132 
               
               
                   
               
               
                  735-753 
                 ACCAGCCUCCCUUUCUCUGNN 
                 4033 
                 CAGAGAAAGGGAGGCUGGUNN 
                 4133 
               
               
                   
               
               
                  737-755 
                 CAGCCUCCCUUUCUCUGUCNN 
                 4034 
                 GACAGAGAAAGGGAGGCUGNN 
                 4134 
               
               
                   
               
               
                  739-757 
                 GCCUCCCUUUCUCUGUCAGNN 
                 4035 
                 CUGACAGAGAAAGGGAGGCNN 
                 4135 
               
               
                   
               
               
                  740-758 
                 CCUCCCUUUCUCUGUCAGUNN 
                 4036 
                 ACUGACAGAGAAAGGGAGGNN 
                 4136 
               
               
                   
               
               
                  746-764 
                 UUUCUCUGUCAGUGGGGACNN 
                 4037 
                 GUCCCCACUGACAGAGAAANN 
                 4137 
               
               
                   
               
               
                  770-788 
                 CAGCCAAGCUGGAAGCCAUNN 
                 4038 
                 AUGGCUUCCAGCUUGGCUGNN 
                 4138 
               
               
                   
               
               
                   26-44 
                 GCUAUGGUGGUGGUGGCAGNN 
                 4039 
                 CUGCCACCACCACCAUAGCNN 
                 4139 
               
               
                   
               
               
                   27-45 
                 CUAUGGUGGUGGUGGCAGCNN 
                 4040 
                 GCUGCCACCACCACCAUAGNN 
                 4140 
               
               
                   
               
               
                  732-750 
                 CUUACCAGCCUCCCUUUCUNN 
                 4041 
                 AGAAAGGGAGGCUGGUAAGNN 
                 4141