Patent Publication Number: US-2020277610-A1

Title: Compositions and Methods for Inhibiting Expression of RRM2 Genes

Description:
PRIORITY TO RELATED APPLICATION(S) 
     This application is a continuation of U.S. patent application Ser. No. 15/906,054, filed Feb. 27, 2018, which is a continuation of U.S. patent application Ser. No. 15/415,415, filed 25 Jan. 2017, which is a continuation of U.S. patent application Ser. No. 14/578,716, filed 22 Dec. 2014, now abandoned, which is a continuation of U.S. patent application Ser. No. 13/275,377, filed 18 Oct. 2011, now U.S. Pat. No. 8,946,176, which claims the benefit of European Patent Application No. 10187851.0, filed Oct. 18, 2010, all of which are hereby incorporated by reference in their entirety. 
    
    
     SEQUENCE LISTING 
     The present application is being filed along with a Sequence Listing, which is provided in electronic format. The Sequence Listing is provided as a file entitled 27028US4_SequenceListing.txt, created 26 Feb. 2018, and is approximately 294 KB in size. The Sequence Listing is hereby incorporated by reference in its entirety. 
     BACKGROUND OF THE INVENTION 
     Cancer remains an important area of high unmet medical need. The majority of current treatments provide small gains in overall survival requiring a delicate balance between efficacy and toxicity. Cancer is a disease characterized by uncontrolled growth and survival driven by improper regulation of the cell cycle. The cell cycle is divided up into four stages culminating in cytokinesis with checkpoint controls ensuring accurate completion of each phase. The cell cycle is designed to duplicate cellular material equally partitioning this material into what will become two new cells. DNA replication occurs during S-phase requiring pools of nucleic acid as the building blocks (dNTP) for new DNA as well as to repair DNA damage. Ribonucleotide reductase (RR) converts ribonucleoside 5′-diphosphates into 2′-deoxyribonucleotides which serve as the dNTP source for DNA synthesis and repair. RR catalyzes the rate-limiting step in the generation of dNTPs and represents an important part of cancer cell growth and repair. (RR) is made up of two subunits called RRM1 and RRM2 both of which are required for catalytic RR activity. RRM2 is overexpressed in a range of tumor types and elevated expression is associated with malignant transformation and metastasis. Overexpression of RRM2 cooperates with other oncogenes to drive the transformation and progression of normal cells. Tumor cells are particularly sensitive to changes in their dNTP pools because they have a high proliferation rate and lack checkpoint controls to monitor and repair DNA damage. Inhibition of RRM2 in tumor cells is expected to enhance DNA damage from a lack of sufficient dNTPs producing an apoptotic response. In nontransformed cells, checkpoint controls monitor the level of dNTPs and have the signaling ability to arrest cells before completing DNA replication and repair protecting cells from incurring incompletely replicated DNA or poorly repaired DNA damage. 
     Despite significant advances in the field of RNA interference (RNAi) and advances in the treatment of fibrosis and proliferative disorders, like cancers, there remains a need for an agent that can selectively and efficiently silence the RRM2 gene. A specific RRM2 inhibitor is expected to provide an improved therapeutic index over existing inhibitors because it is more selective and tumors cells lacking checkpoint controls are dependent on large dNTP pools to support their rapid proliferation and DNA repair. Also, preclinical data supports the potent tumor cell killing effects following RRM2 inhibition. 
     RRM2 mRNA overexpression is associated with rapidly proliferating tumor cells. RRM2 expression is cell cycle regulated peaking at S-phase when DNA replication and repair occur followed by rapid degradation during mitosis. RRM2 is overexpressed in Acute myeloid leukemia (AML), bladder cancer, prostate cancer, Non Small Cell Lung Cancer (NSCLC), breast cancer, Hepatocellular Carcinoma (HCC), and colorectal cancers to name a few. 
     Double-stranded ribonucleic acid (dsRNA) molecules have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi), which is a viable pathway in the development of therapeutically active substances for the treatment of a wide range of proliferating diseases. Accordingly, inhibition of RRM2 expression with the dsRNA molecules of this invention may be used in the treatment of cancer including but not limited to Hepatocellular Carcinoma (HCC) and leukemia as well as other solid tumor types. 
     SUMMARY OF THE INVENTION 
     The invention provides double-stranded ribonucleic acid molecules (dsRNAs), as well as compositions and methods for inhibiting the expression of the RRM2 gene, in particular the expression of the RRM2 gene, in a cell, tissue or mammal using such dsRNA. The invention also provides compositions and methods for treating pathological conditions and diseases caused by the expression of the RRM2 gene such as in proliferative disorders like cancer and inflammation. 
     In one preferred embodiment the described dsRNA molecule is capable of inhibiting the expression of a RRM2 gene by at least 60%, preferably by at least 70%, most preferably by at least 80%. The invention also provides compositions and methods for specifically targeting the liver with RRM2 dsRNA, for treating pathological conditions and diseases caused by the expression of the RRM2 gene including those described above. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention provides double-stranded ribonucleic acid (dsRNA) molecules able to selectively and efficiently decrease the expression of RRM2. The use of RRM2 RNAi provides a method for the therapeutic and/or prophylactic treatment of diseases/disorders which are associated with inflammation and proliferative disorders, like cancers. Particular disease/disorder states include the therapeutic and/or prophylactic treatment of inflammation and proliferative disorders, like cancers, particularly HCC, leukemia and solid tumors, which method comprises administration of dsRNA targeting RRM2 to a human being or animal. 
     In one embodiment, the invention provides double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a RRM2 gene, in particular the expression of the mammalian or human RRM2 gene. The dsRNA comprises at least two sequences that are complementary to each other. The dsRNA comprises a sense strand comprising a first sequence and an antisense strand comprising a second sequence, see sequences provided in the sequence listing and also the specific dsRNA pairs in the appended table 1 and table 2. In one embodiment the sense strand comprises a sequence which has an identity of at least 90% to at least a portion of an mRNA encoding RRM2. Said sequence is located in a region of complementarity of the sense strand to the antisense strand, preferably within nucleotides 2-7 of the 5′ terminus of the antisense strand. In one preferred embodiment the dsRNA specifically targets the human RRM2 gene. 
     In one embodiment, the antisense strand comprises a nucleotide sequence which is substantially complementary to at least part of an mRNA encoding said RRM2 gene, and the region of complementarity is most preferably less than 30 nucleotides in length. Furthermore, it is preferred that the length of the herein described inventive dsRNA molecules (duplex length) is in the range of about 16 to 30 nucleotides, in particular in the range of about 18 to 28 nucleotides. Particularly useful in context of this invention are duplex lengths of about 19, 20, 21, 22, 23 or 24 nucleotides. Most preferred are duplex stretches of 19, 21 or 23 nucleotides. 
     The dsRNA, upon delivery to a cell expressing a RRM2 gene, inhibits the expression of a RRM2 gene in vitro by at least 60%, preferably by at least 70%, and most preferably by 80%. 
     Appended Table 1 relates to preferred molecules to be used as dsRNA in accordance with this invention. Also modified dsRNA molecules are provided herein and are in particular disclosed in appended table 2, providing illustrative examples of modified dsRNA molecules of the present invention. As pointed out herein above, Table 2 provides for illustrative examples of modified dsRNAs of this invention (whereby the corresponding sense strand and antisense strand is provided in this table). The relation of the unmodified preferred molecules shown in Table 1 to the modified dsRNAs of Table 2 is illustrated in Table 5. Yet, the illustrative modifications of these constituents of the inventive dsRNAs are provided herein as examples of modifications. 
     Tables 3 and 4 provide for selective biological, clinical and pharmaceutical relevant parameters of certain dsRNA molecules of this invention. 
     Some of the preferred dsRNA molecules are provided in the appended table 1 and, inter alia and preferably, wherein the sense strand is selected from the group consisting of the nucleic acid sequences depicted in SEQ ID NOs: 8, 39, 56, 3, 82, 33, 9, 29, 444, 492 and 442 and the antisense strand is selected from the group consisting of the nucleic acid sequences depicted in SEQ ID NOs: 241, 272, 289, 236, 315, 266, 242, 262, 806, 852 and 851 Accordingly, the inventive dsRNA molecule may, inter alia, comprise the sequence pairs selected from the group consisting of SEQ ID NOs: 8/241, 39/272, 56/289, 3/236, 82/315, 33/266, 9/242, 29/262 444/806, 492/852 and 442/851. In the context of specific dsRNA molecules provided herein, pairs of SEQ ID NOs relate to corresponding sense and antisense strands sequences (5′ to 3′) as also shown in the tables. 
     In one embodiment the dsRNA molecules comprise an antisense strand with a 3′ overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length. Preferably said overhang of the antisense strand comprises uracil or nucleotides which are complementary to the mRNA encoding RRM2. In another preferred embodiment, said dsRNA molecules comprise a sense strand with a 3′ overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length. Preferably said overhang of the sense strand comprises uracil or nucleotides which are identical to the mRNA encoding RRM2. 
     In another preferred embodiment, the dsRNA molecules comprise a sense strand with a 3′ overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length, and an antisense strand with a 3′ overhang of 1-5 nucleotides in length, preferably 1-2 nucleotides in length. 
     Preferably said overhang of the sense strand comprises uracil or nucleotides which are at least 90% identical to the mRNA encoding RRM2 and said overhang of the antisense strand comprises uracil or nucleotides which are at least 90% complementary to the mRNA encoding RRM2. 
     The dsRNA molecules of the invention may be comprised of naturally occurring nucleotides or may be comprised of at least one modified nucleotide, such as a 2′-O-methyl modified nucleotide, inverted deoxythymidine, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 2′ modified nucleotides may have the additional advantage that certain immunostimulatory factors or cytokines are suppressed when the inventive dsRNA molecules are employed in vivo, for example in a medical setting. Alternatively and non-limiting, the modified nucleotide may be chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. In one preferred embodiment the dsRNA molecules comprises at least one of the following modified nucleotides: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group and a deoxythymidine. Preferred dsRNA molecules comprising modified nucleotides are given in table 2. In another preferred embodiment one of those deoxythymidine nucleotides at the 3′ of both strand is a inverted deoxythymidine. 
     In a preferred embodiment the inventive dsRNA molecules comprise modified nucleotides as detailed in the sequences given in table 2. In one preferred embodiment the inventive dsRNA molecule comprises sequence pairs selected from the group consisting of SEQ ID NOs: 8/241, 39/272, 56/289, 3/236, 82/315, 33/266, 9/242, 29/262, 444/806, 492/852 and 442/851, and comprises overhangs at the antisense and/or sense strand of 1-2 deoxythymidines. In one preferred embodiment the inventive dsRNA molecule comprises sequence pairs selected from the group consisting of SEQ ID NOs: 8/241, 39/272, 56/289, 3/236, 82/315, 33/266, 9/242, 29/262 444/806, 492/852 and 442/851, and comprise modifications as detailed in table 2. Preferred dsRNA molecules comprising modified nucleotides are listed in table 2-4, with the most preferred dsRNA molecules depicted in SEQ ID Nos: 469/742, 475/884, 477/839, 497/711, 501/842, 553/968, 507/841, 525/885, 552/891, 477/963, 526/967 and 476/966. 
     In another embodiment, the inventive dsRNAs comprise modified nucleotides on positions different from those disclosed in table 2. In one preferred embodiment two deoxythymidine nucleotides are found at the 3′ of both strands of the dsRNA molecule. Preferably said deoxythymidine nucleotides form an overhang. 
     In one embodiment the dsRNA molecules of the invention comprise a sense and an antisense strand wherein both strands have a half-life of at least 0.9 hours. In one preferred embodiment the dsRNA molecules of the invention comprise a sense and an antisense strand wherein both strands have a half-life of at least 48 hours, preferably in human serum. In another embodiment the dsRNA molecules of the invention are non-immunostimulatory, e.g. do not stimulate INF-alpha (INF-α) and TNF-alpha (TNF-α) in vitro. In another embodiment, the dsRNA molecules of the invention do stimulate INF-α and TNF-α in vitro to a very minor degree. 
     In another embodiment, a nucleic acid sequence encoding a sense strand and/or an antisense strand comprised in the dsRNAs as defined herein are provided. 
     The invention also provides for cells comprising at least one of the dsRNAs of the invention. The cell is preferably a mammalian cell, such as a human cell. Furthermore, tissues and/or non-human organisms comprising the herein defined dsRNA molecules are an embodiment of this invention, whereby said non-human organisms are particularly useful for research purposes or as research tools, for example in drug testing. 
     Furthermore, the invention relates to a method for inhibiting the expression of a RRM2 gene, in particular a mammalian or human RRM2 gene, in a cell, tissue or organism comprising the following steps:
         a) introducing into the cell, tissue or organism a double-stranded ribonucleic acid (dsRNA) as defined herein; and   b) maintaining said cell, tissue or organism produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a RRM2 gene, thereby inhibiting expression of a RRM2 gene in a given cell.       

     The invention also relates to pharmaceutical compositions comprising the inventive dsRNAs of the invention. These pharmaceutical compositions are particularly useful in the inhibition of the expression of a RRM2 gene in a cell, a tissue or an organism. The pharmaceutical composition comprising one or more of the dsRNA of the invention may also comprise (a) pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s). 
     In another embodiment, the invention provides methods for treating, preventing or managing inflammation and/or proliferative disorders like cancers which are associated with RRM2, said method comprising administering to a subject in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of one or more of the dsRNAs of the invention. Preferably, said subject is a mammal, most preferably a human patient. 
     In one embodiment, the invention provides a method for treating a subject having a pathological condition mediated by the expression of a RRM2 gene. Such conditions comprise disorders associated with inflammation and proliferative disorders, like cancers, as described above. In this embodiment, the dsRNA acts as a therapeutic agent for controlling the expression of a RRM2 gene. The method comprises administering a pharmaceutical composition of the invention to the patient (e.g., human), such that expression of a RRM2 gene is silenced. Because of their high specificity, the dsRNAs of the invention specifically target mRNAs of a RRM2 gene. In one preferred embodiment the described dsRNAs specifically decrease RRM2 mRNA levels and do not directly affect the expression and/or mRNA levels of off-target genes in the cell. 
     In one preferred embodiment the described dsRNA decrease RRM2 mRNA levels in the liver by at least 60%, preferably by at least 70%, and most preferably by at least 80% in vivo. In another embodiment the described dsRNAs decrease RRM2 mRNA levels in vivo for at least 4 days. In another preferred embodiment, the dsRNAs of the invention are used for the preparation of a pharmaceutical composition for the treatment of inflammation and proliferative disorders, like cancer. Cancers to be treated with said pharmaceutical composition comprise but are not limited to: HCC, AML, leukemia, bladder cancer, prostate cancer, NSCLC, breast cancer and colorectal cancer. 
     In another embodiment, the invention provides vectors for inhibiting the expression of a RRM2 gene in a cell, in particular a RRM2 gene comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of the dsRNA molecules of the invention. 
     In another embodiment, the invention provides a cell comprising a vector for inhibiting the expression of a RRM2 gene in a cell. Said vector comprises a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of the dsRNA molecule of the invention. Yet, it is preferred that said vector comprises, besides said regulatory sequence a sequence that encodes at least one “sense strand” of the inventive dsRNA and at least one “anti-sense strand” of said dsRNA. It is also envisaged that the claimed cell comprises two or more vectors comprising, besides said regulatory sequences, the herein defined sequence(s) that encode(s) at least one strand of the dsRNA molecules of the invention. 
     In one embodiment, the method comprises administering a composition comprising a dsRNA, wherein the dsRNA comprises a nucleotide sequence which is complementary to at least a part of an RNA transcript of a RRM2 gene of the mammal to be treated. As pointed out above, also vectors and cells comprising nucleic acid molecules that encode for at least one strand of the herein defined dsRNA molecules can be used as pharmaceutical compositions and may, therefore, also be employed in the herein disclosed methods of treating a subject in need of medical intervention. It is also of note that these embodiments relating to pharmaceutical compositions and to corresponding methods of treating a (human) subject also relate to approaches like gene therapy approaches. RRM2 specific dsRNA molecules as provided herein or nucleic acid molecules encoding individual strands of these inventive dsRNA molecules may also be inserted into vectors and used as gene therapy vectors for human patients. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Pat. No. 5,328,470) or by stereotactic injection (see e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise 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. 
     In another aspect of the invention, RRM2 specific dsRNA molecules that modulate RRM2 gene expression activity are expressed from transcription units inserted into DNA or RNA vectors (see, e.g., Skillern, A., et al., International PCT Publication No. WO 00/22113). These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be incorporated and inherited as a transgene integrated into the host genome. 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 strands of a dsRNA can be transcribed by promoters on two separate expression vectors and co-transfected into a target cell. Alternatively, each individual strand of the dsRNA can be transcribed by promoters both of which are located on the same expression plasmid. In a preferred 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. 
     The recombinant dsRNA expression vectors are preferably DNA plasmids or viral vectors. dsRNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus (for a review, see Muzyczka, et al., Curr. Topics Micro. Immunol. (1992) 158:97-129)); adenovirus (see, for example, Berkner, et al., BioTechniques (1998) 6:616), Rosenfeld et al. (1991, Science 252:431-434), and Rosenfeld et al. (1992), Cell 68:143-155)); or alphavirus as well as others known in the art. Retroviruses have been used to introduce a variety of genes into many different cell types, including epithelial cells, in vitro and/or in vivo (see, e.g., Danos and Mulligan, Proc. Natl. Acad. Sci. USA (1998) 85:6460-6464). Recombinant retroviral vectors capable of transducing and expressing genes inserted into the genome of a cell can be produced by transfecting the recombinant retroviral genome into suitable packaging cell lines such as PA317 and Psi-CRIP (Comette et al., 1991 , Human Gene Therapy  2:5-10; Cone et al., 1984 , Proc. Natl. Acad. Sci. USA  81:6349). Recombinant adenoviral vectors can be used to infect a wide variety of cells and tissues in susceptible hosts (e.g., rat, hamster, dog, and chimpanzee) (Hsu et al., 1992,  J. Infectious Disease,  166:769), and also have the advantage of not requiring mitotically active cells for infection. 
     The promoter driving dsRNA expression in either a DNA plasmid or viral vector of the invention may be a eukaryotic RNA polymerase I (e.g. ribosomal RNA promoter), RNA polymerase II (e.g. CMV early promoter or actin promoter or U1 snRNA promoter) or preferably RNA polymerase III promoter (e.g. U6 snRNA or 7SK RNA promoter) or a prokaryotic promoter, for example the T7 promoter, provided the expression plasmid also encodes T7 RNA polymerase required for transcription from a T7 promoter. The promoter can also direct transgene expression to the pancreas (see, e.g. the insulin regulatory sequence for pancreas (Bucchini et al., 1986 , Proc. Natl. Acad. Sci. USA  83:2511-2515)). 
     In addition, expression of the transgene can be precisely regulated, for example, by using an inducible regulatory sequence and expression systems such as a regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones (Docherty et al., 1994 , FASEB  1 8:20-24). Such inducible expression systems, suitable for the control of transgene expression in cells or in mammals include regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-β-D1-thiogalactopyranoside (EPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the dsRNA transgene. 
     Preferably, recombinant vectors capable of expressing dsRNA molecules are delivered as described below, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of dsRNA molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the dsRNAs bind to target RNA and modulate its function or expression. Delivery of dsRNA 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. 
     dsRNA expression DNA plasmids are typically 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 dsRNA-mediated knockdowns targeting different regions of a single RRM2 gene or multiple RRM2 genes over a period of a week or more are also contemplated by the invention. Successful introduction of the vectors of the invention 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 ex vivo cells 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. 
     The following detailed description discloses how to make and use the dsRNA and compositions containing dsRNA to inhibit the expression of a target RRM2 gene, as well as compositions and methods for treating diseases and disorders caused by the expression of said RRM2 gene. 
     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”, “U”, and “T” or “dT” respectively, each generally stand for a nucleotide that contains guanine, cytosine, adenine, uracil and deoxythymidine as a base, respectively. However, the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. Sequences comprising such replacement moieties are embodiments of the invention. As detailed below, the herein described dsRNA molecules may also comprise “overhangs”, i.e. unpaired, overhanging nucleotides which are not directly involved in the RNA double helical structure normally formed by the herein defined pair of “sense strand” and “anti-sense strand”. Often, such an overhanging stretch comprises the deoxythymidine nucleotide, in most embodiments, 2 deoxythymidines in the 3′ end. Such overhangs will be described and illustrated below. 
     The term “RRM2” as used herein relates in particular to the ribonucleotide reductase M2, also known as the ribonucleotide reductase M2 polypeptide, ribonucleoside-diphosphate reductase subunit M2, ribonucleotide reductase small chain, ribonucleotide reductase small subunit, with synonyms R2, RR2, RR2M, and the like and said term relates to the corresponding gene, encoded mRNA, encoded protein/polypeptide as well as functional fragments of the same. Preferred is the human RRM2 gene. In other preferred embodiments the dsRNAs of the invention target the RRM2 gene of human ( H. sapiens ) and cynomolgous monkey ( Macaca fascicularis ) RRM2 gene. Also dsRNAs targeting the rat ( Rattus norvegicus ) and mouse ( Mus musculus ) RRM2 gene are part of this invention. The term “RRM2 gene/sequence” does not only relate to (the) wild-type sequence(s) but also to mutations and alterations which may be comprised in said gene/sequence. Accordingly, the present invention is not limited to the specific dsRNA molecules provided herein. The invention also relates to dsRNA molecules that comprise an antisense strand that is at least 85% complementary to the corresponding nucleotide stretch of an RNA transcript of a RRM2 gene that comprises such mutations/alterations. 
     As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a RRM2 gene, including mRNA that is a product of RNA processing of a primary transcription product. 
     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. However, as detailed herein, such a “strand comprising a sequence” may also comprise modifications, like modified nucleotides. 
     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. “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. 
     Sequences referred to as “fully complementary” comprise base-pairing of the oligonucleotide or polynucleotide comprising the first nucleotide sequence to the oligonucleotide or polynucleotide comprising the second nucleotide sequence over the entire length of the first and second nucleotide sequence. 
     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 preferably not more than 13 mismatched base pairs upon hybridization. 
     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 a dsRNA and a target sequence, as will be understood from the context of their use. 
     The term “double-stranded RNA”, “dsRNA molecule”, or “dsRNA”, as used herein, refers to a ribonucleic acid molecule, or complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands. The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′ end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop”. Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′ end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker”. The RNA strands may have the same or a different number of nucleotides. In addition to the duplex structure, a dsRNA may comprise one or more nucleotide overhangs. The nucleotides in said “overhangs” may comprise between 0 and 5 nucleotides, whereby “0” means no additional nucleotide(s) that form(s) an “overhang” and whereas “5” means five additional nucleotides on the individual strands of the dsRNA duplex. These optional “overhangs” are located in the 3′ end of the individual strands. As will be detailed below, also dsRNA molecules which comprise only an “overhang” in one of the two strands may be useful and even advantageous in context of this invention. The “overhang” comprises preferably between 0 and 2 nucleotides. Most preferably 2 “dT” (deoxythymidine) nucleotides are found at the 3′ end of both strands of the dsRNA. Also 2 “U” (uracil) nucleotides can be used as overhangs at the 3′ end of both strands of the dsRNA. Accordingly, a “nucleotide overhang” refers to the unpaired nucleotide or nucleotides that protrude from the duplex structure of a dsRNA when a 3′-end of one strand of the dsRNA extends beyond the 5′-end of the other strand, or vice versa. For example the antisense strand comprises 23 nucleotides and the sense strand comprises 21 nucleotides, forming a 2 nucleotide overhang at the 3′ end of the antisense strand. Preferably, the 2 nucleotide overhang is fully complementary to the mRNA of the target gene. “Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the dsRNA, i.e., no nucleotide overhang. A “blunt ended” dsRNA is a dsRNA that is double-stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule. 
     The term “antisense strand” refers to the strand of 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. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most tolerated outside nucleotides 2-7 of the 5′ terminus of the antisense strand 
     The term “sense strand,” as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand. “Substantially complementary” means preferably at least 85% of the overlapping nucleotides in sense and antisense strand are complementary. 
     “Introducing into a cell”, when referring to a dsRNA, means facilitating uptake or absorption into the cell, as is understood by those skilled in the art. Absorption or uptake of dsRNA 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; a dsRNA may also be “introduced into a cell”, wherein the cell is part of a living organism. In such instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery, dsRNA can be injected into a tissue site or administered systemically. It is, for example envisaged that the dsRNA molecules of this invention be administered to a subject in need of medical intervention. Such an administration may comprise the injection of the dsRNA, the vector or a cell of this invention into a diseased site in said subject, for example into liver tissue/cells or into cancerous tissues/cells, like liver cancer tissue. In addition, the injection is preferably in close proximity to the diseased tissue envisaged. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. 
     As used herein, “proliferating” and “proliferation” refer to cells undergoing mitosis. Throughout this application, the term “proliferative disorder” refers to any disease/disorder marked by unwanted or aberrant proliferation of tissue. As used herein, the term “proliferative disorder” also refers to conditions in which the unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous. 
     The term “inflammation” as used herein refers to the biologic response of body tissue to injury, irritation, or disease which can be caused by harmful stimuli, for example; pathogens, damaged cells, or irritants. Inflammation is typically characterized by pain and swelling. Inflammation is intended to encompass both acute responses, in which inflammatory processes are active neutrophils and leukocytes), and chronic responses, which are marked by slow progress, a shift in the type of cell present at the site of inflammation, and the formation of connective tissue. 
     Cancers to be treated comprise, but are again not limited to leukemia, AML, solid tumors, liver cancer, brain cancer, breast cancer, lung cancer, NSCLC, colorectal cancer, bladder cancer and prostate cancer, whereby said liver cancer may, inter alia, be selected from the group consisting of hepatocellular carcinoma (HCC), hepatoblastoma, a mixed liver cancer, a cancer derived from mesenchymal tissue, a liver sarcoma or a cholangiocarcinoma. 
     The terms “silence”, “inhibit the expression of” and “knock down”, in as far as they refer to a RRM2 gene, herein refer to the at least partial suppression of the expression of a RRM2 gene, as manifested by a reduction of the amount of mRNA transcribed from a RRM2 gene which may be isolated from a first cell or group of cells in which a RRM2 gene is transcribed and which has or have been treated such that the expression of a RRM2 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 
     
       
         
           
             
               
                 
                   
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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 the RRM2 gene transcription, e.g. the amount of protein encoded by a RRM2 gene which is secreted by a cell, or the number of cells displaying a certain phenotype. As illustrated in the appended examples and in the appended tables provided herein, the inventive dsRNA molecules are capable of inhibiting the expression of a human RRM2 by at least about 60%, preferably by at least 70%, most preferably by at least 80% in vitro assays, i.e. in vitro. The term “in vitro” as used herein includes but is not limited to cell culture assays. In another embodiment the inventive dsRNA molecules are capable of inhibiting the expression of a mouse or rat RRM2 by at least 60% preferably by at least 70%, most preferably by at least 80%. The person skilled in the art can readily determine such an inhibition rate and related effects, in particular in light of the assays provided herein. 
     The term “off target” as used herein refers to all non-target mRNAs of the transcriptome that are predicted by in silico methods to hybridize to the described dsRNAs based on sequence complementarity. The dsRNAs of the present invention preferably do specifically inhibit the expression of RRM2, i.e. do not inhibit the expression of any off-target. 
     The term “half-life” as used herein is a measure of stability of a compound or molecule and can be assessed by methods known to a person skilled in the art, especially in light of the assays provided herein. 
     The term “non-immunostimulatory” as used herein refers to the absence of any induction of a immune response by the invented dsRNA molecules. Methods to determine immune responses are well known to a person skilled in the art, for example by assessing the release of cytokines, as described in the examples section. 
     The terms “treat”, “treatment”, and the like, mean in context of this invention the relief from or alleviation of a disorder related to RRM2 expression, like inflammation and proliferative disorders, like cancers. 
     As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of a dsRNA and a pharmaceutically acceptable carrier. However, such a “pharmaceutical composition” may also comprise individual strands of such a dsRNA molecule or the herein described vector(s) comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a sense or an antisense strand comprised in the dsRNAs of this invention. It is also envisaged that cells, tissues or isolated organs that express or comprise the herein defined dsRNAs may be used as “pharmaceutical compositions”. As used herein, “pharmacologically effective amount,” “therapeutically effective amount” or simply “effective amount” refers to that amount of an RNA effective to produce the intended pharmacological, therapeutic or preventive result. 
     The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The term specifically excludes cell culture medium. For drugs administered orally, pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives as known to persons skilled in the art. 
     It is in particular envisaged that the pharmaceutically acceptable carrier allows for the systemic administration of the dsRNAs, vectors or cells of this invention. Whereas also the enteric administration is envisaged the parenteral administration and also transdermal or transmucosal (e.g. insufflation, buccal, vaginal, anal) administration as well as inhalation of the drug are feasible ways of administering to a patient in need of medical intervention the compounds of this invention. When parenteral administration is employed, this can comprise the direct injection of the compounds of this invention into the diseased tissue or at least in close proximity. However, also intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, intradermal, intrathecal and other administrations of the compounds of this invention are within the skill of the artisan, for example the attending physician. 
     For intramuscular, subcutaneous and intravenous use, the pharmaceutical compositions of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. In a preferred embodiment, the carrier consists exclusively of an aqueous buffer. In this context, “exclusively” means no auxiliary agents or encapsulating substances are present which might affect or mediate uptake of dsRNA in the cells that express a RRM2 gene. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. The pharmaceutical compositions useful according to the invention also include encapsulated formulations to protect the dsRNA against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in PCT publication WO 91/06309 which is incorporated by reference herein. 
     As used herein, a “transformed cell” is a cell into which at least one vector has been introduced from which a dsRNA molecule or at least one strand of such a dsRNA molecule may be expressed. Such a vector is preferably a vector comprising a regulatory sequence operably linked to nucleotide sequence that encodes at least one sense strand or antisense strand of a dsRNA of the present invention. 
     It can be reasonably expected that shorter dsRNAs comprising one of the sequences in Table 1 and 4 minus only a few nucleotides on one or both ends may be similarly effective as compared to the dsRNAs described above. 
     In one preferred embodiment the inventive dsRNA molecules comprise nucleotides 1-19 of the sequences given in Table 1. 
     As pointed out above, in most embodiments of this invention, the dsRNA molecules provided herein comprise a duplex length (i.e. without “overhangs”) of about 16 to about 30 nucleotides. 
     Particular useful dsRNA duplex lengths are about 19 to about 25 nucleotides. Most preferred are duplex structures with a length of 19 nucleotides. In the inventive dsRNA molecules, the antisense strand is at least partially complementary to the sense strand. 
     The dsRNA of the invention can contain one or more mismatches to the target sequence. In a preferred embodiment, the dsRNA of the invention contains no more than 13 mismatches. If the antisense strand of the dsRNA contains mismatches to a target sequence, it is preferable that the area of mismatch not be located within nucleotides 2-7 of the 5′ terminus of the antisense strand. In another embodiment it is preferable that the area of mismatch not be located within nucleotides 2-9 of the 5′ terminus of the antisense strand. 
     As mentioned above, at least one end/strand of the dsRNA may have a single-stranded nucleotide overhang of 1 to 5, preferably 1 or 2 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts. Moreover, the present inventors have discovered that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA, without affecting its overall stability. dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum. Preferably, 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 may also have a blunt end, preferably located at the 5′-end of the antisense strand. Preferably, the antisense strand of the dsRNA has a nucleotide overhang at the 3′-end, and the 5′-end is blunt. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. 
     The dsRNA of the present invention may also be chemically modified to enhance stability. The nucleic acids of 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. Chemical modifications may include, but are not limited to 2′ modifications, introduction of non-natural bases, covalent attachment to a ligand, and replacement of phosphate linkages with thiophosphate linkages, inverted deoxythymidines. In this embodiment, the integrity of the duplex structure is strengthened by at least one, and preferably two, chemical linkages. Chemical linking may be achieved by any of a variety of well-known techniques, for example by introducing covalent, ionic or hydrogen bonds; hydrophobic interactions, van der Waals or stacking interactions; by means of metal-ion coordination, or through use of purine analogues. Preferably, the chemical groups that can be used to modify the dsRNA include, without limitation, methylene blue; bifunctional groups, preferably bis-(2-chloroethyl)amine; N-acetyl-N′-(p-glyoxylbenzoyl)cystamine; 4-thiouracil; and psoralen. In one preferred embodiment, the linker is a hexa-ethylene glycol linker. In this case, the dsRNA are produced by solid phase synthesis and the hexa-ethylene glycol linker is incorporated according to standard methods (e.g., Williams, D. J., and K. B. Hall, Biochem. (1996) 35:14665-14670). In a particular embodiment, the 5′-end of the antisense strand and the 3′-end of the sense strand are chemically linked via a hexaethylene glycol linker. In another embodiment, at least one nucleotide of the dsRNA comprises a phosphorothioate or phosphorodithioate groups. The chemical bond at the ends of the dsRNA is preferably formed by triple-helix bonds. 
     In certain embodiments, a chemical bond may be formed by means of one or several bonding groups, wherein such bonding groups are preferably poly-(oxyphosphinicooxy-1,3-propandiol)- and/or polyethylene glycol chains. In other embodiments, a chemical bond may also be formed by means of purine analogs introduced into the double-stranded structure instead of purines. In further embodiments, a chemical bond may be formed by azabenzene units introduced into the double-stranded structure. In still further embodiments, a chemical bond may be formed by branched nucleotide analogs instead of nucleotides introduced into the double-stranded structure. In certain embodiments, a chemical bond may be induced by ultraviolet light. 
     In yet another embodiment, the nucleotides at one or both of the two single strands may be modified to prevent or inhibit the activation of cellular enzymes, for example certain nucleases. Techniques for inhibiting the activation of cellular enzymes are known in the art including, but not limited to, 2′-amino modifications, 2′-amino sugar modifications, 2′-F sugar modifications, 2′-F modifications, 2′-alkyl sugar modifications, uncharged backbone modifications, morpholino modifications, 2′-O-methyl modifications, and phosphoramidate (see, e.g., Wagner,  Nat. Med . (1995) 1:1116-8). Thus, at least one 2′-hydroxyl group of the nucleotides on a dsRNA is replaced by a chemical group, preferably by a 2′-amino or a 2′-methyl group. Also, at least one nucleotide may be modified to form a locked nucleotide. Such locked nucleotide contains a methylene bridge that connects the 2′-oxygen of ribose with the 4′-carbon of ribose. Introduction of a locked nucleotide into an oligonucleotide improves the affinity for complementary sequences and increases the melting temperature by several degrees. 
     Modifications of dsRNA molecules provided herein may positively influence their stability in vivo as well as in vitro and also improve their delivery to the (diseased) target side. Furthermore, such structural and chemical modifications may positively influence physiological reactions towards the dsRNA molecules upon administration, e.g. the cytokine release which is preferably suppressed. Such chemical and structural modifications are known in the art and are, inter alia, illustrated in Nawrot (2006)  Current Topics in Med Chem,  6, 913-925. 
     Conjugating a ligand to a dsRNA can enhance its cellular absorption as well as targeting to a particular tissue. In certain instances, a hydrophobic ligand is conjugated to the dsRNA to facilitate direct permeation of the cellular membrane. Alternatively, the ligand conjugated to the dsRNA is a substrate for receptor-mediated endocytosis. These approaches have been used to facilitate cell permeation of antisense oligonucleotides. For example, cholesterol has been conjugated to various antisense oligonucleotides resulting in compounds that are substantially more active compared to their non-conjugated analogs. See M. Manoharan  Antisense  &amp;  Nucleic Acid Drug Development  2002, 12, 103. Other lipophilic compounds that have been conjugated to oligonucleotides include 1-pyrene butyric acid, 1,3-bis-O-(hexadecyl)glycerol, and menthol. One example of a ligand for receptor-mediated endocytosis is folic acid. Folic acid enters the cell by folate-receptor-mediated endocytosis. dsRNA compounds bearing folic acid would be efficiently transported into the cell via the folate-receptor-mediated endocytosis. Attachment of folic acid to the 3′-terminus of an oligonucleotide results in increased cellular uptake of the oligonucleotide (Li, S.; Deshmukh, H. M.; Huang, L.  Pharm. Res.  1998, 15, 1540). Other ligands that have been conjugated to oligonucleotides include polyethylene glycols, carbohydrate clusters, cross-linking agents, porphyrin conjugates, and delivery peptides. 
     In certain instances, conjugation of a cationic ligand to oligonucleotides often results in improved resistance to nucleases. Representative examples of cationic ligands are propylammonium and dimethylpropylammonium. Interestingly, antisense oligonucleotides were reported to retain their high binding affinity to mRNA when the cationic ligand was dispersed throughout the oligonucleotide. See M. Manoharan  Antisense  &amp;  Nucleic Acid Drug Development  2002, 12, 103 and references therein. 
     The ligand-conjugated dsRNA of the invention may be synthesized by the use of a dsRNA that bears a pendant reactive functionality, such as that derived from the attachment of a linking molecule onto the dsRNA. This reactive oligonucleotide may be reacted directly with commercially-available ligands, ligands that are synthesized bearing any of a variety of protecting groups, or ligands that have a linking moiety attached thereto. The methods of the invention facilitate the synthesis of ligand-conjugated dsRNA by the use of, in some preferred embodiments, nucleoside monomers that have been appropriately conjugated with ligands and that may further be attached to a solid-support material. Such ligand-nucleoside conjugates, optionally attached to a solid-support material, are prepared according to some preferred embodiments of the methods of the invention via reaction of a selected serum-binding ligand with a linking moiety located on the 5′ position of a nucleoside or oligonucleotide. In certain instances, an dsRNA bearing an aralkyl ligand attached to the 3′-terminus of the dsRNA is prepared by first covalently attaching a monomer building block to a controlled-pore-glass support via a long-chain aminoalkyl group. Then, nucleotides are bonded via standard solid-phase synthesis techniques to the monomer building-block bound to the solid support. The monomer building block may be a nucleoside or other organic compound that is compatible with solid-phase synthesis. 
     The dsRNA used in the conjugates of the invention may be conveniently and routinely made through the well-known technique of solid-phase synthesis. It is also known to use similar techniques to prepare other oligonucleotides, such as the phosphorothioates and alkylated derivatives. 
     Teachings regarding the synthesis of particular modified oligonucleotides may be found in the following U.S. patents: U.S. Pat. No. 5,218,105, drawn to polyamine conjugated oligonucleotides; U.S. Pat. Nos. 5,541,307, drawn to oligonucleotides having modified backbones; U.S. Pat. No. 5,521,302, drawn to processes for preparing oligonucleotides having chiral phosphorus linkages; U.S. Pat. No. 5,539,082, drawn to peptide nucleic acids; U.S. Pat. No. 5,554,746, drawn to oligonucleotides having β-lactam backbones; U.S. Pat. No. 5,571,902, drawn to methods and materials for the synthesis of oligonucleotides; U.S. Pat. No. 5,578,718, drawn to nucleosides having alkylthio groups, wherein such groups may be used as linkers to other moieties attached at any of a variety of positions of the nucleoside; U.S. Pat. No. 5,587,361 drawn to oligonucleotides having phosphorothioate linkages of high chiral purity; U.S. Pat. No. 5,506,351, drawn to processes for the preparation of 2′-O-alkyl guanosine and related compounds, including 2,6-diaminopurine compounds; U.S. Pat. No. 5,587,469, drawn to oligonucleotides having N-2 substituted purines; U.S. Pat. No. 5,587,470, drawn to oligonucleotides having 3-deazapurines; U.S. Pat. No. 5,608,046, both drawn to conjugated 4′-desmethyl nucleoside analogs; U.S. Pat. No. 5,610,289, drawn to backbone-modified oligonucleotide analogs; U.S. Pat. No. 6,262,241 drawn to, inter alia, methods of synthesizing 2′-fluoro-oligonucleotides. 
     In the ligand-conjugated dsRNA and ligand-molecule bearing sequence-specific linked nucleosides of the invention, the oligonucleotides and oligonucleosides may be assembled on a suitable DNA synthesizer utilizing standard nucleotide or nucleoside precursors, or nucleotide or nucleoside conjugate precursors that already bear the linking moiety, ligand-nucleotide or nucleoside-conjugate precursors that already bear the ligand molecule, or non-nucleoside ligand-bearing building blocks. 
     When using nucleotide-conjugate precursors that already bear a linking moiety, the synthesis of the sequence-specific linked nucleosides is typically completed, and the ligand molecule is then reacted with the linking moiety to form the ligand-conjugated oligonucleotide. Oligonucleotide conjugates bearing a variety of molecules such as steroids, vitamins, lipids and reporter molecules, has previously been described (see Manoharan et al., PCT Application WO 93/07883). In a preferred embodiment, the oligonucleotides or linked nucleosides of the invention are synthesized by an automated synthesizer using phosphoramidites derived from ligand-nucleoside conjugates in addition to commercially available phosphoramidites. 
     The incorporation of a 2′-O-methyl, 2′-O-ethyl, 2′-O-propyl, 2′-O-allyl, 2′-O-aminoalkyl or 2′-deoxy-2′-fluoro group in nucleosides of an oligonucleotide confers enhanced hybridization properties to the oligonucleotide. Further, oligonucleotides containing phosphorothioate backbones have enhanced nuclease stability. Thus, functionalized, linked nucleosides of the invention can be augmented to include either or both a phosphorothioate backbone or a 2′-O-methyl, 2′-O-ethyl, 2′-O-propyl, 2′-O-aminoalkyl, 2′-O-allyl or 2′-deoxy-2′-fluoro group. 
     In some preferred embodiments, functionalized nucleoside sequences of the invention possessing an amino group at the 5′-terminus are prepared using a DNA synthesizer, and then reacted with an active ester derivative of a selected ligand. Active ester derivatives are well known to those skilled in the art. Representative active esters include N-hydrosuccinimide esters, tetrafluorophenolic esters, pentafluorophenolic esters and pentachlorophenolic esters. The reaction of the amino group and the active ester produces an oligonucleotide in which the selected ligand is attached to the 5′-position through a linking group. The amino group at the 5′-terminus can be prepared utilizing a 5′-Amino-Modifier C6 reagent. In a preferred embodiment, ligand molecules may be conjugated to oligonucleotides at the 5′-position by the use of a ligand-nucleoside phosphoramidite wherein the ligand is linked to the 5′-hydroxy group directly or indirectly via a linker. Such ligand-nucleoside phosphoramidites are typically used at the end of an automated synthesis procedure to provide a ligand-conjugated oligonucleotide bearing the ligand at the 5′-terminus. 
     In one preferred embodiment of the methods of the invention, the preparation of ligand conjugated oligonucleotides commences with the selection of appropriate precursor molecules upon which to construct the ligand molecule. Typically, the precursor is an appropriately-protected derivative of the commonly-used nucleosides. For example, the synthetic precursors for the synthesis of the ligand-conjugated oligonucleotides of the invention include, but are not limited to, 2′-aminoalkoxy-5′-ODMT-nucleosides, 2′-6-aminoalkylamino-5′-ODMT-nucleosides, 5′-6-aminoalkoxy-2′-deoxy-nucleosides, 5′-6-aminoalkoxy-2-protected-nucleosides, 3′-6-aminoalkoxy-5′-ODMT-nucleosides, and 3′-aminoalkylamino-5′-ODMT-nucleosides that may be protected in the nucleobase portion of the molecule. Methods for the synthesis of such amino-linked protected nucleoside precursors are known to those of ordinary skill in the art. 
     In many cases, protecting groups are used during the preparation of the compounds of the invention. As used herein, the term “protected” means that the indicated moiety has a protecting group appended thereon. In some preferred embodiments of the invention, compounds contain one or more protecting groups. A wide variety of protecting groups can be employed in the methods of the invention. In general, protecting groups render chemical functionalities inert to specific reaction conditions, and can be appended to and removed from such functionalities in a molecule without substantially damaging the remainder of the molecule. 
     Representative hydroxyl protecting groups, as well as other representative protecting groups, are disclosed in Greene and Wuts,  Protective Groups in Organic Synthesis , Chapter 2, 2d ed., John Wiley &amp; Sons, New York, 1991, and  Oligonucleotides And Analogues A Practical Approach , Ekstein, F. Ed., IRL Press, N.Y., 1991. 
     Amino-protecting groups stable to acid treatment are selectively removed with base treatment, and are used to make reactive amino groups selectively available for substitution. Examples of such groups are the Fmoc (E. Atherton and R. C. Sheppard in  The Peptides , S. Udenfriend, J. Meienhofer, Eds., Academic Press, Orlando, 1987, volume 9, p. 1) and various substituted sulfonylethyl carbamates exemplified by the Nsc group (Samukov et al.,  Tetrahedron Lett.,  1994, 35:7821. 
     Additional amino-protecting groups include, but are not limited to, carbamate protecting groups, such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)-ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenyl-methyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups, such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imide protecting groups, such as phthalimido and dithiasuccinoyl. Equivalents of these amino-protecting groups are also encompassed by the compounds and methods of the invention. 
     Many solid supports are commercially available and one of ordinary skill in the art can readily select a solid support to be used in the solid-phase synthesis steps. In certain embodiments, a universal support is used. A universal support allows for the preparation of oligonucleotides having unusual or modified nucleotides located at the 3′-terminus of the oligonucleotide. For further details about universal supports see Scott et al.,  Innovations and Perspectives in solid - phase Synthesis,  3 rd International Symposium,  1994, Ed. Roger Epton, Mayflower Worldwide, 115-124]. In addition, it has been reported that the oligonucleotide can be cleaved from the universal support under milder reaction conditions when the oligonucleotide is bonded to the solid support via a syn-1,2-acetoxyphosphate group which more readily undergoes basic hydrolysis. See Guzaev, A. I.; Manoharan, M.  J. Am. Chem. Soc.  2003, 125, 2380. 
     The nucleosides are linked by phosphorus-containing or non-phosphorus-containing covalent internucleoside linkages. For the purposes of identification, such conjugated nucleosides can be characterized as ligand-bearing nucleosides or ligand-nucleoside conjugates. The linked nucleosides having an aralkyl ligand conjugated to a nucleoside within their sequence will demonstrate enhanced dsRNA activity when compared to like dsRNA compounds that are not conjugated. 
     The aralkyl-ligand-conjugated oligonucleotides of the invention also include conjugates of oligonucleotides and linked nucleosides wherein the ligand is attached directly to the nucleoside or nucleotide without the intermediacy of a linker group. The ligand may preferably be attached, via linking groups, at a carboxyl, amino or oxo group of the ligand. Typical linking groups may be ester, amide or carbamate groups. 
     Specific examples of preferred modified oligonucleotides envisioned for use in the ligand-conjugated oligonucleotides of the invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined here, oligonucleotides having modified backbones or internucleoside linkages include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of the invention, modified oligonucleotides that do not have a phosphorus atom in their intersugar backbone can also be considered to be oligonucleosides. 
     Specific oligonucleotide chemical modifications are described below. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, more than one modifications may be incorporated in a single dsRNA compound or even in a single nucleotide thereof. 
     Preferred modified internucleoside linkages or 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 United States Patents relating to the preparation of the above phosphorus-atom-containing linkages include, but are not limited to, U.S. Pat. Nos. 4,469,863; 5,023,243; 5,264,423; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233 and 5,466,677, each of which is herein incorporated by reference in their entirety. 
     Preferred modified internucleoside linkages or backbones that do not include a phosphorus atom therein (i.e., oligonucleosides) have backbones that are formed by short chain alkyl or cycloalkyl intersugar linkages, mixed heteroatom and alkyl or cycloalkyl intersugar linkages, or one or more short chain heteroatomic or heterocyclic intersugar 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 United States patents relating to the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,214,134; 5,216,141; 5,264,562; 5,466,677; 5,470,967; 5,489,677; 5,602,240 and 5,663,312, each of which is herein incorporated by reference. 
     In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleoside units are replaced with novel groups. The nucleobase units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligonucleotide, an oligonucleotide 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 oligonucleotide is replaced with an amide-containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to atoms of the amide portion of the backbone. Teaching of PNA compounds can be found for example in U.S. Pat. No. 5,539,082. 
     Some preferred embodiments of the invention employ oligonucleotides with phosphorothioate linkages and oligonucleosides with heteroatom backbones, and in particular —CH 2 NH—O—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 —O—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. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. 
     The oligonucleotides employed in the ligand-conjugated oligonucleotides of the invention may additionally or alternatively comprise 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 and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. 
     Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in the  Concise Encyclopedia Of Polymer Science And Engineering , pages 858-859, Kroschwitz, J. I., ed. John Wiley &amp; Sons, 1990, those disclosed by Englisch et al.,  Angewandte Chemie, International Edition,  1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15 , Antisense 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 oligonucleotides of 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. (Id., pages 276-278) and are presently preferred base substitutions, even more particularly when combined with 2′-methoxyethyl sugar modifications. 
     Representative United States patents relating to 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. 5,134,066; 5,459,255; 5,552,540; 5,594,121 and 5,596,091 all of which are hereby incorporated by reference. 
     In certain embodiments, the oligonucleotides employed in the ligand-conjugated oligonucleotides of the invention may additionally or alternatively comprise one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O-, S-, or N-alkyl, O-, S-, or N-alkenyl, or O, S- or N-alkynyl, 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. Particularly preferred are 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. Other preferred oligonucleotides comprise 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 oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy [2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE], i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in U.S. Pat. No. 6,127,533, filed on Jan. 30, 1998, the contents of which are incorporated by reference. 
     Other preferred modifications include 2′-methoxy (2′-O—CH 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 oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides. 
     As used herein, the term “sugar substituent group” or “2′-substituent group” includes groups attached to the 2′-position of the ribofuranosyl moiety with or without an oxygen atom. Sugar substituent groups include, but are not limited to, fluoro, O-alkyl, O-alkylamino, O-alkylalkoxy, protected O-alkylamino, O-alkylaminoalkyl, O-alkyl imidazole and polyethers of the formula (O-alkyl) m , wherein m is 1 to about 10. Preferred among these polyethers are linear and cyclic polyethylene glycols (PEGs), and (PEG)-containing groups, such as crown ethers and, inter alia, those which are disclosed by Delgardo et. al. ( Critical Reviews in Therapeutic Drug Carrier Systems  1992, 9:249), which is hereby incorporated by reference in its entirety. Further sugar modifications are disclosed by Cook ( Anti - fibrosis Drug Design,  1991, 6:585-607). Fluoro, O-alkyl, O-alkylamino, O-alkyl imidazole, O-alkylaminoalkyl, and alkyl amino substitution is described in U.S. Pat. No. 6,166,197, entitled “Oligomeric Compounds having Pyrimidine Nucleotide(s) with 2′ and 5′ Substitutions,” hereby incorporated by reference in its entirety. 
     Additional sugar substituent groups amenable to the invention include 2′-SR and 2′-NR 2  groups, wherein each R is, independently, hydrogen, a protecting group or substituted or unsubstituted alkyl, alkenyl, or alkynyl. 2′-SR Nucleosides are disclosed in U.S. Pat. No. 5,670,633, hereby incorporated by reference in its entirety. The incorporation of 2′-SR monomer synthons is disclosed by Hamm et al. ( J. Org. Chem.,  1997, 62:3415-3420). 2′-NR nucleosides are disclosed by Goettingen, M.,  J. Org. Chem.,  1996, 61, 6273-6281; and Polushin et al.,  Tetrahedron Lett.,  1996, 37, 3227-3230. Further representative 2′-substituent groups amenable to the invention include those having one of formula I or II: 
     
       
         
         
             
             
         
       
     
     wherein,
         E is C 1 -C 10  alkyl, N(Q 3 )(Q 4 ) or N═C (Q 3 )(Q 4 ); each Q 3  and Q 4  is, independently, H, C 1 -C 10  alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a solid support; or Q 3  and Q 4 , together, form a nitrogen protecting group or a ring structure optionally including at least one additional heteroatom selected from N and 0;   q 1  is an integer from 1 to 10;   q 2  is an integer from 1 to 10;   q 3  is 0 or 1;   q 4  is 0, 1 or 2;   each Z 1 , Z 2  and Z 3  is, independently, C 4 -C 7  cycloalkyl, C 5 -C 14  aryl or C 3 -C 15  heterocyclyl, wherein the heteroatom in said heterocyclyl group is selected from oxygen, nitrogen and sulfur;   Z 4  is OM 1 , SM 1 , or N(M1) 2 ; each M 1  is, independently, H, C 1 -C 8  alkyl, C 1 -C 8  haloalkyl, C(═NH)N(H)M 2 , C(═O)N(H)M 2  or OC(═O)N(H)M 2 ; M 2  is H or C 1 -C 8  alkyl; and   Z 5  is C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 6 -C 14  aryl, N(Q 3 )(Q 4 ), OQ 3 , halo, SQ 3  or CN.       

     Representative 2′-O-sugar substituent groups of formula I are disclosed in U.S. Pat. No. 6,172,209, entitled “Capped 2′-Oxyethoxy Oligonucleotides,” hereby incorporated by reference in its entirety. Representative cyclic 2′-O-sugar substituent groups of formula II are disclosed in U.S. Pat. No. 6,271,358, entitled “RNA Targeted 2′-Modified Oligonucleotides that are Conformationally Preorganized,” hereby incorporated by reference in its entirety. 
     Sugars having O-substitutions on the ribosyl ring are also amenable to the invention. Representative substitutions for ring O include, but are not limited to, S, CH 2 , CHF, and CF 2 . 
     Oligonucleotides may also have sugar mimetics, such as cyclobutyl moieties, in place of the pentofuranosyl sugar. Representative United States patents relating to the preparation of such modified sugars include, but are not limited to, U.S. Pat. Nos. 5,359,044; 5,466,786; 5,519,134; 5,591,722; 5,597,909; 5,646,265 and 5,700,920, all of which are hereby incorporated by reference. 
     Additional modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide. For example, one additional modification of the ligand-conjugated oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more additional non-ligand moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties, such as a cholesterol moiety (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 1,2-di-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). 
     The invention also includes compositions employing oligonucleotides that are substantially chirally pure with regard to particular positions within the oligonucleotides. Examples of substantially chirally pure oligonucleotides include, but are not limited to, those having phosphorothioate linkages that are at least 75% Sp or Rp (Cook et al., U.S. Pat. No. 5,587,361) and those having substantially chirally pure (Sp or Rp) alkylphosphonate, phosphoramidate or phosphotriester linkages (Cook, U.S. Pat. Nos. 5,212,295 and 5,521,302). 
     In certain instances, the oligonucleotide may be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to oligonucleotides in order to enhance the activity, cellular distribution or cellular uptake of the oligonucleotide, and procedures for performing such conjugations are available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (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 1,2-di-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). Typical conjugation protocols involve the synthesis of oligonucleotides 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 oligonucleotide still bound to the solid support or following cleavage of the oligonucleotide in solution phase. Purification of the oligonucleotide conjugate by HPLC typically affords the pure conjugate. 
     Alternatively, the molecule being conjugated may be converted into a building block, such as a phosphoramidite, via an alcohol group present in the molecule or by attachment of a linker bearing an alcohol group that may be phosphorylated. 
     Importantly, each of these approaches may be used for the synthesis of ligand conjugated oligonucleotides. Amino linked oligonucleotides may be coupled directly with ligand via the use of coupling reagents or following activation of the ligand as an NHS or pentfluorophenolate ester. Ligand phosphoramidites may be synthesized via the attachment of an aminohexanol linker to one of the carboxyl groups followed by phosphitylation of the terminal alcohol functionality. Other linkers, such as cysteamine, may also be utilized for conjugation to a chloroacetyl linker present on a synthesized oligonucleotide. 
     The person skilled in the art is readily aware of methods to introduce the molecules of this invention into cells, tissues or organisms. Corresponding examples have also been provided in the detailed description of the invention above. For example, the nucleic acid molecules or the vectors of this invention, encoding for at least one strand of the inventive dsRNAs may be introduced into cells or tissues by methods known in the art, like transfections etc. 
     Also for the introduction of dsRNA molecules, means and methods have been provided. For example, targeted delivery by glycosylated and folate-modified molecules, including the use of polymeric carriers with ligands, such as galactose and lactose or the attachment of folic acid to various macromolecules allows the binding of molecules to be delivered to folate receptors. Targeted delivery by peptides and proteins other than antibodies, for example, including RGD-modified nanoparticles to deliver siRNA in vivo or multicomponent (nonviral) delivery systems including short cyclodextrins, adamantine-PEG are known. Yet, also the targeted delivery using antibodies or antibody fragments, including (monovalent) Fab-fragments of an antibody (or other fragments of such an antibody) or single-chain antibodies are envisaged. 
     Injection approaches for target directed delivery comprise, inter alia, hydrodynamic i.v. injection. Also cholesterol conjugates of dsRNA may be used for targeted delivery, whereby the conjugation to lipohilic groups enhances cell uptake and improve pharmacokinetics and tissue biodistribution of oligonucleotides. Also cationic delivery systems are known, whereby synthetic vectors with net positive (cationic) charge to facilitate the complex formation with the polyanionic nucleic acid and interaction with the negatively charged cell membrane. Such cationic delivery systems comprise also cationic liposomal delivery systems, cationic polymer and peptide delivery systems. Other delivery systems for the cellular uptake of dsRNA/siRNA are aptamer-ds/siRNA. Also gene therapy approaches can be used to deliver the inventive dsRNA molecules or nucleic acid molecules encoding the same. Such systems comprise the use of non-pathogenic virus, modified viral vectors, as well as deliveries with nanoparticles or liposomes. Other delivery methods for the cellular uptake of dsRNA are extracorporeal, for example ex vivo treatments of cells, organs or tissues. Certain of these technologies are described and summarized in publications, like Akhtar (2007),  Journal of Clinical Investigation  117, 3623-3632, Nguyen et al. (2008),  Current Opinion in Moleculare Therapeutics  10, 158-167, Zamboni (2005),  Clin. Cancer Res.  11, 8230-8234 or Ikeda et al. (2006),  Pharmaceutical Research  23, 1631-1640 
     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 invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 
     The above provided embodiments and items of the present invention are now illustrated with the following, non-limiting examples. 
     DESCRIPTION OF FIGURES AND APPENDED TABLES 
     
         
         Table 1. Core sequences of dsRNAs targeting human RRM2 gene Letters in capitals represent RNA nucleotides. 
         Table 2. Characterization of dsRNAs targeting human RRM2: Activity testing with single dose in HeLa-S3 cells. Letters in capitals represent RNA nucleotides, lower case letters “c”, “g”, “a” and “u” represent 2′-O-methyl-modified nucleotides, “s” represents phosphorothioate, “dT” deoxythymidine, and “p” represents 5′-phosphate group (sequences without a “p” are lacking a 5′-phosphate group). S.d.=standard deviation, % mRNA=mean mRNA knockdown. 
         Table 3. Characterization of dsRNAs targeting human RRM2: Activity testing for dose response in HeLa-S3 cells. IC 50: 50% inhibitory concentration, IC 80: 80% inhibitory concentration, IC 20: 20% inhibitory concentration. 
         Table 4. Characterization of dsRNAs targeting human RRM2: Stability and Cytokine Induction. t 1/2: half-life of a strand as defined in examples, PBMC: Human peripheral blood mononuclear cells. 
         Table 5. Core sequences of dsRNAs targeting human RRM2 gene and their modified counterparts. Letters in capitals represent RNA nucleotides, lower case letters “c”, “g”, “a” and “u” represent 2′-O-methyl-modified nucleotides, “s” represents phosphorothioate, “dT” deoxythymidine, and “p” represents 5′-phosphate group (sequences without a “p” in columns 6 and 8 are lacking a 5′-phosphate group). 
         Table 6. Sequences of bDNA probes for determination of human RRM2. LE=label extender, CE=capture extender, BL=blocking probe. 
         Table 7. Sequences of bDNA probes for determination of human GAPDH. LE=label extender, CE=capture extender, BL=blocking probe. 
         Table 8. mRNA knockdown and cell viability dose-response curves, IC50 summary. 
         Table 9. Time course of mRNA knockdown: &gt;80% mRNA knockdown observed at 24 hr, Percent mRNA knockdown with 5 nM siRNA, relative to mock transfection. 
           FIG. 1 . RRM2 protein knockdown dose-response 24 h post-transfection. A: Western blot B: Quantitation of RRM2 protein in Western blot. 
           FIG. 2 . Cell cycle analysis of HepG2 cells with dsRNA 477/839: FACS analysis following propidium iodide staining indicates that following siRNA treatment cells accumulate in S-phase. 
           FIG. 3 . Cell cycle analysis of HepG2 cells with dsRNA 477/839: FACS analysis following propidium iodide staining indicates that following siRNA treatment cells accumulate in S-phase. 
           FIG. 4 . Cell cycle analysis of HLF cells with dsRNA 477/839: FACS analysis following propidium iodide staining indicates that following siRNA treatment cells accumulate in S-phase. 
           FIG. 5 . Cell cycle analysis of HLF cells with dsRNA 477/839: FACS analysis following propidium iodide staining indicates that following siRNA treatment cells accumulate in S-phase. 
           FIG. 6 . Apoptosis assay in HepG2 cells. dsRNA 477/839 activates caspase-3/7. 
           FIG. 7 . Apoptosis assay in HLF cells. dsRNA 477/839 activates caspase-3/7. 
           FIG. 8 . Effects on components of DNA damage pathway 48 hr post-transfection with RRM2 siRNA (5 nM). RRM2 knockdown activates the pathway (pChk1 and γ-H2AX) even in the absence of phleomycin-induced DNA damage. 
       
    
     EXAMPLES 
     Identification of dsRNAs for Therapeutic Use 
     dsRNA design was carried out to identify dsRNAs specifically targeting human RRM2 for therapeutic use. First, the known mRNA sequences of human ( Homo sapiens ) RRM2 (NM_001034.3 and NM_001165931.1 listed as SEQ ID NO. 1013 and 1014) were downloaded from NCBI Genbank. 
     The cynomolgous monkey ( Macaca fascicularis ) RRM2 gene was sequenced (see SEQ ID NO. 1015) 
     The cynomolgus monkey sequence (SEQ ID NO. 1015) was examined together with the human RRM2 mRNA sequences (SEQ ID NO. 1013 and 1014) by computer analysis to identify homologous sequences of 19 nucleotides that yield RNA interference (RNAi) agents cross-reactive to both sequences. 
     In identifying RNAi agents, the selection was limited to 19mer sequences having at least 2 mismatches to any other sequence in the human RefSeq database (release 38), which we assumed to represent the comprehensive human transcriptome, by using a proprietary algorithm. 
     All sequences containing 4 or more consecutive U&#39;s (poly-U sequences) or G&#39;s (poly-G sequences) were excluded from the synthesis. 
     The sequences thus identified formed the basis for the synthesis of the RNAi agents in appended Tables 1, 2 and 5. dsRNAs cross-reactive to human as well as cynomolgous monkey were defined as most preferable for therapeutic use. 
     dsRNA Synthesis 
     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. 
     Single-stranded RNAs were produced by solid phase synthesis on a scale of 1 mole using an Expedite 8909 synthesizer (Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany) and controlled pore glass (CPG, 500 Å, Proligo Biochemie GmbH, Hamburg, Germany) as solid support. RNA and RNA containing 2′-O-methyl nucleotides were generated by solid phase synthesis employing the corresponding phosphoramidites and 2′-O-methyl phosphoramidites, respectively (Proligo Biochemie GmbH, Hamburg, Germany). These building blocks were incorporated at selected sites within the sequence of the oligoribonucleotide chain using standard nucleoside phosphoramidite chemistry such as described in Current protocols in nucleic acid chemistry, Beaucage, S. L. et al. (Edrs.), John Wiley &amp; Sons, Inc., New York, N.Y., USA. Phosphorothioate linkages were introduced by replacement of the iodine oxidizer solution with a solution of the Beaucage reagent (Chruachem Ltd, Glasgow, UK) in acetonitrile (1%). Further ancillary reagents were obtained from Mallinckrodt Baker (Griesheim, Germany). 
     Deprotection and purification of the crude oligoribonucleotides by anion exchange HPLC were carried out according to established procedures. Yields and concentrations were determined by UV absorption of a solution of the respective RNA at a wavelength of 260 nm using a spectral photometer (DU 640B, Beckman Coulter GmbH, Unterschleißheim, Germany). Double stranded RNA was generated by mixing an equimolar solution of complementary strands in annealing buffer (20 mM sodium phosphate, pH 6.8; 100 mM sodium chloride), heated in a water bath at 85-90° C. for 3 minutes and cooled to room temperature over a period of 3-4 hours. The annealed RNA solution was stored at −20° C. until use. 
     Activity Testing 
     The activity of the RRM2 dsRNAs for therapeutic use described above was tested in HeLa-S3 cells. Cells in culture were used for quantitation of RRM2 mRNA by branched DNA in total mRNA derived from cells incubated with RRM2-targeting dsRNAs. 
     HeLa-S3 cells were obtained from American Type Culture Collection (Rockville, Md., cat. No. CCL-2.2) and cultured in Ham&#39;s F12 (Biochrom AG, Berlin, Germany, cat. No. FG 0815) supplemented to contain 10% fetal calf serum (FCS) (Biochrom AG, Berlin, Germany, cat. No. S0115), Penicillin 100 U/ml, Streptomycin 100 mg/ml (Biochrom AG, Berlin, Germany, cat. No. A2213) at 37° C. in an atmosphere with 5% CO 2  in a humidified incubator (Heraeus HERAcell, Kendro Laboratory Products, Langenselbold, Germany). 
     Cell seeding and transfection of dsRNA were performed at the same time. For transfection with dsRNA, cells were seeded at a density of 2.0 times.10.sup.4 cells/well in 96-well plates. Transfection with dsRNA was carried out with lipofectamine 2000 (Invitrogen GmbH, Karlsruhe, Germany, cat.No. 11668-019) as described by the manufacturer. In a first single dose experiment dsRNAs were transfected at a concentration of 50 nM. In a second single dose experiment most active dsRNAs were reanalyzed at 500 pM. Most potent dsRNAs and modification variants thereof were tested for improved silencing of RRM2 in single dose at 30 pM. Very effective dsRNAs from single dose screens were further characterized by dose response curves. For this, transfections were performed as described for the single dose screen above, but with the following concentrations of dsRNA (nM): 24, 6, 1.5, 0.375, 0.0938, 0.0234, 0.0059, 0.0015, 0.0004 and 0.0001 nM. After transfection cells were incubated for 24 h at 37° C. and 5% CO 2  in a humidified incubator (Heraeus HERAcell, Kendro Laboratory Products, Langenselbold, Germany). bDNA Assay Kit QuantiGene 2.0 (Panomics/Affymetrix, Fremont, USA, Cat-No: 15735) was used for quantification of RRM2 mRNA, while QuantiGene Assay 1.0 (Panomics/Affymetrix, Fremont, USA, Cat-No: QG0004) was used for quantification of GAPDH mRNA. 24 hours after transfection cells were harvested and lysed at 53° C. following procedures recommended by the manufacturer Panomics/Affymetrix for bDNA quantitation of mRNA. Afterwards, 50 μl of the lysates were incubated with probesets specific to human RRM2 and human GAPDH (sequence of probesets see appended tables 7 and 8) and processed according to the manufacturer&#39;s protocol for QuantiGene Assay Kit 1 or 2, respectively. Chemoluminescence was measured in a Victor2-Light (Perkin Elmer, Wiesbaden, Germany) as RLUs (relative light units) and values obtained with the human RRM2 probeset were normalized to the respective human GAPDH values for each well. Unrelated control dsRNAs were used as a negative control. 
     Inhibition data are given in appended tables 2 and 3. 
     Stability of dsRNAs 
     Stability of dsRNAs targeting human RRM2 was determined in in vitro assays with either human or mouse serum by measuring the half-life of each single strand. 
     Measurements were carried out in triplicates for each time point, using 3 μl 50 μM dsRNA sample mixed with 30 μl human serum (Sigma) or mouse serum (Sigma). Mixtures were incubated for either 0 min, 30 min, 1 h, 3 h, 6 h, 24 h, or 48 h at 37° C. As control for unspecific degradation dsRNA was incubated with 30 μl 1×PBS pH 6.8 for 48 h. Reactions were stopped by the addition of 4 μl proteinase K (20 mg/ml), 25 μl of—“Tissue and Cell Lysis Solution” (Epicentre) and 38 μl Millipore water for 30 min at 65° C. Samples were afterwards spin filtered through a 0.2 m 96 well filter plate at 1400 rpm for 8 min, washed with 55 μl Millipore water twice and spin filtered again. 
     For separation of single strands and analysis of remaining full length product (FLP), samples were run through an ion exchange Dionex Summit HPLC under denaturing conditions using as eluent A 20 mM Na3PO4 in 10% ACN pH=1 and for eluent B 1 M NaBr in eluent A. 
     The following gradient was applied: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                 Time 
                 % A 
                 % B 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 −1.0 min 
                 75 
                 25 
               
               
                   
                 1.00 min 
                 75 
                 25 
               
               
                   
                 19.0 min 
                 38 
                 62 
               
               
                   
                 19.5 min 
                 0 
                 100 
               
               
                   
                 21.5 min 
                 0 
                 100 
               
               
                   
                 22.0 min 
                 75 
                 25 
               
               
                   
                 24.0 min 
                 75 
                 25 
               
               
                   
                   
               
            
           
         
       
     
     For every injection, the chromatograms were integrated automatically by the Dionex Chromeleon 6.60 HPLC software, and were adjusted manually if necessary. All peak areas were corrected to the internal standard (IS) peak and normalized to the incubation at t=0 min. The area under the peak and resulting remaining FLP was calculated for each single strand and triplicate separately. Half-life (t1/2) of a strand was defined by the average time point [h] for triplicates at which half of the FLP was degraded. Results are given in appended table 4. 
     Cytokine Induction 
     Potential cytokine induction of dsRNAs was determined by measuring the release of INF-α and TNF-α in an in vitro PBMC assay. 
     Human peripheral blood mononuclear cells (PBMC) were isolated from buffy coat blood of two donors by Ficoll centrifugation at the day of transfection. Cells were transfected in quadruplicates with dsRNA and cultured for 24 h at 37° C. at a final concentration of 130 nM in Opti-MEM, using either Gene Porter 2 (GP2) or DOTAP. dsRNA sequences that were known to induce INF-α and TNF-α in this assay, as well as a CpG oligo, were used as positive controls. Chemical conjugated dsRNA or CpG oligonucleotides that did not need a transfection reagent for cytokine induction, were incubated at a concentration of 500 nM in culture medium. At the end of incubation, the quadruplicate culture supernatant were pooled. 
     INF-α and TNF-α was then measured in these pooled supernatants by standard sandwich ELISA with two data points per pool. The degree of cytokine induction was expressed relative to positive controls using a score from 0 to 5, with 5 indicating maximum induction. Results are given in appended table 4. 
     Cell Culture and siRNA Transfections. 
     HepG2, HLF and A549 cells were obtained from ATCC and maintained in the recommended media, supplemented with 10% fetal bovine serum and 2 mM 1-Glutamine (HepG2: MEME; HLF and A549: DMEM). Cells were transfected using 0.1 μl DharmaFect 1 (Thermo Fisher) per well of a 96-well plate, with each well containing a final volume of 100 μl growth media. Transfections in 6-well plates were carried out in a similar manner, with volumes adjusted for the larger well size. Transfections were performed using a “reverse transfection” protocol, in which cells (HepG2: 5,000 cells; HLF: 2,000 cells; A540: 4,000 cells) were mixed with transfection mix immediately prior to plating. 
     bDNA Assay. 
     QuantiGene branched DNA assays (Affymetrix) for mRNA quantitation were run according to the manufacturer&#39;s directions using probe sets designed and synthesized by Affymetrix. 40 μl of lysate were used, and signal was normalized to expression of cyclophin B. Results are summarized in table 8 and 9. 
     Cell Growth Assays. 
     Cell-Titer Glo assays (Promega) were performed according to the manufacturer&#39;s directions. Real-time growth assays were performed on the xCELLigence instrument (Roche) using E-Plate 96 plates. Cell index was measured every hour, and area under the curve calculated at particular time points. Results are summarized in table 8. 
     Western Blots. 
     Antibodies for Western blots were obtained from the following sources: Santa Cruz Biotechnology, Inc. (goat polyclonal anti-RRM2, catalog number sc-10844; goat anti-mouse-HRP, catalog number sc-2005); Cell Signaling Technology (rabbit polyclonal anti-Chk1, catalog number 2345; rabbit polyclonal anti-pChk1 (S317), catalog number 2344; goat anti-rabbit-HRP, catalog number 7074; loading control antibody sampler kit (HRP conjugate), catalog number 4670); R&amp;D Systems (mouse monoclonal anti-H2AX, catalog number MAB3406; rabbit polyclonal anti-gamma-H2AX, catalog number AF2288); Promega (donkey anti-goat-HRP, catalog number V8051). 
     Cells were transfected in 6-well plates and lysed with Pierce M-PER Mammalian Protein Extraction Reagent containing Pierce Halt Protease and Phosphatase Inhibitor Cocktail, according to the manufacturer&#39;s recommendations. Protein concentrations were determined using the Pierce Micro BCA Protein Assay Kit. Lysates were run on Novex NuPAGE 4-12% Bis-Tris gels. Protein was transferred to nitrocellulose using the Invitrogen iBlot Dry Blotting System. Western blots were probed using dilutions of antibodies recommended by the manufacturers, and detected using Amersham ECL Plus Western Blotting Detection Reagents. Gel images were collected on a FujiFilm LAS-4000 instrument and quantitated using Multi Gauge v3.1 software. RRM2 protein knock-down dose-response results are shown in  FIG. 1 . Effects on components of DNA damage pathway (in vivo pharmacodynamic markers) are shown in  FIG. 8 . 
     Cell Cycle Assay. 
     Cells were transfected in 6-well plates and harvested at 24, 48, 72 and 96 hours after transfection. Media was removed and collected in a 50-ml conical tube. Wells were washed with 2 ml PBS and added to the corresponding tubes. Cells were trypsinized, and, once displaced, added to the appropriate tubes. Tubes were centrifuged at 2,000 rpm for 10 min, washed once with 2 ml PBS, and then centrifuged again at 2,000 rpm for 5 min. Supernatants were carefully removed. To fix cells, tubes were tapped to loosen the pellets, and 1.2 ml cold 70% ETOH was added. After vortexing, samples were stored at −20° C. overnight. After thawing cells at room temperature for 20-30 min, 1.2 ml cold PBS was added, and tubes were centrifuged at 2,000 rpm for 10 min. Pellets were washed with 2 ml PBS and centrifuged again at 2,000 rpm. To the pellets was added 0.5 ml propidium iodide/RNase staining buffer (BD Pharmingen, catalog number 550825). Following a 15-min incubation at 37° C., data was collected on FACS LSRII instrument (BD) using DIVA software (10,000 events per sample) and analyzed using FlowJo software. Results are shown in  FIGS. 2-5 . 
     Caspase Assay. 
     Activation of caspase 3/7 was determined using the Apo-ONE Homogeneous Caspase-3/7 assay (Promega), according to the manufacturer&#39;s recommendations. Results are shown in  FIGS. 6 and 7 . 
     All ranges recited herein encompass all combinations and subcombinations included within that range limit. All patents and publications cited herein are hereby incorporated by reference in their entirety. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 SEQ  
                   
                 SEQ 
                   
               
               
                 ID 
                 Sense strand  
                 ID 
                 Antisense strand 
               
               
                 NO 
                 sequence (5′-3′) 
                 NO 
                 sequence (5′-3′) 
               
               
                   
               
             
            
               
                   1 
                 UUGUGGCAGACAGACUUAU 
                 234 
                 AUAAGUCUGUCUGCCACAA 
               
               
                   
               
               
                   2 
                 CCUGAUGUUCAAACACCUG 
                 235 
                 CAGGUGUUUGAACAUCAGG 
               
               
                   
               
               
                   3 
                 AGUCCAACAGAGAAUUCUU 
                 236 
                 AAGAAUUCUCUGUUGGACU 
               
               
                   
               
               
                   4 
                 UAGGCGAGUAUCAGAGGAU 
                 237 
                 AUCCUCUGAUACUCGCCUA 
               
               
                   
               
               
                   5 
                 GGCGAGUAUCAGAGGAUGG 
                 238 
                 CCAUCCUCUGAUACUCGCC 
               
               
                   
               
               
                   6 
                 UGUUCAAACACCUGGUACA 
                 239 
                 UGUACCAGGUGUUUGAACA 
               
               
                   
               
               
                   7 
                 GGGUGACCCUUUAGUGAGC 
                 240 
                 GCUCACUAAAGGGUCACCC 
               
               
                   
               
               
                   8 
                 GAAGGAAAGACUAACUUCU 
                 241 
                 AGAAGUUAGUCUUUCCUUC 
               
               
                   
               
               
                   9 
                 UUCUGAAAUGUAUAGUCUU 
                 242 
                 AAGACUAUACAUUUCAGAA 
               
               
                   
               
               
                  10 
                 CUGUGUAGCUACCUCACAA 
                 243 
                 UUGUGAGGUAGCUACACAG 
               
               
                   
               
               
                  11 
                 UGCACUCUAAUGAAGCAAU 
                 244 
                 AUUGCUUCAUUAGAGUGCA 
               
               
                   
               
               
                  12 
                 CCCAUUUGACUUUAUGGAG 
                 245 
                 CUCCAUAAAGUCAAAUGGG 
               
               
                   
               
               
                  13 
                 AAAUGUAUAGUCUUCUUAU 
                 246 
                 AUAAGAAGACUAUACAUUU 
               
               
                   
               
               
                  14 
                 UACAUUGAGUUUGUGGCAG 
                 247 
                 CUGCCACAAACUCAAUGUA 
               
               
                   
               
               
                  15 
                 CAAUACAUUGAGUUUGUGG 
                 248 
                 CCACAAACUCAAUGUAUUG 
               
               
                   
               
               
                  16 
                 GAACAGGAGUUCCUCACUG 
                 249 
                 CAGUGAGGAACUCCUGUUC 
               
               
                   
               
               
                  17 
                 AUCCCAUGUUCUGGCUUUC 
                 250 
                 GAAAGCCAGAACAUGGGAU 
               
               
                   
               
               
                  18 
                 GUAGGUUGUGUGAGUUAAU 
                 251 
                 AUUAACUCACACAACCUAC 
               
               
                   
               
               
                  19 
                 AUAGUCUUCUUAUUGACAC 
                 252 
                 GUGUCAAUAAGAAGACUAU 
               
               
                   
               
               
                  20 
                 AUUGCACUCUAAUGAAGCA 
                 253 
                 UGCUUCAUUAGAGUGCAAU 
               
               
                   
               
               
                  21 
                 UUAUCAAUGCUGUUCGGAU 
                 254 
                 AUCCGAACAGCAUUGAUAA 
               
               
                   
               
               
                  22 
                 AGAAACGAGGACUGAUGCC 
                 255 
                 GGCAUCAGUCCUCGUUUCU 
               
               
                   
               
               
                  23 
                 CAUUGAGUUUGUGGCAGAC 
                 256 
                 GUCUGCCACAAACUCAAUG 
               
               
                   
               
               
                  24 
                 ACAUUCAGCACUGGGAAUC 
                 257 
                 GAUUCCCAGUGCUGAAUGU 
               
               
                   
               
               
                  25 
                 UGAUGUUCAAACACCUGGU 
                 258 
                 ACCAGGUGUUUGAACAUCA 
               
               
                   
               
               
                  26 
                 GGAUAGAACAGGAGUUCCU 
                 259 
                 AGGAACUCCUGUUCUAUCC 
               
               
                   
               
               
                  27 
                 AAUAUUUCACUGGAAGGAA 
                 260 
                 UUCCUUCCAGUGAAAUAUU 
               
               
                   
               
               
                  28 
                 AAUAAACAUUGUUUGUACU 
                 261 
                 AGUACAAACAAUGUUUAUU 
               
               
                   
               
               
                  29 
                 UCCCAUGUUCUGGCUUUCU 
                 262 
                 AGAAAGCCAGAACAUGGGA 
               
               
                   
               
               
                  30 
                 UUCGGAUAGAACAGGAGUU 
                 263 
                 AACUCCUGUUCUAUCCGAA 
               
               
                   
               
               
                  31 
                 AAGUAGGUUGUGUGAGUUA 
                 264 
                 UAACUCACACAACCUACUU 
               
               
                   
               
               
                  32 
                 UUAUAGUGCUGGUAGUAUC 
                 265 
                 GAUACUACCAGCACUAUAA 
               
               
                   
               
               
                  33 
                 CUUCUUAUUGACACUUACA 
                 266 
                 UGUAAGUGUCAAUAAGAAG 
               
               
                   
               
               
                  34 
                 UACAGAAGCCCGCUGUUUC 
                 267 
                 GAAACAGCGGGCUUCUGUA 
               
               
                   
               
               
                  35 
                 GUGACCCUUUAGUGAGCUU 
                 268 
                 AAGCUCACUAAAGGGUCAC 
               
               
                   
               
               
                  36 
                 AUAGAACAGGAGUUCCUCA 
                 269 
                 UGAGGAACUCCUGUUCUAU 
               
               
                   
               
               
                  37 
                 CUGGCACUUUACAAACAAA 
                 270 
                 UUUGUUUGUAAAGUGCCAG 
               
               
                   
               
               
                  38 
                 UCUAAUGAAGCAAUACAUU 
                 271 
                 AAUGUAUUGCUUCAUUAGA 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
               
               
                   
               
               
                  40 
                 UGUUCGGAUAGAACAGGAG 
                 273 
                 CUCCUGUUCUAUCCGAACA 
               
               
                   
               
               
                  41 
                 AGUACCAUGAUAUCUGGCA 
                 274 
                 UGCCAGAUAUCAUGGUACU 
               
               
                   
               
               
                  42 
                 CAGAGAUGAGGGUUUACAC 
                 275 
                 GUGUAAACCCUCAUCUCUG 
               
               
                   
               
               
                  43 
                 GAAACGAGGACUGAUGCCU 
                 276 
                 AGGCAUCAGUCCUCGUUUC 
               
               
                   
               
               
                  44 
                 AAGAGAGUAGGCGAGUAUC 
                 277 
                 GAUACUCGCCUACUCUCUU 
               
               
                   
               
               
                  45 
                 CAUUAGCUGAAUAAUGUGA 
                 278 
                 UCACAUUAUUCAGCUAAUG 
               
               
                   
               
               
                  46 
                 AGUAGAGAACCCAUUUGAC 
                 279 
                 GUCAAAUGGGUUCUCUACU 
               
               
                   
               
               
                  47 
                 AGGCGAGUAUCAGAGGAUG 
                 280 
                 CAUCCUCUGAUACUCGCCU 
               
               
                   
               
               
                  48 
                 UAGACUAAGCAUGUAAUUU 
                 281 
                 AAAUUACAUGCUUAGUCUA 
               
               
                   
               
               
                  49 
                 AACAUUGUUUGUACUCACA 
                 282 
                 UGUGAGUACAAACAAUGUU 
               
               
                   
               
               
                  50 
                 GAUGGGAGUGAUGUCAAGU 
                 283 
                 ACUUGACAUCACUCCCAUC 
               
               
                   
               
               
                  51 
                 CAGACCAUUUCCUAAUCAG 
                 284 
                 CUGAUUAGGAAAUGGUCUG 
               
               
                   
               
               
                  52 
                 GAUUACAGAAGCCCGCUGU 
                 285 
                 ACAGCGGGCUUCUGUAAUC 
               
               
                   
               
               
                  53 
                 CAUUGAAACGAUGCCUUGU 
                 286 
                 ACAAGGCAUCGUUUCAAUG 
               
               
                   
               
               
                  54 
                 ACUUAUGCUGGAACUGGGU 
                 287 
                 ACCCAGUUCCAGCAUAAGU 
               
               
                   
               
               
                  55 
                 GUCGACAAGGAGAACACGC 
                 288 
                 GCGUGUUCUCCUUGUCGAC 
               
               
                   
               
               
                  56 
                 AGGAAAGACUAACUUCUUU 
                 289 
                 AAAGAAGUUAGUCUUUCCU 
               
               
                   
               
               
                  57 
                 CAAGACCGCGAGGAGGAUC 
                 290 
                 GAUCCUCCUCGCGGUCUUG 
               
               
                   
               
               
                  58 
                 GACAAUGGCAGUCUUGGCU 
                 291 
                 AGCCAAGACUGCCAUUGUC 
               
               
                   
               
               
                  59 
                 AUGCCUUGUGUCAAGAAGA 
                 292 
                 UCUUCUUGACACAAGGCAU 
               
               
                   
               
               
                  60 
                 GCCUCACUGCUUCAACGCA 
                 293 
                 UGCGUUGAAGCAGUGAGGC 
               
               
                   
               
               
                  61 
                 UACCUCACAACCAGUCCUG 
                 294 
                 CAGGACUGGUUGUGAGGUA 
               
               
                   
               
               
                  62 
                 GAGAAGAGAGUAGGCGAGU 
                 295 
                 ACUCGCCUACUCUCUUCUC 
               
               
                   
               
               
                  63 
                 AGACUUAUGCUGGAACUGG 
                 296 
                 CCAGUUCCAGCAUAAGUCU 
               
               
                   
               
               
                  64 
                 UUACAGAAGCCCGCUGUUU 
                 297 
                 AAACAGCGGGCUUCUGUAA 
               
               
                   
               
               
                  65 
                 UUAUGCUGGAACUGGGUUU 
                 298 
                 AAACCCAGUUCCAGCAUAA 
               
               
                   
               
               
                  66 
                 AUAAACAUUGUUUGUACUC 
                 299 
                 GAGUACAAACAAUGUUUAU 
               
               
                   
               
               
                  67 
                 UCAAUGCCAUUGAAACGAU 
                 300 
                 AUCGUUUCAAUGGCAUUGA 
               
               
                   
               
               
                  68 
                 AUAGUGCUGGUAGUAUCAC 
                 301 
                 GUGAUACUACCAGCACUAU 
               
               
                   
               
               
                  69 
                 CAGCCUCACUGCUUCAACG 
                 302 
                 CGUUGAAGCAGUGAGGCUG 
               
               
                   
               
               
                  70 
                 UCUUGGCUUUAAAGUGAGG 
                 303 
                 CCUCACUUUAAAGCCAAGA 
               
               
                   
               
               
                  71 
                 GGCUGUGACUUACCAUAGC 
                 304 
                 GCUAUGGUAAGUCACAGCC 
               
               
                   
               
               
                  72 
                 GGCUACCUAUGGUGAACGU 
                 305 
                 ACGUUCACCAUAGGUAGCC 
               
               
                   
               
               
                  73 
                 CGCGAGGAGGAUCUUCCAG 
                 306 
                 CUGGAAGAUCCUCCUCGCG 
               
               
                   
               
               
                  74 
                 GCCAUUGAAACGAUGCCUU 
                 307 
                 AAGGCAUCGUUUCAAUGGC 
               
               
                   
               
               
                  75 
                 AGCCUCACUGCUUCAACGC 
                 308 
                 GCGUUGAAGCAGUGAGGCU 
               
               
                   
               
               
                  76 
                 GGCAGACAGACUUAUGCUG 
                 309 
                 CAGCAUAAGUCUGUCUGCC 
               
               
                   
               
               
                  77 
                 GUGACUAAAGUAAGUUAAA 
                 310 
                 UUUAACUUACUUUAGUCAC 
               
               
                   
               
               
                  78 
                 AGUUAUUGUUACCUAAAGU 
                 311 
                 ACUUUAGGUAACAAUAACU 
               
               
                   
               
               
                  79 
                 GCCUUUAUGUUUGGGAGAA 
                 312 
                 UUCUCCCAAACAUAAAGGC 
               
               
                   
               
               
                  80 
                 UUCAGAGUAGAGAACCCAU 
                 313 
                 AUGGGUUCUCUACUCUGAA 
               
               
                   
               
               
                  81 
                 AAACGAGGACUGAUGCCUG 
                 314 
                 CAGGCAUCAGUCCUCGUUU 
               
               
                   
               
               
                  82 
                 GUAGGCGAGUAUCAGAGGA 
                 315 
                 UCCUCUGAUACUCGCCUAC 
               
               
                   
               
               
                  83 
                 AAGCCCGCUGUUUCUAUGG 
                 316 
                 CCAUAGAAACAGCGGGCUU 
               
               
                   
               
               
                  84 
                 UCAGCACUGGGAAUCCCUG 
                 317 
                 CAGGGAUUCCCAGUGCUGA 
               
               
                   
               
               
                  85 
                 GAAUAAUGUGAGGAUUAAC 
                 318 
                 GUUAAUCCUCACAUUAUUC 
               
               
                   
               
               
                  86 
                 UGUGGCAGACAGACUUAUG 
                 319 
                 CAUAAGUCUGUCUGCCACA 
               
               
                   
               
               
                  87 
                 AGAGAUAAAUGUUGAUCUU 
                 320 
                 AAGAUCAACAUUUAUCUCU 
               
               
                   
               
               
                  88 
                 UACCAUGAUAUCUGGCAGA 
                 321 
                 UCUGCCAGAUAUCAUGGUA 
               
               
                   
               
               
                  89 
                 CUUCCAAAUUGCCAUGGAA 
                 322 
                 UUCCAUGGCAAUUUGGAAG 
               
               
                   
               
               
                  90 
                 ACCGCGAGGAGGAUCUUCC 
                 323 
                 GGAAGAUCCUCCUCGCGGU 
               
               
                   
               
               
                  91 
                 GAAAUGUAUAGUCUUCUUA 
                 324 
                 UAAGAAGACUAUACAUUUC 
               
               
                   
               
               
                  92 
                 AUGUUCAAACACCUGGUAC 
                 325 
                 GUACCAGGUGUUUGAACAU 
               
               
                   
               
               
                  93 
                 AGGGAAUUUCUCUUCAAUG 
                 326 
                 CAUUGAAGAGAAAUUCCCU 
               
               
                   
               
               
                  94 
                 CCCUGUUAAGUGGUGAAAU 
                 327 
                 AUUUCACCACUUAACAGGG 
               
               
                   
               
               
                  95 
                 GAUGAGGGUUUACACUGUG 
                 328 
                 CACAGUGUAAACCCUCAUC 
               
               
                   
               
               
                  96 
                 UGUGUGAGUUAAUUCAUUU 
                 329 
                 AAAUGAAUUAACUCACACA 
               
               
                   
               
               
                  97 
                 UUGCCUGAUGUUCAAACAC 
                 330 
                 GUGUUUGAACAUCAGGCAA 
               
               
                   
               
               
                  98 
                 AAACUUGUGUAGACUAAGC 
                 331 
                 GCUUAGUCUACACAAGUUU 
               
               
                   
               
               
                  99 
                 UAUAUCCCAUGUUCUGGCU 
                 332 
                 AGCCAGAACAUGGGAUAUA 
               
               
                   
               
               
                 100 
                 UUGUGUAGACUAAGCAUGU 
                 333 
                 ACAUGCUUAGUCUACACAA 
               
               
                   
               
               
                 101 
                 AUGCUGUUCGGAUAGAACA 
                 334 
                 UGUUCUAUCCGAACAGCAU 
               
               
                   
               
               
                 102 
                 AAUUAUCAAUGCUGUUCGG 
                 335 
                 CCGAACAGCAUUGAUAAUU 
               
               
                   
               
               
                 103 
                 GCCUGAUGUUCAAACACCU 
                 336 
                 AGGUGUUUGAACAUCAGGC 
               
               
                   
               
               
                 104 
                 CAUAGCAGUGACAAUGGCA 
                 337 
                 UGCCAUUGUCACUGCUAUG 
               
               
                   
               
               
                 105 
                 UGUGAGUUAAUUCAUUUAU 
                 338 
                 AUAAAUGAAUUAACUCACA 
               
               
                   
               
               
                 106 
                 AGUGCUGGUAGUAUCACCU 
                 339 
                 AGGUGAUACUACCAGCACU 
               
               
                   
               
               
                 107 
                 UAUCAAUGCUGUUCGGAUA 
                 340 
                 UAUCCGAACAGCAUUGAUA 
               
               
                   
               
               
                 108 
                 GACUAAAGUAAGUUAAACU 
                 341 
                 AGUUUAACUUACUUUAGUC 
               
               
                   
               
               
                 109 
                 AAUGCUGUUCGGAUAGAAC 
                 342 
                 GUUCUAUCCGAACAGCAUU 
               
               
                   
               
               
                 110 
                 AGAAUAUUUCACUGGAAGG 
                 343 
                 CCUUCCAGUGAAAUAUUCU 
               
               
                   
               
               
                 111 
                 AUCUGGCAGAUGUAUAAGA 
                 344 
                 UCUUAUACAUCUGCCAGAU 
               
               
                   
               
               
                 112 
                 UAUAGUGCUGGUAGUAUCA 
                 345 
                 UGAUACUACCAGCACUAUA 
               
               
                   
               
               
                 113 
                 GGCCAGCAAGACCGCGAGG 
                 346 
                 CCUCGCGGUCUUGCUGGCC 
               
               
                   
               
               
                 114 
                 CCAUGAUAUCUGGCAGAUG 
                 347 
                 CAUCUGCCAGAUAUCAUGG 
               
               
                   
               
               
                 115 
                 UUAAACUUGUGUAGACUAA 
                 348 
                 UUAGUCUACACAAGUUUAA 
               
               
                   
               
               
                 116 
                 UUCAAUGCCAUUGAAACGA 
                 349 
                 UCGUUUCAAUGGCAUUGAA 
               
               
                   
               
               
                 117 
                 AGAAAGCUGAGACAUUGCA 
                 350 
                 UGCAAUGUCUCAGCUUUCU 
               
               
                   
               
               
                 118 
                 CUAUGGCUUCCAAAUUGCC 
                 351 
                 GGCAAUUUGGAAGCCAUAG 
               
               
                   
               
               
                 119 
                 AAGUGACUAAAGUAAGUUA 
                 352 
                 UAACUUACUUUAGUCACUU 
               
               
                   
               
               
                 120 
                 UGACUAAAGUAAGUUAAAC 
                 353 
                 GUUUAACUUACUUUAGUCA 
               
               
                   
               
               
                 121 
                 UGCUGUUCGGAUAGAACAG 
                 354 
                 CUGUUCUAUCCGAACAGCA 
               
               
                   
               
               
                 122 
                 GCGAGUAUCAGAGGAUGGG 
                 355 
                 CCCAUCCUCUGAUACUCGC 
               
               
                   
               
               
                 123 
                 GGGCCUUGCGCUGGAUUGG 
                 356 
                 CCAAUCCAGCGCAAGGCCC 
               
               
                   
               
               
                 124 
                 ACCUCACAACCAGUCCUGU 
                 357 
                 ACAGGACUGGUUGUGAGGU 
               
               
                   
               
               
                 125 
                 ACUAAGUGACUAAAGUAAG 
                 358 
                 CUUACUUUAGUCACUUAGU 
               
               
                   
               
               
                 126 
                 AUUACAGAAGCCCGCUGUU 
                 359 
                 AACAGCGGGCUUCUGUAAU 
               
               
                   
               
               
                 127 
                 GAGUAGGCGAGUAUCAGAG 
                 360 
                 CUCUGAUACUCGCCUACUC 
               
               
                   
               
               
                 128 
                 CAGUGACAAUGGCAGUCUU 
                 361 
                 AAGACUGCCAUUGUCACUG 
               
               
                   
               
               
                 129 
                 GGCCUUGCGCUGGAUUGGG 
                 362 
                 CCCAAUCCAGCGCAAGGCC 
               
               
                   
               
               
                 130 
                 UUCUUAUUGACACUUACAU 
                 363 
                 AUGUAAGUGUCAAUAAGAA 
               
               
                   
               
               
                 131 
                 UUCACUAAGUGACUAAAGU 
                 364 
                 ACUUUAGUCACUUAGUGAA 
               
               
                   
               
               
                 132 
                 GUGUGAGUUAAUUCAUUUA 
                 365 
                 UAAAUGAAUUAACUCACAC 
               
               
                   
               
               
                 133 
                 CCCGCUCGCGCCCAUCACG 
                 366 
                 CGUGAUGGGCGCGAGCGGG 
               
               
                   
               
               
                 134 
                 GUAAGUUAAACUUGUGUAG 
                 367 
                 CUACACAAGUUUAACUUAC 
               
               
                   
               
               
                 135 
                 CGGAAGUUGGAAUCAGGUU 
                 368 
                 AACCUGAUUCCAACUUCCG 
               
               
                   
               
               
                 136 
                 AUGUGAGGAUUAACUUCUG 
                 369 
                 CAGAAGUUAAUCCUCACAU 
               
               
                   
               
               
                 137 
                 UUAAGUGGUGAAAUCAACU 
                 370 
                 AGUUGAUUUCACCACUUAA 
               
               
                   
               
               
                 138 
                 UGUAGACUAAGCAUGUAAU 
                 371 
                 AUUACAUGCUUAGUCUACA 
               
               
                   
               
               
                 139 
                 AUAAUGUGAGGAUUAACUU 
                 372 
                 AAGUUAAUCCUCACAUUAU 
               
               
                   
               
               
                 140 
                 GGCUGGCUGUGACUUACCA 
                 373 
                 UGGUAAGUCACAGCCAGCC 
               
               
                   
               
               
                 141 
                 AAGAGGCUACCUAUGGUGA 
                 374 
                 UCACCAUAGGUAGCCUCUU 
               
               
                   
               
               
                 142 
                 CAGAUUACAGAAGCCCGCU 
                 375 
                 AGCGGGCUUCUGUAAUCUG 
               
               
                   
               
               
                 143 
                 UGAGGCCUUGCCUGUGAAG 
                 376 
                 CUUCACAGGCAAGGCCUCA 
               
               
                   
               
               
                 144 
                 AUAAUUAUCAAUGCUGUUC 
                 377 
                 GAACAGCAUUGAUAAUUAU 
               
               
                   
               
               
                 145 
                 GUGACUUACCAUAGCAGUG 
                 466 
                 CACUGCUAUGGUAAGUCAC 
               
               
                   
               
               
                 146 
                 UAGGGCUACUUUGAAUUAA 
                 378 
                 UUAAUUCAAAGUAGCCCUA 
               
               
                   
               
               
                 147 
                 UGGCAGAUGUAUAAGAAGG 
                 379 
                 CCUUCUUAUACAUCUGCCA 
               
               
                   
               
               
                 148 
                 AUAGCUUGAUUUAUUUGGU 
                 380 
                 ACCAAAUAAAUCAAGCUAU 
               
               
                   
               
               
                 149 
                 CAGCAAGACCGCGAGGAGG 
                 381 
                 CCUCCUCGCGGUCUUGCUG 
               
               
                   
               
               
                 150 
                 GACUGAUGCCUGGCCUCAC 
                 382 
                 GUGAGGCCAGGCAUCAGUC 
               
               
                   
               
               
                 151 
                 UUACCUUGGAUGCUGACUU 
                 383 
                 AAGUCAGCAUCCAAGGUAA 
               
               
                   
               
               
                 152 
                 AUUCAGCACUGGGAAUCCC 
                 384 
                 GGGAUUCCCAGUGCUGAAU 
               
               
                   
               
               
                 153 
                 AGCAAGACCGCGAGGAGGA 
                 385 
                 UCCUCCUCGCGGUCUUGCU 
               
               
                   
               
               
                 154 
                 AGGGCUACUUUGAAUUAAU 
                 386 
                 AUUAAUUCAAAGUAGCCCU 
               
               
                   
               
               
                 155 
                 UAAGUUAUUGUUACCUAAA 
                 387 
                 UUUAGGUAACAAUAACUUA 
               
               
                   
               
               
                 156 
                 UUUAUAGUGCUGGUAGUAU 
                 388 
                 AUACUACCAGCACUAUAAA 
               
               
                   
               
               
                 157 
                 GCAAGACCGCGAGGAGGAU 
                 389 
                 AUCCUCCUCGCGGUCUUGC 
               
               
                   
               
               
                 158 
                 UCUAUGGCUUCCAAAUUGC 
                 390 
                 GCAAUUUGGAAGCCAUAGA 
               
               
                   
               
               
                 159 
                 AAAGACUAACUUCUUUGAG 
                 391 
                 CUCAAAGAAGUUAGUCUUU 
               
               
                   
               
               
                 160 
                 ACCAUGAUAUCUGGCAGAU 
                 392 
                 AUCUGCCAGAUAUCAUGGU 
               
               
                   
               
               
                 161 
                 GACCAUUUCCUAAUCAGUU 
                 393 
                 AACUGAUUAGGAAAUGGUC 
               
               
                   
               
               
                 162 
                 UUACCAUAGCAGUGACAAU 
                 394 
                 AUUGUCACUGCUAUGGUAA 
               
               
                   
               
               
                 163 
                 AAUGUGAGGAUUAACUUCU 
                 395 
                 AGAAGUUAAUCCUCACAUU 
               
               
                   
               
               
                 164 
                 UAGUGUCCUGGGAUUCUCU 
                 396 
                 AGAGAAUCCCAGGACACUA 
               
               
                   
               
               
                 165 
                 UGUUAAGUGGUGAAAUCAA 
                 397 
                 UUGAUUUCACCACUUAACA 
               
               
                   
               
               
                 166 
                 ACAAAUAUUCUUAAUAGGG 
                 398 
                 CCCUAUUAAGAAUAUUUGU 
               
               
                   
               
               
                 167 
                 GCGGAAGUUGGAAUCAGGU 
                 399 
                 ACCUGAUUCCAACUUCCGC 
               
               
                   
               
               
                 168 
                 AACUUGUGUAGACUAAGCA 
                 400 
                 UGCUUAGUCUACACAAGUU 
               
               
                   
               
               
                 169 
                 AUUCUUAAUAGGGCUACUU 
                 401 
                 AAGUAGCCCUAUUAAGAAU 
               
               
                   
               
               
                 170 
                 CCUAAAGUUAAUCCAGAUU 
                 402 
                 AAUCUGGAUUAACUUUAGG 
               
               
                   
               
               
                 171 
                 UAUUGUUACCUAAAGUUAA 
                 403 
                 UUAACUUUAGGUAACAAUA 
               
               
                   
               
               
                 172 
                 GUGCUGGUAGUAUCACCUU 
                 404 
                 AAGGUGAUACUACCAGCAC 
               
               
                   
               
               
                 173 
                 CUGUGACUUACCAUAGCAG 
                 405 
                 CUGCUAUGGUAAGUCACAG 
               
               
                   
               
               
                 174 
                 GAGCUUCUUAAGUUAAAUC 
                 406 
                 GAUUUAACUUAAGAAGCUC 
               
               
                   
               
               
                 175 
                 CUGUUCGGAUAGAACAGGA 
                 407 
                 UCCUGUUCUAUCCGAACAG 
               
               
                   
               
               
                 176 
                 GUUAUUGUUACCUAAAGUU 
                 408 
                 AACUUUAGGUAACAAUAAC 
               
               
                   
               
               
                 177 
                 UAAUGUGAGGAUUAACUUC 
                 409 
                 GAAGUUAAUCCUCACAUUA 
               
               
                   
               
               
                 178 
                 ACCACUAAUGGGAGCCAAU 
                 410 
                 AUUGGCUCCCAUUAGUGGU 
               
               
                   
               
               
                 179 
                 UGUGUAGACUAAGCAUGUA 
                 411 
                 UACAUGCUUAGUCUACACA 
               
               
                   
               
               
                 180 
                 UGGGCCUUGCGCUGGAUUG 
                 412 
                 CAAUCCAGCGCAAGGCCCA 
               
               
                   
               
               
                 181 
                 AGGAGCUUCUUAAGUUAAA 
                 413 
                 UUUAACUUAAGAAGCUCCU 
               
               
                   
               
               
                 182 
                 GGUGACCCUUUAGUGAGCU 
                 414 
                 AGCUCACUAAAGGGUCACC 
               
               
                   
               
               
                 183 
                 AGAGUAGGCGAGUAUCAGA 
                 415 
                 UCUGAUACUCGCCUACUCU 
               
               
                   
               
               
                 184 
                 GCAGUGACAAUGGCAGUCU 
                 416 
                 AGACUGCCAUUGUCACUGC 
               
               
                   
               
               
                 185 
                 AAACGAUGCCUUGUGUCAA 
                 417 
                 UUGACACAAGGCAUCGUUU 
               
               
                   
               
               
                 186 
                 GGACUGAUGCCUGGCCUCA 
                 418 
                 UGAGGCCAGGCAUCAGUCC 
               
               
                   
               
               
                 187 
                 UGAGAGAUAAAUGUUGAUC 
                 419 
                 GAUCAACAUUUAUCUCUCA 
               
               
                   
               
               
                 188 
                 UGGUUUCUACACCAAAUAC 
                 420 
                 GUAUUUGGUGUAGAAACCA 
               
               
                   
               
               
                 189 
                 UCUCUGUAAUAUGAUACAU 
                 421 
                 AUGUAUCAUAUUACAGAGA 
               
               
                   
               
               
                 190 
                 GAGAGAUAAAUGUUGAUCU 
                 422 
                 AGAUCAACAUUUAUCUCUC 
               
               
                   
               
               
                 191 
                 ACUCUAAUGAAGCAAUACA 
                 423 
                 UGUAUUGCUUCAUUAGAGU 
               
               
                   
               
               
                 192 
                 UGAAGUGUUACCAACUAGC 
                 424 
                 GCUAGUUGGUAACACUUCA 
               
               
                   
               
               
                 193 
                 AAUGAAGCAAUACAUUGAG 
                 425 
                 CUCAAUGUAUUGCUUCAUU 
               
               
                   
               
               
                 194 
                 ACGAUGCCUUGUGUCAAGA 
                 426 
                 UCUUGACACAAGGCAUCGU 
               
               
                   
               
               
                 195 
                 AGACCGCGAGGAGGAUCUU 
                 427 
                 AAGAUCCUCCUCGCGGUCU 
               
               
                   
               
               
                 196 
                 UUGUUACCUAAAGUUAAUC 
                 428 
                 GAUUAACUUUAGGUAACAA 
               
               
                   
               
               
                 197 
                 CAGAAGCCCGCUGUUUCUA 
                 429 
                 UAGAAACAGCGGGCUUCUG 
               
               
                   
               
               
                 198 
                 UUUGACUUUAUGGAGAAUA 
                 430 
                 UAUUCUCCAUAAAGUCAAA 
               
               
                   
               
               
                 199 
                 UACCUAAAGUUAAUCCAGA 
                 431 
                 UCUGGAUUAACUUUAGGUA 
               
               
                   
               
               
                 200 
                 UUCAAACACCUGGUACACA 
                 432 
                 UGUGUACCAGGUGUUUGAA 
               
               
                   
               
               
                 201 
                 UUGCACUCUAAUGAAGCAA 
                 433 
                 UUGCUUCAUUAGAGUGCAA 
               
               
                   
               
               
                 202 
                 UGUUACCUAAAGUUAAUCC 
                 434 
                 GGAUUAACUUUAGGUAACA 
               
               
                   
               
               
                 203 
                 CACUAAGUGACUAAAGUAA 
                 435 
                 UUACUUUAGUCACUUAGUG 
               
               
                   
               
               
                 204 
                 UGCCAGAUAGAAGACAGGU 
                 436 
                 ACCUGUCUUCUAUCUGGCA 
               
               
                   
               
               
                 205 
                 AAUGUAUAGUCUUCUUAUU 
                 437 
                 AAUAAGAAGACUAUACAUU 
               
               
                   
               
               
                 206 
                 GACCACUAAUGGGAGCCAA 
                 438 
                 UUGGCUCCCAUUAGUGGUC 
               
               
                   
               
               
                 207 
                 GUUACCUAAAGUUAAUCCA 
                 439 
                 UGGAUUAACUUUAGGUAAC 
               
               
                   
               
               
                 208 
                 UGAUGCCUGGCCUCACAUU 
                 440 
                 AAUGUGAGGCCAGGCAUCA 
               
               
                   
               
               
                 209 
                 CCAACUUUAAAGUCAGUCC 
                 441 
                 GGACUGACUUUAAAGUUGG 
               
               
                   
               
               
                 210 
                 UAAACUUGUGUAGACUAAG 
                 442 
                 CUUAGUCUACACAAGUUUA 
               
               
                   
               
               
                 211 
                 AGUAGGUUGUGUGAGUUAA 
                 443 
                 UUAACUCACACAACCUACU 
               
               
                   
               
               
                 212 
                 GUUAAACUUGUGUAGACUA 
                 444 
                 UAGUCUACACAAGUUUAAC 
               
               
                   
               
               
                 213 
                 CUGACCACUAAUGGGAGCC 
                 445 
                 GGCUCCCAUUAGUGGUCAG 
               
               
                   
               
               
                 214 
                 UAUUCUUAAUAGGGCUACU 
                 446 
                 AGUAGCCCUAUUAAGAAUA 
               
               
                   
               
               
                 215 
                 GUAGUGUCCUGGGAUUCUC 
                 447 
                 GAGAAUCCCAGGACACUAC 
               
               
                   
               
               
                 216 
                 UAUCUGGCAGAUGUAUAAG 
                 448 
                 CUUAUACAUCUGCCAGAUA 
               
               
                   
               
               
                 217 
                 AGGCUACCUAUGGUGAACG 
                 449 
                 CGUUCACCAUAGGUAGCCU 
               
               
                   
               
               
                 218 
                 UCAGACCAUUUCCUAAUCA 
                 450 
                 UGAUUAGGAAAUGGUCUGA 
               
               
                   
               
               
                 219 
                 UUACCUAAAGUUAAUCCAG 
                 451 
                 CUGGAUUAACUUUAGGUAA 
               
               
                   
               
               
                 220 
                 GGUUUCUACACCAAAUACA 
                 452 
                 UGUAUUUGGUGUAGAAACC 
               
               
                   
               
               
                 221 
                 GUUGGUGCCAGAUAGAAGA 
                 453 
                 UCUUCUAUCUGGCACCAAC 
               
               
                   
               
               
                 222 
                 GCUACCUAUGGUGAACGUG 
                 454 
                 CACGUUCACCAUAGGUAGC 
               
               
                   
               
               
                 223 
                 UCACUAAGUGACUAAAGUA 
                 455 
                 UACUUUAGUCACUUAGUGA 
               
               
                   
               
               
                 224 
                 UUAUUGUUACCUAAAGUUA 
                 456 
                 UAACUUUAGGUAACAAUAA 
               
               
                   
               
               
                 225 
                 UAGCUGAAUAAUGUGAGGA 
                 457 
                 UCCUCACAUUAUUCAGCUA 
               
               
                   
               
               
                 226 
                 UGACCACUAAUGGGAGCCA 
                 458 
                 UGGCUCCCAUUAGUGGUCA 
               
               
                   
               
               
                 227 
                 GUAGCUACCUCACAACCAG 
                 459 
                 CUGGUUGUGAGGUAGCUAC 
               
               
                   
               
               
                 228 
                 UCCCGCUCGCGCCCAUCAC 
                 460 
                 GUGAUGGGCGCGAGCGGGA 
               
               
                   
               
               
                 229 
                 CUUGGCUUUAAAGUGAGGG 
                 461 
                 CCCUCACUUUAAAGCCAAG 
               
               
                   
               
               
                 230 
                 AGAAGCCCGCUGUUUCUAU 
                 462 
                 AUAGAAACAGCGGGCUUCU 
               
               
                   
               
               
                 231 
                 ACUAAAGUAAGUUAAACUU 
                 463 
                 AAGUUUAACUUACUUUAGU 
               
               
                   
               
               
                 232 
                 AGUAAGUUAAACUUGUGUA 
                 464 
                 UACACAAGUUUAACUUACU 
               
               
                   
               
               
                 233 
                 AAUAAUUAUCAAUGCUGUU 
                 465 
                 AACAGCAUUGAUAAUUAUU 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
               
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                   
                   
                   
                   
                 Activity 
                   
                   
                 Activity 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 testing with 
                 Activity 
                 testing with 
                 Activity 
               
               
                   
                   
                   
                   
                 50 nM siRNA in 
                 testing with 
                 50 nM siRNA in 
                 testing with 
               
               
                   
                   
                   
                   
                 HeLaS3 cells, 
                 500 pM siRNA 
                 HeLaS3 cells, 
                 30 pM siRNA 
               
               
                 SEQ 
                   
                 SEQ 
                   
                 transfection 1 
                 in HeLaS3 cells 
                 transfection 2 
                 in HeLaS3 cells 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 ID 
                 sense strand sequence 
                 ID 
                 antisense strand sequence 
                 mRNA 
                 s.d. 
                 mRNA 
                 s.d. 
                 mRNA 
                 s.d. 
                 mRNA 
                 s.d. 
               
               
                 NO 
                 (5&#39;-3&#39;) 
                 NO 
                 (5&#39;-3&#39;) 
                 [%] 
                 [%] 
                 [%] 
                 [%] 
                 [%] 
                 [%] 
                 [%] 
                 [%] 
               
               
                   
               
               
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 967 
                 AAAGAAGUuAGUCUUUCCUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 10 
                  2 
                  42 
                  1 
               
               
                   
               
               
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 963 
                 AAGACuAuAcAUUUcAGAAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  8 
                  1 
                  48 
                  2 
               
               
                   
               
               
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 962 
                 AAGAAUUCUCUGUUGGACUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  7 
                  0 
                  49 
                  2 
               
               
                   
               
               
                 476 
                 gaAGGAAAGAcuAAcuucudTsdT 
                 966 
                 AGAAGUuAGUCUUUCCUUCdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  8 
                  2 
                  50 
                  2 
               
               
                   
               
               
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 964 
                 GUAAGUGUcAAuAAGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  3 
                  1 
                  53 
                  3 
               
               
                   
               
               
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 968 
                 UCCUCUGAuACUCGCCuACdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 12 
                  2 
                  54 
                  4 
               
               
                   
               
               
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 965 
                 UGuAAGUGUcAAuAAGAAGdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  9 
                  1 
                  58 
                  7 
               
               
                   
               
               
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 961 
                 AGAAAGCcAGAAcAUGGGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                  5 
                  1 
                  70 
                  7 
               
               
                   
               
               
                 508 
                 ucuucuUAuuGAcAcuuAcdTsdT 
                 972 
                 GUAAGUGUcAAuAaGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 14 
                  1 
                  85 
                  8 
               
               
                   
               
               
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 970 
                 AAGAAUUCUCUGUUGGACUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 15 
                  1 
                  89 
                  2 
               
               
                   
               
               
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 971 
                 AAGACuAuAcAUUucAGAAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 18 
                  3 
                  89 
                  9 
               
               
                   
               
               
                 508 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 985 
                 GuAAGUGUcAAuAAGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 11 
                  2 
                  91 
                  5 
               
               
                   
               
               
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 972 
                 GUAAGUGUcAAuAaGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 14 
                  2 
                  91 
                 10 
               
               
                   
               
               
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 978 
                 AaGAAUUCUCUGUuGGACUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 24 
                  3 
                  92 
                  7 
               
               
                   
               
               
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 973 
                 UGuAAGUGUcAAuaAGAAGdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 34 
                  4 
                  95 
                  5 
               
               
                   
               
               
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 969 
                 AGAAAGCcAGAAcaUGGGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 39 
                  5 
                  96 
                  9 
               
               
                   
               
               
                 476 
                 gaAGGAAAGAcuAAcuucudTsdT 
                 974 
                 AGAAGUuAGUCUUUCCUUCdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 14 
                  1 
                  97 
                  8 
               
               
                   
               
               
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 984 
                 UcCUCUGAuACUCgCCuACdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 35 
                  3 
                  98 
                  9 
               
               
                   
               
               
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 983 
                 AaAGAAGUuAGUCuUUCCUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 26 
                  3 
                  98 
                  8 
               
               
                   
               
               
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 976 
                 UCCUCUGAuACUCgCCuACdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 23 
                  1 
                  99 
                 11 
               
               
                   
               
               
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 975 
                 AAAGAAGUuAGUCuUUCCUdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 20 
                  1 
                 102 
                  6 
               
               
                   
               
               
                 508 
                 ucuucuUAuuGAcAcuuAcdTsdT 
                 980 
                 GuAAGUGUcAAuAaGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 21 
                  1 
                 102 
                 13 
               
               
                   
               
               
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 979 
                 AaGACuAuAcAUUucAGAAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 25 
                  3 
                 104 
                 16 
               
               
                   
               
               
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 977 
                 AgAAAGCcAGAAcaUGGGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 43 
                  2 
                 106 
                  8 
               
               
                   
               
               
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 981 
                 UguAAGUGUcAAuaAGAAGdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 66 
                 14 
                 111 
                 14 
               
               
                   
               
               
                 476 
                 gaAGGAAAGAcuAAcuucudTSdT 
                 982 
                 AgAAGUuAGUCUUuCCUUCdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 23 
                  4 
                 111 
                 13 
               
               
                   
               
               
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 980 
                 GuAAGUGUcAAuAaGAAGAdTsdT 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 21 
                  5 
                 115 
                 15 
               
               
                   
               
               
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 841 
                 pGUAAGUGUcAAuAAGAAGAdTsdT 
                   7 
                  2 
                  11 
                  2 
                  2 
                  0 
                  45 
                  2 
               
               
                   
               
               
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 839 
                 pAAGACuAuAcAUUUcAGAAdTsdT 
                  10 
                  1 
                  12 
                  2 
                  8 
                  1 
                  43 
                  4 
               
               
                   
               
               
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 842 
                 pUGuAAGUGUcAAuAAGAAGdTsdT 
                  12 
                  1 
                  14 
                  0 
                  8 
                  2 
                  52 
                  6 
               
               
                   
               
               
                 469 
                 AguccAAcAGAGAAuucuudTsdT 
                 742 
                 pAAGAAUUCUCUGUUGGACUdTsdT 
                  11 
                  1 
                  14 
                  0 
                  8 
                  0 
                  38 
                  4 
               
               
                   
               
               
                 475 
                 GaAGGAAAGAcuAAcuucudTsdT 
                 884 
                 pAGAAGUuAGUCUUUCCUUCdTsdT 
                  10 
                  1 
                  14 
                  0 
                  7 
                  1 
                  48 
                  5 
               
               
                   
               
               
                 522 
                 cauuGAAAcGAuGccuuGudTsdT 
                 845 
                 pACAAGGcAUCGUUUcAAUGdTsdT 
                  11 
                  2 
                  14 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 525 
                 AgGAAAGAcuAAcuucuuudTsdT 
                 885 
                 pAAAGAAGUuAGUCUUUCCUdTsdT 
                  12 
                  2 
                  15 
                  1 
                  8 
                  1 
                  44 
                  6 
               
               
                   
               
               
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 711 
                 pAGAAAGCcAGAAcAUGGGAdTsdT 
                  12 
                  1 
                  15 
                  2 
                  6 
                  1 
                  71 
                  5 
               
               
                   
               
               
                 471 
                 uaGGcGAGuAucAGAGGAudTsdT 
                 892 
                 pAUCCUCUGAuACUCGCCuAdTsdT 
                  14 
                  1 
                  16 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 552 
                 GuAGGcGAGuAucAGAGGAdTsdT 
                 891 
                 pUCCUCUGAuACUCGCCuACdTsdT 
                  14 
                  2 
                  16 
                  1 
                 10 
                  0 
                  51 
                  5 
               
               
                   
               
               
                 494 
                 GgAuAGAAcAGGAGuuccudTsdT 
                 866 
                 pAGGAACUCCUGUUCuAUCCdTsdT 
                  17 
                  1 
                  16 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 473 
                 uguucAAAcAccuGGuAcAdTsdT 
                 863 
                 pUGuACcAGGUGUUUGAAcAdTsdT 
                  17 
                  1 
                  16 
                  0 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 560 
                 cuuccAAAuuGccAuGGAAdTsdT 
                 838 
                 pUUCcAUGGcAAUUUGGAAGdTsdT 
                  16 
                  2 
                  16 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 544 
                 GccAuuGAAAcGAuGccuudTsdT 
                 718 
                 pAAGGcAUCGUUUcAAUGGCdTsdT 
                  13 
                  2 
                  17 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 493 
                 ugAuGuucAAAcAccuGGudTsdT 
                 861 
                 pACcAGGUGUUUGAAcAUcAdTsdT 
                  21 
                  1 
                  17 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 481 
                 AaAuGuAuAGucuucuuAudTsdT 
                 714 
                 pAUAAGAAGACuAuAcAUUUdTsdT 
                  14 
                  1 
                  17 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 488 
                 AuuGcAcucuAAuGAAGcAdTsdT 
                 735 
                 pUGCUUcAUuAGAGUGcAAUdTsdT 
                  13 
                  1 
                  18 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 532 
                 GaGAAGAGAGuAGGcGAGudTsdT 
                 887 
                 pACUCGCCuACUCUCUUCUCdTsdT 
                  18 
                  2 
                  18 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 535 
                 uuAuGcuGGAAcuGGGuuudTsdT 
                 881 
                 pAAACCcAGUUCcAGcAuAAdTsdT 
                  19 
                  2 
                  18 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 467 
                 uuGuGGcAGAcAGAcuuAudTsdT 
                 737 
                 pAUAAGUCUGUCUGCcAcAAdTsdT 
                  22 
                  0 
                  19 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 489 
                 uuAucAAuGcuGuucGGAudTsdT 
                 728 
                 pAUCCGAAcAGcAUUGAuAAdTsdT 
                  15 
                  1 
                  19 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 480 
                 cccAuuuGAcuuuAuGGAGdTsdT 
                 739 
                 pCUCcAuAAAGUcAAAUGGGdTsdT 
                  13 
                  1 
                  19 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 533 
                 AgAcuuAuGcuGGAAcuGGdTsdT 
                 879 
                 pCCAGUUCcAGcAuAAGUCUdTsdT 
                  14 
                  2 
                  19 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 582 
                 AucuGGcAGAuGuAuAAGAdTsdT 
                 825 
                 pUCUuAuAcAUCUGCcAGAUdTsdT 
                  19 
                  3 
                  19 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 495 
                 AauAuuucAcuGGAAGGAAdTsdT 
                 741 
                 pUUCCUUCcAGUGAAAuAUUdTsdT 
                  16 
                  1 
                  19 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 534 
                 uuAcAGAAGcccGcuGuuudTsdT 
                 831 
                 pAAAcAGCGGGCUUCUGuAAdTsdT 
                  23 
                  2 
                  20 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 487 
                 AuAGucuucuuAuuGAcAcdTsdT 
                 715 
                 pGUGUcAAuAAGAAGACuAUdTsdT 
                  19 
                  1 
                  20 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 521 
                 GauuAcAGAAGcccGcuGudTsdT 
                 712 
                 pACAGCGGGCUUCUGuAAUCdTsdT 
                  19 
                  2 
                  20 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 663 
                 ugAAGuGuuAccAAcuAGcdTsdT 
                 743 
                 pGCuAGUUGGuAAcACUUcAdTsdT 
                  29 
                  5 
                  20 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 578 
                 uaucAAuGcuGuucGGAuAdTsdT 
                 865 
                 puAUCCGAAcAGcAUUGAuAdTsdT 
                  19 
                  3 
                  20 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 482 
                 uacAuuGAGuuuGuGGcAGdTsdT 
                 875 
                 pCUGCcAcAAACUcAAUGuAdTsdT 
                  15 
                  1 
                  20 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 528 
                 GacAAuGGcAGucuuGGcudTsdT 
                 755 
                 pAGCcAAGACUGCcAUUGUCdTsdT 
                  20 
                  2 
                  21 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 479 
                 ugcAcucuAAuGAAGcAAudTsdT 
                 871 
                 pAUUGCUUcAUuAGAGUGcAdTsdT 
                  15 
                  1 
                  21 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 559 
                 uaccAuGAuAucuGGcAGAdTsdT 
                 821 
                 pUCUGCcAGAuAUcAUGGuAdTsdT 
                  23 
                  2 
                  21 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 481 
                 AaAuGuAuAGucuucuuAudTsdT 
                 939 
                 pAuAAGAAGACuAuAcAUUUdTsdT 
                  18 
                  2 
                  21 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 484 
                 GaAcAGGAGuuccucAcuGdTsdT 
                 868 
                 pcAGUGAGGAACUCCUGUUCdTsdT 
                  28 
                  1 
                  21 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 498 
                 uucGGAuAGAAcAGGAGuudTsdT 
                 734 
                 pAACUCCUGUUCuAUCCGAAdTsdT 
                  18 
                  1 
                  21 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 512 
                 GaAAcGAGGAcuGAuGccudTsdT 
                 852 
                 pAGGcAUcAGUCCUCGUUUCdTsdT 
                  17 
                  2 
                  21 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 491 
                 cauuGAGuuuGuGGcAGAcdTsdT 
                 876 
                 pGUCUGCcAcAAACUcAAUGdTsdT 
                  17 
                  1 
                  21 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 485 
                 AucccAuGuucuGGcuuucdTsdT 
                 710 
                 pGAAAGCcAGAAcAUGGGAUdTsdT 
                  12 
                  1 
                  22 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 516 
                 AgGcGAGuAucAGAGGAuGdTsdT 
                 893 
                 pcAUCCUCUGAuACUCGCCUdTsdT 
                  21 
                  2 
                  22 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 518 
                 AacAuuGuuuGuAcucAcAdTsdT 
                 913 
                 pUGUGAGuAcAAAcAAUGUUdTsdT 
                  27 
                  2 
                  22 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 502 
                 uacAGAAGcccGcuGuuucdTsdT 
                 832 
                 pGAAAcAGCGGGCUUCUGuAdTsdT 
                  23 
                  1 
                  22 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 504 
                 AuAGAAcAGGAGuuccucAdTsdT 
                 867 
                 pUGAGGAACUCCUGUUCuAUdTsdT 
                  23 
                  1 
                  22 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 561 
                 AccGcGAGGAGGAucuuccdTsdT 
                 818 
                 pGGAAGAUCCUCCUCGCGGUdTsdT 
                  21 
                  2 
                  22 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 529 
                 AuGccuuGuGucAAGAAGAdTsdT 
                 846 
                 pUCUUCUUGAcAcAAGGcAUdTsdT 
                  19 
                  2 
                  22 
                  0 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 568 
                 uuGccuGAuGuucAAAcAcdTsdT 
                 858 
                 pGUGUUUGAAcAUcAGGcAAdTsdT 
                  31 
                  3 
                  22 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 597 
                 AuuAcAGAAGcccGcuGuudTsdT 
                 830 
                 pAAcAGCGGGCUUCUGuAAUdTsdT 
                  23 
                  3 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 510 
                 AguAccAuGAuAucuGGcAdTsdT 
                 820 
                 pUGCcAGAuAUcAUGGuACUdTsdT 
                  26 
                  2 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 633 
                 uuAccAuAGcAGuGAcAAudTsdT 
                 754 
                 pAUUGUcACUGCuAUGGuAAdTsdT 
                  20 
                  4 
                  23 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 564 
                 AgGGAAuuucucuucAAuGdTsdT 
                 716 
                 pcAUUGAAGAGAAAUUCCCUdTsdT 
                  22 
                  2 
                  23 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 515 
                 AguAGAGAAcccAuuuGAcdTsdT 
                 738 
                 pGUcAAAUGGGUUCUCuACUdTsdT 
                  20 
                  2 
                  23 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 523 
                 AcuuAuGcuGGAAcuGGGudTsdT 
                 880 
                 pACCcAGUUCcAGcAuAAGUdTsdT 
                  20 
                  2 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 490 
                 AgAAAcGAGGAcuGAuGccdTsdT 
                 851 
                 pGGcAUcAGUCCUCGUUUCUdTsdT 
                  20 
                  1 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 545 
                 AgccucAcuGcuucAAcGcdTsdT 
                 758 
                 pGCGUUGAAGcAGUGAGGCUdTsdT 
                  23 
                  2 
                  23 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 599 
                 caGuGAcAAuGGcAGucuudTsdT 
                 904 
                 pAAGACUGCcAUUGUcACUGdTsdT 
                  26 
                  3 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 539 
                 caGccucAcuGcuucAAcGdTsdT 
                 908 
                 pCGUUGAAGcAGUGAGGCUGdTsdT 
                  25 
                  2 
                  23 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 521 
                 GauuAcAGAAGcccGcuGudTsdT 
                 938 
                 pAcAGCGGGCUUCUGuAAUCdTsdT 
                  22 
                  1 
                  23 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 573 
                 AauuAucAAuGcuGuucGGdTsdT 
                 727 
                 pCCGAAcAGcAUUGAuAAUUdTsdT 
                  20 
                  3 
                  24 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 505 
                 CuGGcAcuuuAcAAAcAAAdTsdT 
                 910 
                 pUUUGUUUGuAAAGUGCcAGdTsdT 
                  32 
                  1 
                  24 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 585 
                 ccAuGAuAucuGGcAGAuGdTsdT 
                 823 
                 pcAUCUGCcAGAuAUcAUGGdTsdT 
                  23 
                  3 
                  25 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 531 
                 uaccucAcAAccAGuccuGdTsdT 
                 745 
                 pcAGGACUGGUUGUGAGGuAdTsdT 
                  25 
                  2 
                  25 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 574 
                 GccuGAuGuucAAAcAccudTsdT 
                 859 
                 pAGGUGUUUGAAcAUcAGGCdTsdT 
                  21 
                  3 
                  25 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 492 
                 AcAuucAGcAcuGGGAAucdTsdT 
                 708 
                 pGAUUCCcAGUGCUGAAUGUdTsdT 
                  17 
                  1 
                  25 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 513 
                 AaGAGAGuAGGcGAGuAucdTsdT 
                 888 
                 pGAuACUCGCCuACUCUCUUdTsdT 
                  21 
                  2 
                  25 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 474 
                 GgGuGAcccuuuAGuGAGcdTsdT 
                 756 
                 pGCUcACuAAAGGGUcACCCdTsdT 
                  24 
                  1 
                  25 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 598 
                 GaGuAGGcGAGuAucAGAGdTsdT 
                 890 
                 pCUCUGAuACUCGCCuACUCdTsdT 
                  23 
                  3 
                  25 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 496 
                 AauAAAcAuuGuuuGuAcudTsdT 
                 911 
                 pAGuAcAAAcAAUGUUuAUUdTsdT 
                  25 
                  1 
                  25 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 506 
                 ucuAAuGAAGcAAuAcAuudTsdT 
                 872 
                 pAAUGuAUUGCUUcAUuAGAdTsdT 
                  22 
                  1 
                  26 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 500 
                 uuAuAGuGcuGGuAGuAucdTsdT 
                 746 
                 pGAuACuACcAGcACuAuAAdTsdT 
                  28 
                  1 
                  26 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 583 
                 uauAGuGcuGGuAGuAucAdTsdT 
                 747 
                 pUGAuACuACcAGcACuAuAdTsdT 
                  26 
                  3 
                  26 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 563 
                 AuGuucAAAcAccuGGuAcdTsdT 
                 862 
                 pGUACcAGGUGUUUGAAcAUdTsdT 
                  20 
                  2 
                  26 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 468 
                 ccuGAuGuucAAAcAccuGdTsdT 
                 860 
                 pcAGGUGUUUGAAcAUcAGGdTsdT 
                  18 
                  0 
                  27 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 587 
                 uucAAuGccAuuGAAAcGAdTsdT 
                 844 
                 pUCGUUUcAAUGGcAUUGAAdTsdT 
                  27 
                  3 
                  27 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 550 
                 uucAGAGuAGAGAAcccAudTsdT 
                 882 
                 pAUGGGUUCUCuACUCUGAAdTsdT 
                  25 
                  2 
                  27 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 575 
                 cauAGcAGuGAcAAuGGcAdTsdT 
                 902 
                 pUGCcAUUGUcACUGCuAUGdTsdT 
                  33 
                  3 
                  28 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 624 
                 AgcAAGAccGcGAGGAGGAdTsdT 
                 814 
                 pUCCUCCUCGCGGUCUUGCUdTsdT 
                  29 
                  4 
                  28 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 627 
                 uuuAuAGuGcuGGuAGuAudTsdT 
                 900 
                 pAUACuACcAGcACuAuAAAdTsdT 
                  30 
                  4 
                  28 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 613 
                 caGAuuAcAGAAGcccGcudTsdT 
                 829 
                 pAGCGGGCUUCUGuAAUCUGdTsdT 
                  27 
                  3 
                  29 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 949 
                 pGuAAGUGUcAAuAAGAAGAdTsdT 
                  18 
                  2 
                  29 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 509 
                 uguucGGAuAGAAcAGGAGdTsdT 
                 733 
                 pCUCCUGUUCuAUCCGAAcAdTsdT 
                  18 
                  2 
                  30 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 530 
                 GccucAcuGcuucAAcGcAdTsdT 
                 909 
                 pUGCGUUGAAGcAGUGAGGCdTsdT 
                  28 
                  2 
                  30 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 483 
                 caAuAcAuuGAGuuuGuGGdTsdT 
                 874 
                 pCCAcAAACUcAAUGuAUUGdTsdT 
                  19 
                  1 
                  30 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 519 
                 GauGGGAGuGAuGucAAGudTsdT 
                 896 
                 pACUUGAcAUcACUCCcAUCdTsdT 
                  26 
                  2 
                  30 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 537 
                 ucAAuGccAuuGAAAcGAudTsdT 
                 717 
                 pAUCGUUUcAAUGGcAUUGAdTsdT 
                  31 
                  2 
                  30 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 511 
                 caGAGAuGAGGGuuuAcAcdTsdT 
                 856 
                 pGUGuAAACCCUcAUCUCUGdTsdT 
                  23 
                  2 
                  30 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 620 
                 caGcAAGAccGcGAGGAGGdTsdT 
                 707 
                 pCCUCCUCGCGGUCUUGCUGdTsdT 
                  30 
                  4 
                  31 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 595 
                 AccucAcAAccAGuccuGudTsdT 
                 899 
                 pACAGGACUGGUUGUGAGGUdTsdT 
                  31 
                  3 
                  31 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 668 
                 caGAAGcccGcuGuuucuAdTsdT 
                 833 
                 puAGAAAcAGCGGGCUUCUGdTsdT 
                  32 
                  6 
                  32 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 577 
                 AguGcuGGuAGuAucAccudTsdT 
                 749 
                 pAGGUGAuACuACcAGcACUdTsdT 
                  28 
                  3 
                  32 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 654 
                 AgAGuAGGcGAGuAucAGAdTsdT 
                 889 
                 pUCUGAuACUCGCCuACUCUdTsdT 
                  48 
                  5 
                  33 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 546 
                 GgcAGAcAGAcuuAuGcuGdTsdT 
                 878 
                 pcAGcAuAAGUCUGUCUGCCdTsdT 
                  21 
                  2 
                  33 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 622 
                 uuAccuuGGAuGcuGAcuudTsdT 
                 897 
                 pAAGUcAGcAUCcAAGGuAAdTsdT 
                  50 
                  4 
                  33 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 541 
                 GgcuGuGAcuuAccAuAGcdTsdT 
                 751 
                 pGCuAUGGuAAGUcAcAGCCdTsdT 
                  21 
                  2 
                  33 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 566 
                 GauGAGGGuuuAcAcuGuGdTsdT 
                 857 
                 pcAcAGUGuAAACCCUcAUCdTsdT 
                  33 
                  2 
                  34 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 503 
                 GuGAcccuuuAGuGAGcuudTsdT 
                 907 
                 pAAGCUcACuAAAGGGUcACdTsdT 
                  25 
                  1 
                  34 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 527 
                 caAGAccGcGAGGAGGAucdTsdT 
                 816 
                 pGAUCCUCCUCGCGGUCUUGdTsdT 
                  29 
                  2 
                  35 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 589 
                 cuAuGGcuuccAAAuuGccdTsdT 
                 837 
                 pGGcAAUUUGGAAGCcAuAGdTsdT 
                  23 
                  3 
                  36 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 643 
                 GuGcuGGuAGuAucAccuudTsdT 
                 750 
                 pAAGGUGAuACuACcAGcACdTsdT 
                  37 
                  4 
                  37 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 600 
                 GgccuuGcGcuGGAuuGGGdTsdT 
                 849 
                 pCCcAAUCcAGCGcAAGGCCdTsdT 
                  27 
                  3 
                  38 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 572 
                 AuGcuGuucGGAuAGAAcAdTsdT 
                 730 
                 pUGUUCuAUCCGAAcAGcAUdTsdT 
                  32 
                  3 
                  38 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 517 
                 uaGAcuAAGcAuGuAAuuudTsdT 
                 784 
                 pAAAUuAcAUGCUuAGUCuAdTsdT 
                  32 
                  2 
                  39 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 611 
                 GgcuGGcuGuGAcuuAccAdTsdT 
                 901 
                 pUGGuAAGUcAcAGCcAGCCdTsdT 
                  38 
                  3 
                  40 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 540 
                 ucuuGGcuuuAAAGuGAGGdTsdT 
                 905 
                 pCCUcACUUuAAAGCcAAGAdTsdT 
                  23 
                  2 
                  40 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 536 
                 AuAAAcAuuGuuuGuAcucdTsdT 
                 912 
                 pGAGuAcAAAcAAUGUUuAUdTsdT 
                  50 
                  2 
                  40 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 524 
                 GucGAcAAGGAGAAcAcGcdTsdT 
                 705 
                 pGCGUGUUCUCCUUGUCGACdTsdT 
                  32 
                  2 
                  41 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 551 
                 AaAcGAGGAcuGAuGccuGdTsdT 
                 724 
                 pcAGGcAUcAGUCCUCGUUUdTsdT 
                  26 
                  2 
                  42 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 601 
                 uucuuAuuGAcAcuuAcAudTsdT 
                 843 
                 pAUGuAAGUGUcAAuAAGAAdTsdT 
                  31 
                  3 
                  43 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 586 
                 uuAAAcuuGuGuAGAcuAAdTsdT 
                 777 
                 pUUAGUCuAcAcAAGUUuAAdTsdT 
                  37 
                  3 
                  43 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 616 
                 GuGAcuuAccAuAGcAGuGdTsdT 
                 753 
                 pcACUGCuAUGGuAAGUcACdTsdT 
                  24 
                  4 
                  43 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 472 
                 GgcGAGuAucAGAGGAuGGdTsdT 
                 894 
                 pCCAUCCUCUGAuACUCGCCdTsdT 
                  26 
                  1 
                  44 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 570 
                 uauAucccAuGuucuGGcudTsdT 
                 828 
                 pAGCcAGAAcAUGGGAuAuAdTsdT 
                  28 
                  3 
                  44 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 655 
                 GcAGuGAcAAuGGcAGucudTsdT 
                 903 
                 pAGACUGCcAUUGUcACUGCdTsdT 
                  34 
                  5 
                  44 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 671 
                 uucAAAcAccuGGuAcAcAdTsdT 
                 864 
                 pUGUGuACcAGGUGUUUGAAdTsdT 
                  59 
                  6 
                  44 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 580 
                 AauGcuGuucGGAuAGAAcdTsdT 
                 729 
                 pGUUCuAUCCGAAcAGcAUUdTsdT 
                  31 
                  3 
                  44 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 618 
                 ugGcAGAuGuAuAAGAAGGdTsdT 
                 826 
                 pCCUUCUuAuAcAUCUGCcAdTsdT 
                  36 
                  4 
                  44 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 478 
                 cuGuGuAGcuAccucAcAAdTsdT 
                 744 
                 pUUGUGAGGuAGCuAcAcAGdTsdT 
                  24 
                  1 
                  46 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 533 
                 AgAcuuAuGcuGGAAcuGGdTsdT 
                 954 
                 pCcAGUUCcAGcAuAAGUCUdTsdT 
                  26 
                  1 
                  46 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 605 
                 GuAAGuuAAAcuuGuGuAGdTsdT 
                 775 
                 pCUAcAcAAGUUuAACUuACdTsdT 
                  44 
                  3 
                  46 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 571 
                 uuGuGuAGAcuAAGcAuGudTsdT 
                 781 
                 pACAUGCUuAGUCuAcAcAAdTsdT 
                  47 
                  3 
                  47 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 557 
                 uguGGcAGAcAGAcuuAuGdTsdT 
                 877 
                 pcAuAAGUCUGUCUGCcAcAdTsdT 
                  31 
                  2 
                  47 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 467 
                 uuGuGGcAGAcAGAcuuAudTsdT 
                 940 
                 pAuAAGUCUGUCUGCcAcAAdTsdT 
                  86 
                 15 
                  47 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 579 
                 GacuAAAGuAAGuuAAAcudTsdT 
                 772 
                 pAGUUuAACUuACUUuAGUCdTsdT 
                  32 
                  3 
                  47 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 543 
                 cgcGAGGAGGAucuuccAGdTsdT 
                 819 
                 pCUGGAAGAUCCUCCUCGCGdTsdT 
                  52 
                  2 
                  48 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 547 
                 GuGAcuAAAGuAAGuuAAAdTsdT 
                 770 
                 pUUuAACUuACUUuAGUcACdTsdT 
                  39 
                  2 
                  48 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 602 
                 uucAcuAAGuGAcuAAAGudTsdT 
                 765 
                 pACUUuAGUcACUuAGUGAAdTsdT 
                  39 
                  3 
                  49 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 628 
                 GcAAGAccGcGAGGAGGAudTsdT 
                 815 
                 pAUCCUCCUCGCGGUCUUGCdTsdT 
                  36 
                  4 
                  49 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 571 
                 uuGuGuAGAcuAAGcAuGudTsdT 
                 945 
                 pAcAUGCUuAGUCuAcAcAAdTsdT 
                  59 
                  3 
                  50 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 562 
                 GaAAuGuAuAGucuucuuAdTsdT 
                 713 
                 puAAGAAGACuAuAcAUUUCdTsdT 
                  49 
                  2 
                  51 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 593 
                 GcGAGuAucAGAGGAuGGGdTsdT 
                 895 
                 pCCcAUCCUCUGAuACUCGCdTsdT 
                  27 
                  3 
                  52 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 538 
                 AuAGuGcuGGuAGuAucAcdTsdT 
                 748 
                 pGUGAuACuACcAGcACuAUdTsdT 
                  57 
                  2 
                  52 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 666 
                 AgAccGcGAGGAGGAucuudTsdT 
                 817 
                 pAAGAUCCUCCUCGCGGUCUdTsdT 
                  52 
                  6 
                  52 
                 15 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 567 
                 uguGuGAGuuAAuucAuuudTsdT 
                 922 
                 pAAAUGAAUuAACUcAcAcAdTsdT 
                  48 
                  2 
                  53 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 629 
                 ucuAuGGcuuccAAAuuGcdTsdT 
                 836 
                 pGCAAUUUGGAAGCcAuAGAdTsdT 
                  63 
                  4 
                  53 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 590 
                 AaGuGAcuAAAGuAAGuuAdTsdT 
                 769 
                 puAACUuACUUuAGUcACUUdTsdT 
                  62 
                  3 
                  53 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 681 
                 uaAAcuuGuGuAGAcuAAGdTsdT 
                 778 
                 pCUuAGUCuAcAcAAGUUuAdTsdT 
                  52 
                  7 
                  53 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 703 
                 AguAAGuuAAAcuuGuGuAdTsdT 
                 774 
                 puAcAcAAGUUuAACUuACUdTsdT 
                  50 
                 13 
                  54 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 603 
                 GuGuGAGuuAAuucAuuuAdTsdT 
                 791 
                 puAAAUGAAUuAACUcAcACdTsdT 
                  46 
                  3 
                  54 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 642 
                 uauuGuuAccuAAAGuuAAdTsdT 
                 803 
                 pUUAACUUuAGGuAAcAAuAdTsdT 
                  44 
                  4 
                  55 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 674 
                 cacuAAGuGAcuAAAGuAAdTsdT 
                 942 
                 pUuACUUuAGUcACUuAGUGdTsdT 
                  51 
                  3 
                  55 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 569 
                 AaAcuuGuGuAGAcuAAGcdTsdT 
                 779 
                 pGCUuAGUCuAcAcAAGUUUdTsdT 
                  60 
                  3 
                  56 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 636 
                 uguuAAGuGGuGAAAucAAdTsdT 
                 918 
                 pUUGAUUUcACcACUuAAcAdTsdT 
                  38 
                  4 
                  56 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 659 
                 ugGuuucuAcAccAAAuAcdTsdT 
                 941 
                 pGuAUUUGGUGuAGAAACcAdTsdT 
                  51 
                  4 
                  56 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 588 
                 AgAAAGcuGAGAcAuuGcAdTsdT 
                 925 
                 pUGcAAUGUCUcAGCUUUCUdTsdT 
                  43 
                  3 
                  57 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 596 
                 AcuAAGuGAcuAAAGuAAGdTsdT 
                 768 
                 pCUuACUUuAGUcACUuAGUdTsdT 
                  52 
                  3 
                  57 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 609 
                 uguAGAcuAAGcAuGuAAudTsdT 
                 783 
                 pAUuAcAUGCUuAGUCuAcAdTsdT 
                  60 
                  3 
                  58 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 650 
                 uguGuAGAcuAAGcAuGuAdTsdT 
                 782 
                 puAcAUGCUuAGUCuAcAcAdTsdT 
                  54 
                  5 
                  58 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 591 
                 ugAcuAAAGuAAGuuAAAcdTsdT 
                 771 
                 pGUUuAACUuACUUuAGUcAdTsdT 
                  54 
                  3 
                  58 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 639 
                 AacuuGuGuAGAcuAAGcAdTsdT 
                 780 
                 pUGCUuAGUCuAcAcAAGUUdTsdT 
                  57 
                  4 
                  58 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 683 
                 GuuAAAcuuGuGuAGAcuAdTsdT 
                 776 
                 puAGUCuAcAcAAGUUuAACdTsdT 
                  55 
                  7 
                  58 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 586 
                 uuAAAcuuGuGuAGAcuAAdTsdT 
                 944 
                 pUuAGUCuAcAcAAGUUuAAdTsdT 
                  62 
                  6 
                  59 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 653 
                 GguGAcccuuuAGuGAGcudTsdT 
                 757 
                 pAGCUcACuAAAGGGUcACCdTsdT 
                  60 
                  5 
                  60 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 542 
                 GgcuAccuAuGGuGAAcGudTsdT 
                 722 
                 pACGUUcACcAuAGGuAGCCdTsdT 
                  30 
                  2 
                  60 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 631 
                 AccAuGAuAucuGGcAGAudTsdT 
                 822 
                 pAUCUGCcAGAuAUcAUGGUdTsdT 
                  65 
                  4 
                  60 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 605 
                 GuAAGuuAAAcuuGuGuAGdTsdT 
                 943 
                 pCuAcAcAAGUUuAACUuACdTsdT 
                  51 
                  3 
                  60 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 676 
                 AauGuAuAGucuucuuAuudTsdT 
                 840 
                 pAAuAAGAAGACuAuAcAUUdTsdT 
                  62 
                  6 
                  60 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 499 
                 AaGuAGGuuGuGuGAGuuAdTsdT 
                 790 
                 puAACUcAcAcAACCuACUUdTsdT 
                  56 
                  1 
                  60 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 669 
                 uuuGAcuuuAuGGAGAAuAdTsdT 
                 883 
                 puAUUCUCcAuAAAGUcAAAdTsdT 
                  61 
                  6 
                  60 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 677 
                 GaccAcuAAuGGGAGccAAdTsdT 
                 914 
                 pUUGGCUCCcAUuAGUGGUCdTsdT 
                  56 
                  6 
                  60 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 627 
                 uuuAuAGuGcuGGuAGuAudTsdT 
                 957 
                 pAuACuACcAGcACuAuAAAdTsdT 
                  74 
                  9 
                  61 
                  1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 656 
                 AaAcGAuGccuuGuGucAAdTsdT 
                 719 
                 pUUGAcAcAAGGcAUCGUUUdTsdT 
                  40 
                  5 
                  62 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 647 
                 GuuAuuGuuAccuAAAGuudTsdT 
                 801 
                 pAACUUuAGGuAAcAAuAACdTsdT 
                  63 
                  5 
                  62 
                 14 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 644 
                 cuGuGAcuuAccAuAGcAGdTsdT 
                 752 
                 pCUGCuAUGGuAAGUcAcAGdTsdT 
                  30 
                  4 
                  62 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 652 
                 AgGAGcuucuuAAGuuAAAdTsdT 
                 788 
                 pUUuAACUuAAGAAGCUCCUdTsdT 
                  61 
                  5 
                  62 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 672 
                 uuGcAcucuAAuGAAGcAAdTsdT 
                 870 
                 pUUGCUUcAUuAGAGUGcAAdTsdT 
                  88 
                  6 
                  63 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 682 
                 AguAGGuuGuGuGAGuuAAdTsdT 
                 920 
                 pUUAACUcAcAcAACCuACUdTsdT 
                  60 
                  7 
                  63 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 594 
                 GgGccuuGcGcuGGAuuGGdTsdT 
                 848 
                 pCCAAUCcAGCGcAAGGCCCdTsdT 
                  32 
                  3 
                  63 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 701 
                 AgAAGcccGcuGuuucuAudTsdT 
                 834 
                 pAUAGAAAcAGCGGGCUUCUdTsdT 
                  79 
                 11 
                  63 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 697 
                 ugAccAcuAAuGGGAGccAdTsdT 
                 763 
                 pUGGCUCCcAUuAGUGGUcAdTsdT 
                  68 
                  9 
                  64 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 664 
                 AauGAAGcAAuAcAuuGAGdTsdT 
                 873 
                 pCUcAAUGuAUUGCUUcAUUdTsdT 
                  63 
                  5 
                  64 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 662 
                 AcucuAAuGAAGcAAuAcAdTsdT 
                 736 
                 pUGuAUUGCUUcAUuAGAGUdTsdT 
                  71 
                  5 
                  64 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 659 
                 ugGuuucuAcAccAAAuAcdTsdT 
                 760 
                 pGUAUUUGGUGuAGAAACcAdTsdT 
                  54 
                  5 
                  64 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 615 
                 AuAAuuAucAAuGcuGuucdTsdT 
                 726 
                 pGAAcAGcAUUGAuAAUuAUdTsdT 
                  45 
                  4 
                  65 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 558 
                 AgAGAuAAAuGuuGAucuudTsdT 
                 798 
                 pAAGAUcAAcAUUuAUCUCUdTsdT 
                  67 
                  2 
                  65 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 651 
                 ugGGccuuGcGcuGGAuuGdTsdT 
                 847 
                 pcAAUCcAGCGcAAGGCCcAdTsdT 
                  67 
                  5 
                  65 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 698 
                 GuAGcuAccucAcAAccAGdTsdT 
                 898 
                 pCUGGUUGUGAGGuAGCuACdTsdT 
                  61 
                  9 
                  65 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 680 
                 ccAAcuuuAAAGucAGuccdTsdT 
                 915 
                 pGGACUGACUUuAAAGUUGGdTsdT 
                  59 
                  6 
                  65 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 645 
                 GaGcuucuuAAGuuAAAucdTsdT 
                 917 
                 pGAUUuAACUuAAGAAGCUCdTsdT 
                  59 
                  5 
                  65 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 642 
                 uauuGuuAccuAAAGuuAAdTsdT 
                 947 
                 pUuAACUUuAGGuAAcAAuAdTsdT 
                  69 
                  4 
                  65 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 486 
                 GuAGGuuGuGuGAGuuAAudTsdT 
                 921 
                 pAUuAACUcAcAcAACCuACdTsdT 
                  61 
                  1 
                  65 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 692 
                 GuuGGuGccAGAuAGAAGAdTsdT 
                 785 
                 pUCUUCuAUCUGGcACcAACdTsdT 
                  65 
                  8 
                  65 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 691 
                 GguuucuAcAccAAAuAcAdTsdT 
                 761 
                 pUGuAUUUGGUGuAGAAACCdTsdT 
                  63 
                  7 
                  66 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 674 
                 cacuAAGuGAcuAAAGuAAdTsdT 
                 767 
                 pUUACUUuAGUcACUuAGUGdTsdT 
                  61 
                  6 
                  66 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 623 
                 AuucAGcAcuGGGAAucccdTsdT 
                 709 
                 pGGGAUUCCcAGUGCUGAAUdTsdT 
                  68 
                  4 
                  66 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 581 
                 AgAAuAuuucAcuGGAAGGdTsdT 
                 740 
                 pCCUUCcAGUGAAAuAUUCUdTsdT 
                  43 
                  3 
                  67 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 673 
                 uguuAccuAAAGuuAAuccdTsdT 
                 805 
                 pGGAUuAACUUuAGGuAAcAdTsdT 
                  70 
                  6 
                  67 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 607 
                 AuGuGAGGAuuAAcuucuGdTsdT 
                 810 
                 pcAGAAGUuAAUCCUcAcAUdTsdT 
                  69 
                  3 
                  67 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 686 
                 GuAGuGucouGGGAuucucdTsdT 
                 787 
                 pGAGAAUCCcAGGAcACuACdTsdT 
                  72 
                  7 
                  68 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 576 
                 uguGAGuuAAuucAuuuAudTsdT 
                 923 
                 pAUAAAUGAAUuAACUcAcAdTsdT 
                  64 
                  3 
                  68 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 619 
                 AuAGcuuGAuuuAuuuGGudTsdT 
                 759 
                 pACcAAAuAAAUcAAGCuAUdTsdT 
                  59 
                  4 
                  68 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 608 
                 uuAAGuGGuGAAAucAAcudTsdT 
                 919 
                 pAGUUGAUUUcACcACUuAAdTsdT 
                  62 
                  3 
                  68 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 682 
                 AguAGGuuGuGuGAGuuAAdTsdT 
                 958 
                 pUuAACUcAcAcAACCuACUdTsdT 
                  75 
                  5 
                  69 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 549 
                 GccuuuAuGuuuGGGAGAAdTsdT 
                 924 
                 pUUCUCCcAAAcAuAAAGGCdTsdT 
                  48 
                  2 
                  69 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 520 
                 caGAccAuuuccuAAucAGdTsdT 
                 937 
                 pCUGAUuAGGAAAUGGUCUGdTsdT 
                  70 
                  2 
                  69 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 556 
                 GaAuAAuGuGAGGAuuAAcdTsdT 
                 933 
                 pGUuAAUCCUcAcAUuAUUCdTsdT 
                  64 
                  2 
                  70 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 679 
                 ugAuGccuGGccucAcAuudTsdT 
                 855 
                 pAAUGUGAGGCcAGGcAUcAdTsdT 
                  72 
                  6 
                  70 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 660 
                 ucucuGuAAuAuGAuAcAudTsdT 
                 927 
                 pAUGuAUcAuAUuAcAGAGAdTsdT 
                  62 
                  5 
                  70 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 694 
                 ucAcuAAGuGAcuAAAGuAdTsdT 
                 766 
                 puACUUuAGUcACUuAGUGAdTsdT 
                  68 
                  8 
                  70 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 675 
                 ugccAGAuAGAAGAcAGGudTsdT 
                 786 
                 pACCUGUCUUCuAUCUGGcAdTsdT 
                  64 
                  6 
                  70 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 658 
                 ugAGAGAuAAAuGuuGAucdTsdT 
                 797 
                 pGAUcAAcAUUuAUCUCUcAdTsdT 
                  70 
                  5 
                  71 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 684 
                 cuGAccAcuAAuGGGAGccdTsdT 
                 762 
                 pGGCUCCcAUuAGUGGUcAGdTsdT 
                  68 
                  7 
                  72 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 625 
                 AgGGcuAcuuuGAAuuAAudTsdT 
                 796 
                 pAUuAAUUcAAAGuAGCCCUdTsdT 
                  70 
                  4 
                  72 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 649 
                 AccAcuAAuGGGAGccAAudTsdT 
                 764 
                 pAUUGGCUCCcAUuAGUGGUdTsdT 
                  61 
                  5 
                  72 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 617 
                 uaGGGcuAcuuuGAAuuAAdTsdT 
                 946 
                 pUuAAUUcAAAGuAGCCCuAdTsdT 
                  73 
                  3 
                  72 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 606 
                 cgGAAGuuGGAAucAGGuudTsdT 
                 931 
                 pAACCUGAUUCcAACUUCCGdTsdT 
                  57 
                  3 
                  73 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 661 
                 GaGAGAuAAAuGuuGAucudTsdT 
                 926 
                 pAGAUcAAcAUUuAUCUCUCdTsdT 
                  60 
                  5 
                  73 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 584 
                 GgccAGcAAGAccGcGAGGdTsdT 
                 706 
                 pCCUCGCGGUCUUGCUGGCCdTsdT 
                  49 
                  3 
                  74 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 695 
                 uuAuuGuuAccuAAAGuuAdTsdT 
                 802 
                 puAACUUuAGGuAAcAAuAAdTsdT 
                  74 
                  9 
                  74 
                 13 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 576 
                 uguGAGuuAAuucAuuuAudTsdT 
                 959 
                 pAuAAAUGAAUuAACUcAcAdTsdT 
                  67 
                  4 
                  74 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 617 
                 uaGGGcuAcuuuGAAuuAAdTsdT 
                 795 
                 pUUAAUUcAAAGuAGCCCuAdTsdT 
                  51 
                  4 
                  74 
                 13 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 635 
                 uaGuGuccuGGGAuucucudTsdT 
                 916 
                 pAGAGAAUCCcAGGAcACuAdTsdT 
                  72 
                  4 
                  74 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 687 
                 uaucuGGcAGAuGuAuAAGdTsdT 
                 824 
                 pCUuAuAcAUCUGCcAGAuAdTsdT 
                  86 
                  7 
                  74 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 632 
                 GaccAuuuccuAAucAGuudTsdT 
                 811 
                 pAACUGAUuAGGAAAUGGUCdTsdT 
                  61 
                  4 
                  75 
                 10 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 626 
                 uaAGuuAuuGuuAccuAAAdTsdT 
                 799 
                 pUUuAGGuAAcAAuAACUuAdTsdT 
                  84 
                  4 
                  75 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 667 
                 uuGuuAccuAAAGuuAAucdTsdT 
                 804 
                 pGAUuAACUUuAGGuAAcAAdTsdT 
                  76 
                  6 
                  76 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 630 
                 AaAGAcuAAcuucuuuGAGdTsdT 
                 886 
                 pCUcAAAGAAGUuAGUCUUUdTsdT 
                  49 
                  4 
                  76 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 621 
                 GacuGAuGccuGGccucAcdTsdT 
                 854 
                 pGUGAGGCcAGGcAUcAGUCdTsdT 
                  67 
                  4 
                  76 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 670 
                 uaccuAAAGuuAAuccAGAdTsdT 
                 807 
                 pUCUGGAUuAACUUuAGGuAdTsdT 
                  80 
                  6 
                  76 
                 10 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 634 
                 AauGuGAGGAuuAAcuucudTsdT 
                 809 
                 pAGAAGUuAAUCCUcAcAUUdTsdT 
                  69 
                  4 
                  77 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 612 
                 AaGAGGcuAccuAuGGuGAdTsdT 
                 850 
                 pUCACcAuAGGuAGCCUCUUdTsdT 
                  65 
                  3 
                  78 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 678 
                 GuuAccuAAAGuuAAuccAdTsdT 
                 928 
                 pUGGAUuAACUUuAGGuAACdTsdT 
                  73 
                  6 
                  79 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 648 
                 uaAuGuGAGGAuuAAcuucdTsdT 
                 935 
                 pGAAGUuAAUCCUcAcAUuAdTsdT 
                  75 
                  5 
                  80 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 689 
                 ucAGAccAuuuccuAAucAdTsdT 
                 936 
                 pUGAUuAGGAAAUGGUCUGAdTsdT 
                  75 
                  7 
                  81 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 641 
                 ccuAAAGuuAAuccAGAuudTsdT 
                 929 
                 pAAUCUGGAUuAACUUuAGGdTsdT 
                  72 
                  4 
                  81 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 555 
                 ucAGcAcuGGGAAucccuGdTsdT 
                 827 
                 pcAGGGAUUCCcAGUGCUGAdTsdT 
                  81 
                  2 
                  82 
                 12 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 565 
                 cccuGuuAAGuGGuGAAAudTsdT 
                 789 
                 pAUUUcACcACUuAAcAGGGdTsdT 
                  76 
                  2 
                  83 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 554 
                 AaGcccGcuGuuucuAuGGdTsdT 
                 835 
                 pCCAuAGAAAcAGCGGGCUUdTsdT 
                  72 
                  2 
                  84 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 696 
                 uaGcuGAAuAAuGuGAGGAdTsdT 
                 808 
                 pUCCUcAcAUuAUUcAGCuAdTsdT 
                  84 
                  9 
                  84 
                 11 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 483 
                 caAuAcAuuGAGuuuGuGGdTsdT 
                 953 
                 pCcAcAAACUcAAUGuAUUGdTsdT 
                  31 
                  2 
                  84 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 638 
                 GcGGAAGuuGGAAucAGGudTsdT 
                 930 
                 pACCUGAUUCcAACUUCCGCdTsdT 
                  72 
                  4 
                  84 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 514 
                 cauuAGcuGAAuAAuGuGAdTsdT 
                 932 
                 pUCAcAUuAUUcAGCuAAUGdTsdT 
                  72 
                  2 
                  85 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 702 
                 AcuAAAGuAAGuuAAAcuudTsdT 
                 773 
                 pAAGUUuAACUuACUUuAGUdTsdT 
                  87 
                 12 
                  86 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 595 
                 AccucAcAAccAGuccuGudTsdT 
                 956 
                 pAcAGGACUGGUUGUGAGGUdTsdT 
                  35 
                  1 
                  86 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 472 
                 GgcGAGuAucAGAGGAuGGdTsdT 
                 955 
                 pCcAUCCUCUGAuACUCGCCdTsdT 
                  23 
                  1 
                  87 
                  5 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 690 
                 uuAccuAAAGuuAAuccAGdTsdT 
                 806 
                 pCUGGAUuAACUUuAGGuAAdTsdT 
                  89 
                  7 
                  88 
                 12 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 592 
                 ugcuGuucGGAuAGAAcAGdTsdT 
                 731 
                 pCUGUUCuAUCCGAAcAGcAdTsdT 
                  76 
                  3 
                  89 
                  3 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 693 
                 GcuAccuAuGGuGAAcGuGdTsdT 
                 723 
                 pcACGUUcACcAuAGGuAGCdTsdT 
                  77 
                  8 
                  89 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 665 
                 AcGAuGccuuGuGucAAGAdTsdT 
                 720 
                 pUCUUGAcAcAAGGcAUCGUdTsdT 
                  76 
                  6 
                  90 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 688 
                 AgGcuAccuAuGGuGAAcGdTsdT 
                 721 
                 pCGUUcACcAuAGGuAGCCUdTsdT 
                  90 
                  7 
                  90 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 685 
                 uauucuuAAuAGGGcuAcudTsdT 
                 793 
                 pAGuAGCCCuAUuAAGAAuAdTsdT 
                  93 
                  7 
                  90 
                 17 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 701 
                 AgAAGcccGcuGuuucuAudTsdT 
                 948 
                 pAuAGAAAcAGCGGGCUUCUdTsdT 
                  79 
                  3 
                  90 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 646 
                 CuGuucGGAuAGAAcAGGAdTsdT 
                 732 
                 pUCCUGUUCuAUCCGAAcAGdTsdT 
                  67 
                  5 
                  91 
                  9 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 640 
                 AuucuuAAuAGGGcuAcuudTsdT 
                 794 
                 pAAGuAGCCCuAUuAAGAAUdTsdT 
                 114 
                  4 
                  92 
                 15 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 548 
                 AguuAuuGuuAccuAAAGudTsdT 
                 800 
                 pACUUuAGGuAAcAAuAACUdTsdT 
                  67 
                  2 
                  92 
                 10 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 610 
                 AuAAuGuGAGGAuuAAcuudTsdT 
                 934 
                 pAAGUuAAUCCUcAcAUuAUdTsdT 
                  90 
                  3 
                  93 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 637 
                 AcAAAuAuucuuAAuAGGGdTsdT 
                 792 
                 pCCCuAUuAAGAAuAUUUGUdTsdT 
                  79 
                  4 
                  94 
                 18 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 514 
                 cauuAGcuGAAuAAuGuGAdTsdT 
                 960 
                 pUcAcAUuAUUcAGCuAAUGdTsdT 
                  85 
                  4 
                  94 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 614 
                 ugAGGccuuGccuGuGAAGdTsdT 
                 869 
                 pCUUcAcAGGcAAGGCCUcAdTsdT 
                 100 
                  3 
                  95 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 563 
                 AuGuucAAAcAccuGGuAcdTsdT 
                 952 
                 pGuACcAGGUGUUUGAAcAUdTsdT 
                  96 
                  9 
                  95 
                 14 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 699 
                 ucccGcucGcGcccAucAcdTsdT 
                 812 
                 pGUGAUGGGCGCGAGCGGGAdTsdT 
                  94 
                 10 
                  95 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 604 
                 cccGcucGcGcccAucAcGdTsdT 
                 813 
                 pCGUGAUGGGCGCGAGCGGGdTsdT 
                  90 
                  3 
                  96 
                  4 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 657 
                 GgAcuGAuGccuGGccucAdTsdT 
                 853 
                 pUGAGGCcAGGcAUcAGUCCdTsdT 
                  87 
                  5 
                  97 
                  8 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 612 
                 AaGAGGcuAccuAuGGuGAdTsdT 
                 951 
                 pUcACcAuAGGuAGCCUCUUdTsdT 
                  79 
                  9 
                  97 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 522 
                 cauuGAAAcGAuGccuuGudTsdT 
                 950 
                 pAcAAGGcAUCGUUUcAAUGdTsdT 
                  93 
                 11 
                 100 
                  6 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 700 
                 cuuGGcuuuAAAGuGAGGGdTsdT 
                 906 
                 pCCCUcACUUuAAAGCcAAGdTsdT 
                  90 
                 10 
                 100 
                  7 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
               
                 704 
                 AauAAuuAucAAuGcuGuudTsdT 
                 725 
                 pAAcAGcAUUGAuAAUuAUUdTsdT 
                 134 
                 14 
                 101 
                  2 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 3 
               
             
            
               
                   
                   
               
               
                   
                 Activity testing for dose 
                 Activity testing for 
                 Activity testing for 
               
               
                   
                 response in HeLaS3 cells, 
                 dose response in HeLaS3 
                 dose response in HeLaS3 
               
               
                   
                 means of two transfections 
                 cells, transfection 3 
                 cells, transfection 4 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 mean 
                   
                   
                   
                 mean 
                   
                   
                   
                 mean 
               
               
                   
                 mean 
                 mean 
                 mean 
                 max. 
                 mean 
                 mean 
                 mean 
                 max. 
                 mean 
                 mean 
                 mean 
                 max. 
               
               
                 SEQ ID NO 
                 IC50 
                 IC80 
                 IC20 
                 inh 
                 IC50 
                 IC80 
                 IC20 
                 inh 
                 IC50 
                 IC80 
                 IC20 
                 inh 
               
               
                 pair 
                 [nM] 
                 [nM] 
                 [nM] 
                 [%] 
                 [nM] 
                 [nM] 
                 [nM] 
                 [%] 
                 [nM] 
                 [nM] 
                 [nM] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 469/742 
                 0.004 
                 0.059 
                 0.001 
                 91 
                 0.013 
                 0.124 
                 0.002 
                 95 
                 0.014 
                 0.158 
                 0.002 
                 91 
               
               
                 525/885 
                 0.004 
                 0.074 
                 0.001 
                 90 
                 0.01 
                 0.10 
                 0.00 
                 92 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 477/839 
                 0.006 
                 0.066 
                 0.001 
                 91 
                 0.016 
                 0.143 
                 0.003 
                 93 
                 0.013 
                 0.198 
                 0.002 
                 90 
               
               
                 552/891 
                 0.006 
                 0.107 
                 0.001 
                 88 
                 0.02 
                 0.14 
                 0.00 
                 90 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 475/884 
                 0.006 
                 0.073 
                 0.001 
                 91 
                 0.02 
                 0.16 
                 0.00 
                 93 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 501/842 
                 0.007 
                 0.091 
                 0.001 
                 90 
                 0.02 
                 0.18 
                 0.00 
                 91 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 473/863 
                 0.009 
                 0.330 
                 0.002 
                 84 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 507/841 
                 0.010 
                 0.081 
                 0.002 
                 97 
                 0.03 
                 0.21 
                 0.01 
                 97 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 494/866 
                 0.011 
                 0.810 
                 0.003 
                 84 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 544/718 
                 0.014 
                 0.145 
                 0.003 
                 92 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 497/711 
                 0.015 
                 0.116 
                 0.003 
                 89 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 560/838 
                 0.021 
                 0.265 
                 0.004 
                 86 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 522/845 
                 0.029 
                 0.295 
                 0.006 
                 90 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 471/892 
                 0.029 
                 0.361 
                 0.005 
                 88 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 488/735 
                 0.030 
                 0.262 
                 0.006 
                 89 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 507/949 
                 0.204 
                 2.588 
                 0.053 
                 82 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 526/967 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.015 
                 0.120 
                 0.0016 
                 92 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 470/962 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.022 
                 0.219 
                 0.004 
                 94 
                 0.020 
                 0.314 
                 0.002 
                 90 
               
               
                 553/968 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.024 
                 0.152 
                 0.0041 
                 89 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 477/963 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.024 
                 0.189 
                 0.005 
                 93 
                 0.016 
                 0.251 
                 0.002 
                 90 
               
               
                 501/965 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.036 
                 0.281 
                 0.0053 
                 91 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 476/966 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.038 
                 0.313 
                 0.0062 
                 93 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 507/964 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.045 
                 0.310 
                 0.0077 
                 97 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 477/971 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.154 
                 2.062 
                 0.034 
                 85 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 470/970 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.184 
                 2.134 
                 0.040 
                 87 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 470/978 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.479 
                 #N/A 
                 0.073 
                 72 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 477/979 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 0.906 
                 #N/A 
                 0.142 
                 78 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 4 
               
             
            
               
                   
                   
               
               
                   
                 Stability Cyno 
                 Stability Human 
                 Stability Mouse 
                   
               
               
                   
                 Serum 
                 Serum 
                 Serum 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 sense 
                 antisense 
                 sense 
                 antisense 
                 sense 
                 antisense 
                 Human PBMC 
               
               
                 SEQ ID NO 
                 t½ 
                 t½ 
                 t½ 
                 t½ 
                 t½ 
                 t½ 
                 assay 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 pair 
                 [hr] 
                 [hr] 
                 [hr] 
                 [hr] 
                 [hr] 
                 [hr] 
                 IFN-a 
                 TNF-a 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 475/884 
                 15.8 
                 2.2 
                 &gt;48 
                 0.9 
                 15.5 
                 9.2 
                 0 
                 0 
               
               
                 507/841 
                 16.2 
                 0.7 
                 &gt;48 
                 1.7 
                 12.1 
                 0.6 
                 0 
                 0 
               
               
                 525/885 
                 41.1 
                 4.2 
                 &gt;48 
                 2.0 
                 13.1 
                 7.7 
                 0 
                 0 
               
               
                 469/742 
                 36.4 
                 4.7 
                 &gt;48 
                 2.5 
                 14.2 
                 7.5 
                 0 
                 0 
               
               
                 552/891 
                 13.6 
                 9.8 
                 &gt;48 
                 7.1 
                 10.3 
                 11.6 
                 0 
                 0 
               
               
                 501/842 
                 17.4 
                 2.2 
                 &gt;48 
                 11.4 
                 13.5 
                 3.2 
                 0 
                 0 
               
               
                 477/839 
                 40.8 
                 16.8 
                 &gt;48 
                 &gt;48 
                 27.4 
                 10.7 
                 0 
                 0 
               
               
                 497/711 
                 &gt;48 
                 11.8 
                 &gt;48 
                 &gt;48 
                 &gt;48 
                 14.2 
                 0 
                 0 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                   
                 sense 
                   
                 antisense 
                   
                   
                   
                 antisense 
               
               
                 SEQ ID 
                 strand sequence 
                 SEQ ID 
                 strand sequence 
                 SEQ ID 
                 sense strand sequence 
                 SEQ ID 
                 strand sequence 
               
               
                 NO 
                 (5′-3′) 
                 NO 
                 (5′-3′) 
                 NO 
                 (5′-3′) 
                 NO 
                 (5′-3′) 
               
               
                   
               
             
            
               
                   1 
                 UUGUGGCAGACAGACUUAU 
                 234 
                 AUAAGUCUGUCUGCCACAA 
                 467 
                 uuGuGGcAGAcAGAcuuAudTsdT 
                 737 
                 pAUAAGUCUGUCUGCcAcAAdTsdT 
               
               
                   
               
               
                   1 
                 UUGUGGCAGACAGACUUAU 
                 234 
                 AUAAGUCUGUCUGCCACAA 
                 467 
                 uuGuGGcAGAcAGAcuuAudTsdT 
                 940 
                 pAuAAGUCUGUCUGCcAcAAdTsdT 
               
               
                   
               
               
                   2 
                 CCUGAUGUUCAAACACCUG 
                 235 
                 CAGGUGUUUGAACAUCAGG 
                 468 
                 ccuGAuGuucAAAcAccuGdTsdT 
                 860 
                 pcAGGUGUUUGAAcAUcAGGdTsdT 
               
               
                   
               
               
                   3 
                 AGUCCAACAGAGAAUUCUU 
                 236 
                 AAGAAUUCUCUGUUGGACU 
                 469 
                 AguccAAcAGAGAAuucuudTsdT 
                 742 
                 pAAGAAUUCUCUGUUGGACUdTsdT 
               
               
                   
               
               
                   3 
                 AGUCCAACAGAGAAUUCUU 
                 236 
                 AAGAAUUCUCUGUUGGACU 
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 962 
                 AAGAAUUCUCUGUUGGACUdTsdT 
               
               
                   
               
               
                   3 
                 AGUCCAACAGAGAAUUCUU 
                 236 
                 AAGAAUUCUCUGUUGGACU 
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 970 
                 AAGAAUUCUCUGUuGGACUdTsdT 
               
               
                   
               
               
                   3 
                 AGUCCAACAGAGAAUUCUU 
                 236 
                 AAGAAUUCUCUGUUGGACU 
                 470 
                 aguccAAcAGAGAAuucuudTsdT 
                 978 
                 AaGAAUUCUCUGUuGGACUdTsdT 
               
               
                   
               
               
                   4 
                 UAGGCGAGUAUCAGAGGAU 
                 237 
                 AUCCUCUGAUACUCGCCUA 
                 471 
                 uaGGcGAGuAucAGAGGAudTsdT 
                 892 
                 pAUCCUCUGAuACUCGCCuAdTsdT 
               
               
                   
               
               
                   5 
                 GGCGAGUAUCAGAGGAUGG 
                 238 
                 CCAUCCUCUGAUACUCGCC 
                 472 
                 GgcGAGuAucAGAGGAuGGdTsdT 
                 894 
                 pCCAUCCUCUGAuACUCGCCdTsdT 
               
               
                   
               
               
                   5 
                 GGCGAGUAUCAGAGGAUGG 
                 238 
                 CCAUCCUCUGAUACUCGCC 
                 472 
                 GgcGAGuAucAGAGGAuGGdTsdT 
                 955 
                 pCcAUCCUCUGAuACUCGCCdTsdT 
               
               
                   
               
               
                   6 
                 UGUUCAAACACCUGGUACA 
                 239 
                 UGUACCAGGUGUUUGAACA 
                 473 
                 uguucAAAcAccuGGuAcAdTsdT 
                 863 
                 pUGuACcAGGUGUUUGAAcAdTsdT 
               
               
                   
               
               
                   7 
                 GGGUGACCCUUUAGUGAGC 
                 240 
                 GCUCACUAAAGGGUCACCC 
                 474 
                 GgGuGAcccuuuAGuGAGcdTsdT 
                 756 
                 pGCUcACuAAAGGGUcACCCdTsdT 
               
               
                   
               
               
                   8 
                 GAAGGAAAGACUAACUUCU 
                 241 
                 AGAAGUUAGUCUUUCCUUC 
                 475 
                 GaAGGAAAGAcuAAcuucudTsdT 
                 884 
                 pAGAAGUuAGUCUUUCCUUCdTsdT 
               
               
                   
               
               
                   8 
                 GAAGGAAAGACUAACUUCU 
                 241 
                 AGAAGUUAGUCUUUCCUUC 
                 476 
                 gaAGGAAAGAcuAAcuucudTsdT 
                 966 
                 AGAAGUuAGUCUUUCCUUCdTsdT 
               
               
                   
               
               
                   8 
                 GAAGGAAAGACUAACUUCU 
                 241 
                 AGAAGUUAGUCUUUCCUUC 
                 476 
                 gaAGGAAAGAcuAAcuucudTsdT 
                 974 
                 AGAAGUuAGUCUUuCCUUCdTsdT 
               
               
                   
               
               
                   8 
                 GAAGGAAAGACUAACUUCU 
                 241 
                 AGAAGUUAGUCUUUCCUUC 
                 476 
                 gaAGGAAAGAcuAAcuucudTsdT 
                 982 
                 AgAAGUuAGUCUUuCCUUCdTsdT 
               
               
                   
               
               
                   9 
                 UUCUGAAAUGUAUAGUCUU 
                 242 
                 AAGACUAUACAUUUCAGAA 
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 839 
                 pAAGACuAuAcAUUUcAGAAdTsdT 
               
               
                   
               
               
                   9 
                 UUCUGAAAUGUAUAGUCUU 
                 242 
                 AAGACUAUACAUUUCAGAA 
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 963 
                 AAGACuAuAcAUUUcAGAAdTsdT 
               
               
                   
               
               
                   9 
                 UUCUGAAAUGUAUAGUCUU 
                 242 
                 AAGACUAUACAUUUCAGAA 
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 971 
                 AAGACuAuAcAUUucAGAAdTsdT 
               
               
                   
               
               
                   9 
                 UUCUGAAAUGUAUAGUCUU 
                 242 
                 AAGACUAUACAUUUCAGAA 
                 477 
                 uucuGAAAuGuAuAGucuudTsdT 
                 979 
                 AaGACuAuAcAUUucAGAAdTsdT 
               
               
                   
               
               
                  10 
                 CUGUGUAGCUACCUCACAA 
                 243 
                 UUGUGAGGUAGCUACACAG 
                 478 
                 cuGuGuAGcuAccucAcAAdTsdT 
                 744 
                 pUUGUGAGGuAGCuAcAcAGdTsdT 
               
               
                   
               
               
                  11 
                 UGCACUCUAAUGAAGCAAU 
                 244 
                 AUUGCUUCAUUAGAGUGCA 
                 479 
                 ugcAcucuAAuGAAGcAAudTsdT 
                 871 
                 pAUUGCUUcAUuAGAGUGcAdTsdT 
               
               
                   
               
               
                  12 
                 CCCAUUUGACUUUAUGGAG 
                 245 
                 CUCCAUAAAGUCAAAUGGG 
                 480 
                 cccAuuuGAcuuuAuGGAGdTsdT 
                 739 
                 pCUCcAuAAAGUcAAAUGGGdTsdT 
               
               
                   
               
               
                  13 
                 AAAUGUAUAGUCUUCUUAU 
                 246 
                 AUAAGAAGACUAUACAUUU 
                 481 
                 AaAuGuAuAGucuucuuAudTsdT 
                 714 
                 pAUAAGAAGACuAuAcAUUUdTsdT 
               
               
                   
               
               
                  13 
                 AAAUGUAUAGUCUUCUUAU 
                 246 
                 AUAAGAAGACUAUACAUUU 
                 481 
                 AaAuGuAuAGucuucuuAudTsdT 
                 939 
                 pAuAAGAAGACuAuAcAUUUdTsdT 
               
               
                   
               
               
                  14 
                 UACAUUGAGUUUGUGGCAG 
                 247 
                 CUGCCACAAACUCAAUGUA 
                 482 
                 uacAuuGAGuuuGuGGcAGdTsdT 
                 875 
                 pCUGCcAcAAACUcAAUGuAdTsdT 
               
               
                   
               
               
                  15 
                 CAAUACAUUGAGUUUGUGG 
                 248 
                 CCACAAACUCAAUGUAUUG 
                 483 
                 caAuAcAuuGAGuuuGuGGdTsdT 
                 874 
                 pCCAcAAACUcAAUGuAUUGdTsdT 
               
               
                   
               
               
                  15 
                 CAAUACAUUGAGUUUGUGG 
                 248 
                 CCACAAACUCAAUGUAUUG 
                 483 
                 caAuAcAuuGAGuuuGuGGdTsdT 
                 953 
                 pCcAcAAACUcAAUGuAUUGdTsdT 
               
               
                   
               
               
                  16 
                 GAACAGGAGUUCCUCACUG 
                 249 
                 CAGUGAGGAACUCCUGUUC 
                 484 
                 GaAcAGGAGuuccucAcuGdTsdT 
                 868 
                 pcAGUGAGGAACUCCUGUUCdTsdT 
               
               
                   
               
               
                  17 
                 AUCCCAUGUUCUGGCUUUC 
                 250 
                 GAAAGCCAGAACAUGGGAU 
                 485 
                 AucccAuGuucuGGcuuucdTsdT 
                 710 
                 pGAAAGCcAGAAcAUGGGAUdTsdT 
               
               
                   
               
               
                  18 
                 GUAGGUUGUGUGAGUUAAU 
                 251 
                 AUUAACUCACACAACCUAC 
                 486 
                 GuAGGuuGuGuGAGuuAAudTsdT 
                 921 
                 pAUuAACUcAcAcAACCuACdTsdT 
               
               
                   
               
               
                  19 
                 AUAGUCUUCUUAUUGACAC 
                 252 
                 GUGUCAAUAAGAAGACUAU 
                 487 
                 AuAGucuucuuAuuGAcAcdTsdT 
                 715 
                 pGUGUcAAuAAGAAGACuAUdTsdT 
               
               
                   
               
               
                  20 
                 AUUGCACUCUAAUGAAGCA 
                 253 
                 UGCUUCAUUAGAGUGCAAU 
                 488 
                 AuuGcAcucuAAuGAAGcAdTsdT 
                 735 
                 pUGCUUcAUuAGAGUGcAAUdTsdT 
               
               
                   
               
               
                  21 
                 UUAUCAAUGCUGUUCGGAU 
                 254 
                 AUCCGAACAGCAUUGAUAA 
                 489 
                 uuAucAAuGcuGuucGGAudTsdT 
                 728 
                 pAUCCGAAcAGcAUUGAuAAdTsdT 
               
               
                   
               
               
                  22 
                 AGAAACGAGGACUGAUGCC 
                 255 
                 GGCAUCAGUCCUCGUUUCU 
                 490 
                 AgAAAcGAGGAcuGAuGccdTsdT 
                 851 
                 pGGcAUcAGUCCUCGUUUCUdTsdT 
               
               
                   
               
               
                  23 
                 CAUUGAGUUUGUGGCAGAC 
                 256 
                 GUCUGCCACAAACUCAAUG 
                 491 
                 cauuGAGuuuGuGGcAGAcdTsdT 
                 876 
                 pGUCUGCcAcAAACUcAAUGdTsdT 
               
               
                   
               
               
                  24 
                 ACAUUCAGCACUGGGAAUC 
                 257 
                 GAUUCCCAGUGCUGAAUGU 
                 492 
                 AcAuucAGcAcuGGGAAucdTsdT 
                 708 
                 pGAUUCCcAGUGCUGAAUGUdTsdT 
               
               
                   
               
               
                  25 
                 UGAUGUUCAAACACCUGGU 
                 258 
                 ACCAGGUGUUUGAACAUCA 
                 493 
                 ugAuGuucAAAcAccuGGudTsdT 
                 861 
                 pACcAGGUGUUUGAAcAUcAdTsdT 
               
               
                   
               
               
                  26 
                 GGAUAGAACAGGAGUUCCU 
                 259 
                 AGGAACUCCUGUUCUAUCC 
                 494 
                 GgAuAGAAcAGGAGuuccudTsdT 
                 866 
                 pAGGAACUCCUGUUCuAUCCdTsdT 
               
               
                   
               
               
                  27 
                 AAUAUUUCACUGGAAGGAA 
                 260 
                 UUCCUUCCAGUGAAAUAUU 
                 495 
                 AauAuuucAcuGGAAGGAAdTsdT 
                 741 
                 pUUCCUUCcAGUGAAAuAUUdTsdT 
               
               
                   
               
               
                  28 
                 AAUAAACAUUGUUUGUACU 
                 261 
                 AGUACAAACAAUGUUUAUU 
                 496 
                 AauAAAcAuuGuuuGuAcudTsdT 
                 911 
                 pAGuAcAAAcAAUGUUuAUUdTsdT 
               
               
                   
               
               
                  29 
                 UCCCAUGUUCUGGCUUUCU 
                 262 
                 AGAAAGCCAGAACAUGGGA 
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 711 
                 pAGAAAGCcAGAAcAUGGGAdTsdT 
               
               
                   
               
               
                  29 
                 UCCCAUGUUCUGGCUUUCU 
                 262 
                 AGAAAGCCAGAACAUGGGA 
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 961 
                 AGAAAGCcAGAAcAUGGGAdTsdT 
               
               
                   
               
               
                  29 
                 UCCCAUGUUCUGGCUUUCU 
                 262 
                 AGAAAGCCAGAACAUGGGA 
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 969 
                 AGAAAGCcAGAAcaUGGGAdTsdT 
               
               
                   
               
               
                  29 
                 UCCCAUGUUCUGGCUUUCU 
                 262 
                 AGAAAGCCAGAACAUGGGA 
                 497 
                 ucccAuGuucuGGcuuucudTsdT 
                 977 
                 AgAAAGCcAGAAcaUGGGAdTsdT 
               
               
                   
               
               
                  30 
                 UUCGGAUAGAACAGGAGUU 
                 263 
                 AACUCCUGUUCUAUCCGAA 
                 498 
                 uucGGAuAGAAcAGGAGuudTsdT 
                 734 
                 pAACUCCUGUUCuAUCCGAAdTsdT 
               
               
                   
               
               
                  31 
                 AAGUAGGUUGUGUGAGUUA 
                 264 
                 UAACUCACACAACCUACUU 
                 499 
                 AaGuAGGuuGuGuGAGuuAdTsdT 
                 790 
                 puAACUcAcAcAACCuACUUdTsdT 
               
               
                   
               
               
                  32 
                 UUAUAGUGCUGGUAGUAUC 
                 265 
                 GAUACUACCAGCACUAUAA 
                 500 
                 uuAuAGuGcuGGuAGuAucdTsdT 
                 746 
                 pGAuACuACcAGcACuAuAAdTsdT 
               
               
                   
               
               
                  33 
                 CUUCUUAUUGACACUUACA 
                 266 
                 UGUAAGUGUCAAUAAGAAG 
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 842 
                 pUGuAAGUGUcAAuAAGAAGdTsdT 
               
               
                   
               
               
                  33 
                 CUUCUUAUUGACACUUACA 
                 266 
                 UGUAAGUGUCAAUAAGAAG 
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 965 
                 UGuAAGUGUcAAuAAGAAGdTsdT 
               
               
                   
               
               
                  33 
                 CUUCUUAUUGACACUUACA 
                 266 
                 UGUAAGUGUCAAUAAGAAG 
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 973 
                 UGuAAGUGUcAAuaAGAAGdTsdT 
               
               
                   
               
               
                  33 
                 CUUCUUAUUGACACUUACA 
                 266 
                 UGUAAGUGUCAAUAAGAAG 
                 501 
                 cuucuuAuuGAcAcuuAcAdTsdT 
                 981 
                 UguAAGUGUcAAuaAGAAGdTsdT 
               
               
                   
               
               
                  34 
                 UACAGAAGCCCGCUGUUUC 
                 267 
                 GAAACAGCGGGCUUCUGUA 
                 502 
                 uacAGAAGcccGcuGuuucdTsdT 
                 832 
                 pGAAAcAGCGGGCUUCUGuAdTsdT 
               
               
                   
               
               
                  35 
                 GUGACCCUUUAGUGAGCUU 
                 268 
                 AAGCUCACUAAAGGGUCAC 
                 503 
                 GuGAcccuuuAGuGAGcuudTsdT 
                 907 
                 pAAGCUcACuAAAGGGUcACdTsdT 
               
               
                   
               
               
                  36 
                 AUAGAACAGGAGUUCCUCA 
                 269 
                 UGAGGAACUCCUGUUCUAU 
                 504 
                 AuAGAAcAGGAGuuccucAdTsdT 
                 867 
                 pUGAGGAACUCCUGUUCuAUdTsdT 
               
               
                   
               
               
                  37 
                 CUGGCACUUUACAAACAAA 
                 270 
                 UUUGUUUGUAAAGUGCCAG 
                 505 
                 cuGGcAcuuuAcAAAcAAAdTsdT 
                 910 
                 pUUUGUUUGuAAAGUGCcAGdTsdT 
               
               
                   
               
               
                  38 
                 UCUAAUGAAGCAAUACAUU 
                 271 
                 AAUGUAUUGCUUCAUUAGA 
                 506 
                 ucuAAuGAAGcAAuAcAuudTsdT 
                 872 
                 pAAUGuAUUGCUUcAUuAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 841 
                 pGUAAGUGUcAAuAAGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 949 
                 pGuAAGUGUcAAuAAGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 964 
                 GUAAGUGUcAAuAAGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 972 
                 GUAAGUGUcAAuAaGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 508 
                 ucuucuUAuuGAcAcuuAcdTsdT 
                 972 
                 GUAAGUGUcAAuAaGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 507 
                 ucuucuuAuuGAcAcuuAcdTsdT 
                 980 
                 GuAAGUGUcAAuAaGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 508 
                 ucuucuUAuuGAcAcuuAcdTsdT 
                 980 
                 GuAAGUGUcAAuAaGAAGAdTsdT 
               
               
                   
               
               
                  39 
                 UCUUCUUAUUGACACUUAC 
                 272 
                 GUAAGUGUCAAUAAGAAGA 
                 508 
                 ucuucuUAuuGAcAcuuAcdTsdT 
                 985 
                 GuAAGUGUcAAuAAGAAGAdTsdT 
               
               
                   
               
               
                  40 
                 UGUUCGGAUAGAACAGGAG 
                 273 
                 CUCCUGUUCUAUCCGAACA 
                 509 
                 uguucGGAuAGAAcAGGAGdTsdT 
                 733 
                 pCUCCUGUUCuAUCCGAAcAdTsdT 
               
               
                   
               
               
                  41 
                 AGUACCAUGAUAUCUGGCA 
                 274 
                 UGCCAGAUAUCAUGGUACU 
                 510 
                 AguAccAuGAuAucuGGcAdTsdT 
                 820 
                 pUGCcAGAuAUcAUGGuACUdTsdT 
               
               
                   
               
               
                  42 
                 CAGAGAUGAGGGUUUACAC 
                 275 
                 GUGUAAACCCUCAUCUCUG 
                 511 
                 caGAGAuGAGGGuuuAcAcdTsdT 
                 856 
                 pGUGuAAACCCUcAUCUCUGdTsdT 
               
               
                   
               
               
                  43 
                 GAAACGAGGACUGAUGCCU 
                 276 
                 AGGCAUCAGUCCUCGUUUC 
                 512 
                 GaAAcGAGGAcuGAuGccudTsdT 
                 852 
                 pAGGcAUcAGUCCUCGUUUCdTsdT 
               
               
                   
               
               
                  44 
                 AAGAGAGUAGGCGAGUAUC 
                 277 
                 GAUACUCGCCUACUCUCUU 
                 513 
                 AaGAGAGuAGGcGAGuAucdTsdT 
                 888 
                 pGAuACUCGCCuACUCUCUUdTsdT 
               
               
                   
               
               
                  45 
                 CAUUAGCUGAAUAAUGUGA 
                 278 
                 UCACAUUAUUCAGCUAAUG 
                 514 
                 cauuAGcuGAAuAAuGuGAdTsdT 
                 932 
                 pUCAcAUuAUUcAGCuAAUGdTsdT 
               
               
                   
               
               
                  45 
                 CAUUAGCUGAAUAAUGUGA 
                 278 
                 UCACAUUAUUCAGCUAAUG 
                 514 
                 cauuAGcuGAAuAAuGuGAdTsdT 
                 960 
                 pUcAcAUuAUUcAGCuAAUGdTsdT 
               
               
                   
               
               
                  46 
                 AGUAGAGAACCCAUUUGAC 
                 279 
                 GUCAAAUGGGUUCUCUACU 
                 515 
                 AguAGAGAAcccAuuuGAcdTsdT 
                 738 
                 pGUcAAAUGGGUUCUCuACUdTsdT 
               
               
                   
               
               
                  47 
                 AGGCGAGUAUCAGAGGAUG 
                 280 
                 CAUCCUCUGAUACUCGCCU 
                 516 
                 AgGcGAGuAucAGAGGAuGdTsdT 
                 893 
                 pcAUCCUCUGAuACUCGCCUdTsdT 
               
               
                   
               
               
                  48 
                 UAGACUAAGCAUGUAAUUU 
                 281 
                 AAAUUACAUGCUUAGUCUA 
                 517 
                 uaGAcuAAGcAuGuAAuuudTsdT 
                 784 
                 pAAAUuAcAUGCUuAGUCuAdTsdT 
               
               
                   
               
               
                  49 
                 AACAUUGUUUGUACUCACA 
                 282 
                 UGUGAGUACAAACAAUGUU 
                 518 
                 AacAuuGuuuGuAcucAcAdTsdT 
                 913 
                 pUGUGAGuAcAAAcAAUGUUdTsdT 
               
               
                   
               
               
                  50 
                 GAUGGGAGUGAUGUCAAGU 
                 283 
                 ACUUGACAUCACUCCCAUC 
                 519 
                 GauGGGAGuGAuGucAAGudTsdT 
                 896 
                 pACUUGAcAUcACUCCcAUCdTsdT 
               
               
                   
               
               
                  51 
                 CAGACCAUUUCCUAAUCAG 
                 284 
                 CUGAUUAGGAAAUGGUCUG 
                 520 
                 caGAccAuuuccuAAucAGdTsdT 
                 937 
                 pCUGAUuAGGAAAUGGUCUGdTsdT 
               
               
                   
               
               
                  52 
                 GAUUACAGAAGCCCGCUGU 
                 285 
                 ACAGCGGGCUUCUGUAAUC 
                 521 
                 GauuAcAGAAGcccGcuGudTsdT 
                 712 
                 pACAGCGGGCUUCUGuAAUCdTsdT 
               
               
                   
               
               
                  52 
                 GAUUACAGAAGCCCGCUGU 
                 285 
                 ACAGCGGGCUUCUGUAAUC 
                 521 
                 GauuAcAGAAGcccGcuGudTsdT 
                 938 
                 pAcAGCGGGCUUCUGuAAUCdTsdT 
               
               
                   
               
               
                  53 
                 CAUUGAAACGAUGCCUUGU 
                 286 
                 ACAAGGCAUCGUUUCAAUG 
                 522 
                 cauuGAAAcGAuGccuuGudTsdT 
                 845 
                 pACAAGGcAUCGUUUcAAUGdTsdT 
               
               
                   
               
               
                  53 
                 CAUUGAAACGAUGCCUUGU 
                 286 
                 ACAAGGCAUCGUUUCAAUG 
                 522 
                 cauuGAAAcGAuGccuuGudTsdT 
                 950 
                 pAcAAGGcAUCGUUUcAAUGdTsdT 
               
               
                   
               
               
                  54 
                 ACUUAUGCUGGAACUGGGU 
                 287 
                 ACCCAGUUCCAGCAUAAGU 
                 523 
                 AcuuAuGcuGGAAcuGGGudTsdT 
                 880 
                 pACCcAGUUCcAGcAuAAGUdTsdT 
               
               
                   
               
               
                  55 
                 GUCGACAAGGAGAACACGC 
                 288 
                 GCGUGUUCUCCUUGUCGAC 
                 524 
                 GucGAcAAGGAGAAcAcGcdTsdT 
                 705 
                 pGCGUGUUCUCCUUGUCGACdTsdT 
               
               
                   
               
               
                  56 
                 AGGAAAGACUAACUUCUUU 
                 289 
                 AAAGAAGUUAGUCUUUCCU 
                 525 
                 AgGAAAGAcuAAcuucuuudTsdT 
                 885 
                 pAAAGAAGUuAGUCUUUCCUdTsdT 
               
               
                   
               
               
                  56 
                 AGGAAAGACUAACUUCUUU 
                 289 
                 AAAGAAGUUAGUCUUUCCU 
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 967 
                 AAAGAAGUuAGUCUUUCCUdTsdT 
               
               
                   
               
               
                  56 
                 AGGAAAGACUAACUUCUUU 
                 289 
                 AAAGAAGUUAGUCUUUCCU 
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 975 
                 AAAGAAGUuAGUCuUUCCUdTsdT 
               
               
                   
               
               
                  56 
                 AGGAAAGACUAACUUCUUU 
                 289 
                 AAAGAAGUUAGUCUUUCCU 
                 526 
                 agGAAAGAcuAAcuucuuudTsdT 
                 983 
                 AaAGAAGUuAGUCuUUCCUdTsdT 
               
               
                   
               
               
                  57 
                 CAAGACCGCGAGGAGGAUC 
                 290 
                 GAUCCUCCUCGCGGUCUUG 
                 527 
                 caAGAccGcGAGGAGGAucdTsdT 
                 816 
                 pGAUCCUCCUCGCGGUCUUGdTsdT 
               
               
                   
               
               
                  58 
                 GACAAUGGCAGUCUUGGCU 
                 291 
                 AGCCAAGACUGCCAUUGUC 
                 528 
                 GacAAuGGcAGucuuGGcudTsdT 
                 755 
                 pAGCcAAGACUGCcAUUGUCdTsdT 
               
               
                   
               
               
                  59 
                 AUGCCUUGUGUCAAGAAGA 
                 292 
                 UCUUCUUGACACAAGGCAU 
                 529 
                 AuGccuuGuGucAAGAAGAdTsdT 
                 846 
                 pUCUUCUUGAcAcAAGGcAUdTsdT 
               
               
                   
               
               
                  60 
                 GCCUCACUGCUUCAACGCA 
                 293 
                 UGCGUUGAAGCAGUGAGGC 
                 530 
                 GccucAcuGcuucAAcGcAdTsdT 
                 909 
                 pUGCGUUGAAGcAGUGAGGCdTsdT 
               
               
                   
               
               
                  61 
                 UACCUCACAACCAGUCCUG 
                 294 
                 CAGGACUGGUUGUGAGGUA 
                 531 
                 uaccucAcAAccAGuccuGdTsdT 
                 745 
                 pcAGGACUGGUUGUGAGGuAdTsdT 
               
               
                   
               
               
                  62 
                 GAGAAGAGAGUAGGCGAGU 
                 295 
                 ACUCGCCUACUCUCUUCUC 
                 532 
                 GaGAAGAGAGuAGGcGAGudTsdT 
                 887 
                 pACUCGCCuACUCUCUUCUCdTsdT 
               
               
                   
               
               
                  63 
                 AGACUUAUGCUGGAACUGG 
                 296 
                 CCAGUUCCAGCAUAAGUCU 
                 533 
                 AgAcuuAuGcuGGAAcuGGdTsdT 
                 879 
                 pCCAGUUCcAGcAuAAGUCUdTsdT 
               
               
                   
               
               
                  63 
                 AGACUUAUGCUGGAACUGG 
                 296 
                 CCAGUUCCAGCAUAAGUCU 
                 533 
                 AgAcuuAuGcuGGAAcuGGdTsdT 
                 954 
                 pCcAGUUCcAGcAuAAGUCUdTsdT 
               
               
                   
               
               
                  64 
                 UUACAGAAGCCCGCUGUUU 
                 297 
                 AAACAGCGGGCUUCUGUAA 
                 534 
                 uuAcAGAAGcccGcuGuuudTsdT 
                 831 
                 pAAAcAGCGGGCUUCUGuAAdTsdT 
               
               
                   
               
               
                  65 
                 UUAUGCUGGAACUGGGUUU 
                 298 
                 AAACCCAGUUCCAGCAUAA 
                 535 
                 uuAuGcuGGAAcuGGGuuudTsdT 
                 881 
                 pAAACCcAGUUCcAGcAuAAdTsdT 
               
               
                   
               
               
                  66 
                 AUAAACAUUGUUUGUACUC 
                 299 
                 GAGUACAAACAAUGUUUAU 
                 536 
                 AuAAAcAuuGuuuGuAcucdTsdT 
                 912 
                 pGAGuAcAAAcAAUGUUuAUdTsdT 
               
               
                   
               
               
                  67 
                 UCAAUGCCAUUGAAACGAU 
                 300 
                 AUCGUUUCAAUGGCAUUGA 
                 537 
                 ucAAuGccAuuGAAAcGAudTsdT 
                 717 
                 pAUCGUUUcAAUGGcAUUGAdTsdT 
               
               
                   
               
               
                  68 
                 AUAGUGCUGGUAGUAUCAC 
                 301 
                 GUGAUACUACCAGCACUAU 
                 538 
                 AuAGuGcuGGuAGuAucAcdTsdT 
                 748 
                 pGUGAuACuACcAGcACuAUdTsdT 
               
               
                   
               
               
                  69 
                 CAGCCUCACUGCUUCAACG 
                 302 
                 CGUUGAAGCAGUGAGGCUG 
                 539 
                 caGccucAcuGcuucAAcGdTsdT 
                 908 
                 pCGUUGAAGcAGUGAGGCUGdTsdT 
               
               
                   
               
               
                  70 
                 UCUUGGCUUUAAAGUGAGG 
                 303 
                 CCUCACUUUAAAGCCAAGA 
                 540 
                 ucuuGGcuuuAAAGuGAGGdTsdT 
                 905 
                 pCCUcACUUuAAAGCcAAGAdTsdT 
               
               
                   
               
               
                  71 
                 GGCUGUGACUUACCAUAGC 
                 304 
                 GCUAUGGUAAGUCACAGCC 
                 541 
                 GgcuGuGAcuuAccAuAGcdTsdT 
                 751 
                 pGCuAUGGuAAGUcAcAGCCdTsdT 
               
               
                   
               
               
                  72 
                 GGCUACCUAUGGUGAACGU 
                 305 
                 ACGUUCACCAUAGGUAGCC 
                 542 
                 GgcuAccuAuGGuGAAcGudTsdT 
                 722 
                 pACGUUcACcAuAGGuAGCCdTsdT 
               
               
                   
               
               
                  73 
                 CGCGAGGAGGAUCUUCCAG 
                 306 
                 CUGGAAGAUCCUCCUCGCG 
                 543 
                 cgcGAGGAGGAucuuccAGdTsdT 
                 819 
                 pCUGGAAGAUCCUCCUCGCGdTsdT 
               
               
                   
               
               
                  74 
                 GCCAUUGAAACGAUGCCUU 
                 307 
                 AAGGCAUCGUUUCAAUGGC 
                 544 
                 GccAuuGAAAcGAuGccuudTsdT 
                 718 
                 pAAGGcAUCGUUUcAAUGGCdTsdT 
               
               
                   
               
               
                  75 
                 AGCCUCACUGCUUCAACGC 
                 308 
                 GCGUUGAAGCAGUGAGGCU 
                 545 
                 AgccucAcuGcuucAAcGcdTsdT 
                 758 
                 pGCGUUGAAGcAGUGAGGCUdTsdT 
               
               
                   
               
               
                  76 
                 GGCAGACAGACUUAUGCUG 
                 309 
                 CAGCAUAAGUCUGUCUGCC 
                 546 
                 GgcAGAcAGAcuuAuGcuGdTsdT 
                 878 
                 pcAGcAuAAGUCUGUCUGCCdTsdT 
               
               
                   
               
               
                  77 
                 GUGACUAAAGUAAGUUAAA 
                 310 
                 UUUAACUUACUUUAGUCAC 
                 547 
                 GuGAcuAAAGuAAGuuAAAdTsdT 
                 770 
                 pUUuAACUuACUUuAGUcACdTsdT 
               
               
                   
               
               
                  78 
                 AGUUAUUGUUACCUAAAGU 
                 311 
                 ACUUUAGGUAACAAUAACU 
                 548 
                 AguuAuuGuuAccuAAAGudTsdT 
                 800 
                 pACUUuAGGuAAcAAuAACUdTsdT 
               
               
                   
               
               
                  79 
                 GCCUUUAUGUUUGGGAGAA 
                 312 
                 UUCUCCCAAACAUAAAGGC 
                 549 
                 GccuuuAuGuuuGGGAGAAdTsdT 
                 924 
                 pUUCUCCcAAAcAuAAAGGCdTsdT 
               
               
                   
               
               
                  80 
                 UUCAGAGUAGAGAACCCAU 
                 313 
                 AUGGGUUCUCUACUCUGAA 
                 550 
                 uucAGAGuAGAGAAcccAudTsdT 
                 882 
                 pAUGGGUUCUCuACUCUGAAdTsdT 
               
               
                   
               
               
                  81 
                 AAACGAGGACUGAUGCCUG 
                 314 
                 CAGGCAUCAGUCCUCGUUU 
                 551 
                 AaAcGAGGAcuGAuGccuGdTsdT 
                 724 
                 pcAGGcAUcAGUCCUCGUUUdTsdT 
               
               
                   
               
               
                  82 
                 GUAGGCGAGUAUCAGAGGA 
                 315 
                 UCCUCUGAUACUCGCCUAC 
                 552 
                 GuAGGcGAGuAucAGAGGAdTsdT 
                 891 
                 pUCCUCUGAuACUCGCCuACdTsdT 
               
               
                   
               
               
                  82 
                 GUAGGCGAGUAUCAGAGGA 
                 315 
                 UCCUCUGAUACUCGCCUAC 
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 968 
                 UCCUCUGAuACUCGCCuACdTsdT 
               
               
                   
               
               
                  82 
                 GUAGGCGAGUAUCAGAGGA 
                 315 
                 UCCUCUGAUACUCGCCUAC 
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 976 
                 UCCUCUGAuACUCgCCuACdTsdT 
               
               
                   
               
               
                  82 
                 GUAGGCGAGUAUCAGAGGA 
                 315 
                 UCCUCUGAUACUCGCCUAC 
                 553 
                 guAGGcGAGuAucAGAGGAdTsdT 
                 984 
                 UcCUCUGAuACUCgCCuACdTsdT 
               
               
                   
               
               
                  83 
                 AAGCCCGCUGUUUCUAUGG 
                 316 
                 CCAUAGAAACAGCGGGCUU 
                 554 
                 AaGcccGcuGuuucuAuGGdTsdT 
                 835 
                 pCCAuAGAAAcAGCGGGCUUdTsdT 
               
               
                   
               
               
                  84 
                 UCAGCACUGGGAAUCCCUG 
                 317 
                 CAGGGAUUCCCAGUGCUGA 
                 555 
                 ucAGcAcuGGGAAucccuGdTsdT 
                 827 
                 pcAGGGAUUCCcAGUGCUGAdTsdT 
               
               
                   
               
               
                  85 
                 GAAUAAUGUGAGGAUUAAC 
                 318 
                 GUUAAUCCUCACAUUAUUC 
                 556 
                 GaAuAAuGuGAGGAuuAAcdTsdT 
                 933 
                 pGUuAAUCCUcAcAUuAUUCdTsdT 
               
               
                   
               
               
                  86 
                 UGUGGCAGACAGACUUAUG 
                 319 
                 CAUAAGUCUGUCUGCCACA 
                 557 
                 uguGGcAGAcAGAcuuAuGdTsdT 
                 877 
                 pcAuAAGUCUGUCUGCcAcAdTsdT 
               
               
                   
               
               
                  87 
                 AGAGAUAAAUGUUGAUCUU 
                 320 
                 AAGAUCAACAUUUAUCUCU 
                 558 
                 AgAGAuAAAuGuuGAucuudTsdT 
                 798 
                 pAAGAUcAAcAUUuAUCUCUdTsdT 
               
               
                   
               
               
                  88 
                 UACCAUGAUAUCUGGCAGA 
                 321 
                 UCUGCCAGAUAUCAUGGUA 
                 559 
                 uaccAuGAuAucuGGcAGAdTsdT 
                 821 
                 pUCUGCcAGAuAUcAUGGuAdTsdT 
               
               
                   
               
               
                  89 
                 CUUCCAAAUUGCCAUGGAA 
                 322 
                 UUCCAUGGCAAUUUGGAAG 
                 560 
                 cuuccAAAuuGccAuGGAAdTsdT 
                 838 
                 pUUCcAUGGcAAUUUGGAAGdTsdT 
               
               
                   
               
               
                  90 
                 ACCGCGAGGAGGAUCUUCC 
                 323 
                 GGAAGAUCCUCCUCGCGGU 
                 561 
                 AccGcGAGGAGGAucuuccdTsdT 
                 818 
                 pGGAAGAUCCUCCUCGCGGUdTsdT 
               
               
                   
               
               
                  91 
                 GAAAUGUAUAGUCUUCUUA 
                 324 
                 UAAGAAGACUAUACAUUUC 
                 562 
                 GaAAuGuAuAGucuucuuAdTsdT 
                 713 
                 puAAGAAGACuAuAcAUUUCdTsdT 
               
               
                   
               
               
                  92 
                 AUGUUCAAACACCUGGUAC 
                 325 
                 GUACCAGGUGUUUGAACAU 
                 563 
                 AuGuucAAAcAccuGGuAcdTsdT 
                 862 
                 pGUACcAGGUGUUUGAAcAUdTsdT 
               
               
                   
               
               
                  92 
                 AUGUUCAAACACCUGGUAC 
                 325 
                 GUACCAGGUGUUUGAACAU 
                 563 
                 AuGuucAAAcAccuGGuAcdTsdT 
                 952 
                 pGuACcAGGUGUUUGAAcAUdTsdT 
               
               
                   
               
               
                  93 
                 AGGGAAUUUCUCUUCAAUG 
                 326 
                 CAUUGAAGAGAAAUUCCCU 
                 564 
                 AgGGAAuuucucuucAAuGdTsdT 
                 716 
                 pcAUUGAAGAGAAAUUCCCUdTsdT 
               
               
                   
               
               
                  94 
                 CCCUGUUAAGUGGUGAAAU 
                 327 
                 AUUUCACCACUUAACAGGG 
                 565 
                 cccuGuuAAGuGGuGAAAudTsdT 
                 789 
                 pAUUUcACcACUuAAcAGGGdTsdT 
               
               
                   
               
               
                  95 
                 GAUGAGGGUUUACACUGUG 
                 328 
                 CACAGUGUAAACCCUCAUC 
                 566 
                 GauGAGGGuuuAcAcuGuGdTsdT 
                 857 
                 pcAcAGUGuAAACCCUcAUCdTsdT 
               
               
                   
               
               
                  96 
                 UGUGUGAGUUAAUUCAUUU 
                 329 
                 AAAUGAAUUAACUCACACA 
                 567 
                 uguGuGAGuuAAuucAuuudTsdT 
                 922 
                 pAAAUGAAUuAACUcAcAcAdTsdT 
               
               
                   
               
               
                  97 
                 UUGCCUGAUGUUCAAACAC 
                 330 
                 GUGUUUGAACAUCAGGCAA 
                 568 
                 uuGccuGAuGuucAAAcAcdTsdT 
                 858 
                 pGUGUUUGAAcAUcAGGcAAdTsdT 
               
               
                   
               
               
                  98 
                 AAACUUGUGUAGACUAAGC 
                 331 
                 GCUUAGUCUACACAAGUUU 
                 569 
                 AaAcuuGuGuAGAcuAAGcdTsdT 
                 779 
                 pGCUuAGUCuAcAcAAGUUUdTsdT 
               
               
                   
               
               
                  99 
                 UAUAUCCCAUGUUCUGGCU 
                 332 
                 AGCCAGAACAUGGGAUAUA 
                 570 
                 uauAucccAuGuucuGGcudTsdT 
                 828 
                 pAGCcAGAAcAUGGGAuAuAdTsdT 
               
               
                   
               
               
                 100 
                 UUGUGUAGACUAAGCAUGU 
                 333 
                 ACAUGCUUAGUCUACACAA 
                 571 
                 uuGuGuAGAcuAAGcAuGudTsdT 
                 781 
                 pACAUGCUuAGUCuAcAcAAdTsdT 
               
               
                   
               
               
                 100 
                 UUGUGUAGACUAAGCAUGU 
                 333 
                 ACAUGCUUAGUCUACACAA 
                 571 
                 uuGuGuAGAcuAAGcAuGudTsdT 
                 945 
                 pAcAUGCUuAGUCuAcAcAAdTsdT 
               
               
                   
               
               
                 101 
                 AUGCUGUUCGGAUAGAACA 
                 334 
                 UGUUCUAUCCGAACAGCAU 
                 572 
                 AuGcuGuucGGAuAGAAcAdTsdT 
                 730 
                 pUGUUCuAUCCGAAcAGcAUdTsdT 
               
               
                   
               
               
                 102 
                 AAUUAUCAAUGCUGUUCGG 
                 335 
                 CCGAACAGCAUUGAUAAUU 
                 573 
                 AauuAucAAuGcuGuucGGdTsdT 
                 727 
                 pCCGAAcAGcAUUGAuAAUUdTsdT 
               
               
                   
               
               
                 103 
                 GCCUGAUGUUCAAACACCU 
                 336 
                 AGGUGUUUGAACAUCAGGC 
                 574 
                 GccuGAuGuucAAAcAccudTsdT 
                 859 
                 pAGGUGUUUGAAcAUcAGGCdTsdT 
               
               
                   
               
               
                 104 
                 CAUAGCAGUGACAAUGGCA 
                 337 
                 UGCCAUUGUCACUGCUAUG 
                 575 
                 cauAGcAGuGAcAAuGGcAdTsdT 
                 902 
                 pUGCcAUUGUcACUGCuAUGdTsdT 
               
               
                   
               
               
                 105 
                 UGUGAGUUAAUUCAUUUAU 
                 338 
                 AUAAAUGAAUUAACUCACA 
                 576 
                 uguGAGuuAAuucAuuuAudTsdT 
                 923 
                 pAUAAAUGAAUuAACUcAcAdTsdT 
               
               
                   
               
               
                 105 
                 UGUGAGUUAAUUCAUUUAU 
                 338 
                 AUAAAUGAAUUAACUCACA 
                 576 
                 uguGAGuuAAuucAuuuAudTsdT 
                 959 
                 pAuAAAUGAAUuAACUcAcAdTsdT 
               
               
                   
               
               
                 106 
                 AGUGCUGGUAGUAUCACCU 
                 339 
                 AGGUGAUACUACCAGCACU 
                 577 
                 AguGcuGGuAGuAucAccudTsdT 
                 749 
                 pAGGUGAuACuACcAGcACUdTsdT 
               
               
                   
               
               
                 107 
                 UAUCAAUGCUGUUCGGAUA 
                 340 
                 UAUCCGAACAGCAUUGAUA 
                 578 
                 uaucAAuGcuGuucGGAuAdTsdT 
                 865 
                 puAUCCGAAcAGcAUUGAuAdTsdT 
               
               
                   
               
               
                 108 
                 GACUAAAGUAAGUUAAACU 
                 341 
                 AGUUUAACUUACUUUAGUC 
                 579 
                 GacuAAAGuAAGuuAAAcudTsdT 
                 772 
                 pAGUUuAACUuACUUuAGUCdTsdT 
               
               
                   
               
               
                 109 
                 AAUGCUGUUCGGAUAGAAC 
                 342 
                 GUUCUAUCCGAACAGCAUU 
                 580 
                 AauGcuGuucGGAuAGAAcdTsdT 
                 729 
                 pGUUCuAUCCGAAcAGcAUUdTsdT 
               
               
                   
               
               
                 110 
                 AGAAUAUUUCACUGGAAGG 
                 343 
                 CCUUCCAGUGAAAUAUUCU 
                 581 
                 AgAAuAuuucAcuGGAAGGdTsdT 
                 740 
                 pCCUUCcAGUGAAAuAUUCUdTsdT 
               
               
                   
               
               
                 111 
                 AUCUGGCAGAUGUAUAAGA 
                 344 
                 UCUUAUACAUCUGCCAGAU 
                 582 
                 AucuGGcAGAuGuAuAAGAdTsdT 
                 825 
                 pUCUuAuAcAUCUGCcAGAUdTsdT 
               
               
                   
               
               
                 112 
                 UAUAGUGCUGGUAGUAUCA 
                 345 
                 UGAUACUACCAGCACUAUA 
                 583 
                 uauAGuGcuGGuAGuAucAdTsdT 
                 747 
                 pUGAuACuACcAGcACuAuAdTsdT 
               
               
                   
               
               
                 113 
                 GGCCAGCAAGACCGCGAGG 
                 346 
                 CCUCGCGGUCUUGCUGGCC 
                 584 
                 GgccAGcAAGAccGcGAGGdTsdT 
                 706 
                 pCCUCGCGGUCUUGCUGGCCdTsdT 
               
               
                   
               
               
                 114 
                 CCAUGAUAUCUGGCAGAUG 
                 347 
                 CAUCUGCCAGAUAUCAUGG 
                 585 
                 ccAuGAuAucuGGcAGAuGdTsdT 
                 823 
                 pcAUCUGCcAGAuAUcAUGGdTsdT 
               
               
                   
               
               
                 115 
                 UUAAACUUGUGUAGACUAA 
                 348 
                 UUAGUCUACACAAGUUUAA 
                 586 
                 uuAAAcuuGuGuAGAcuAAdTsdT 
                 777 
                 pUUAGUCuAcAcAAGUUuAAdTsdT 
               
               
                   
               
               
                 115 
                 UUAAACUUGUGUAGACUAA 
                 348 
                 UUAGUCUACACAAGUUUAA 
                 586 
                 uuAAAcuuGuGuAGAcuAAdTsdT 
                 944 
                 pUuAGUCuAcAcAAGUUuAAdTsdT 
               
               
                   
               
               
                 116 
                 UUCAAUGCCAUUGAAACGA 
                 349 
                 UCGUUUCAAUGGCAUUGAA 
                 587 
                 uucAAuGccAuuGAAAcGAdTsdT 
                 844 
                 pUCGUUUcAAUGGcAUUGAAdTsdT 
               
               
                   
               
               
                 117 
                 AGAAAGCUGAGACAUUGCA 
                 350 
                 UGCAAUGUCUCAGCUUUCU 
                 588 
                 AgAAAGcuGAGAcAuuGcAdTsdT 
                 925 
                 pUGcAAUGUCUcAGCUUUCUdTsdT 
               
               
                   
               
               
                 118 
                 CUAUGGCUUCCAAAUUGCC 
                 351 
                 GGCAAUUUGGAAGCCAUAG 
                 589 
                 cuAuGGcuuccAAAuuGccdTsdT 
                 837 
                 pGGcAAUUUGGAAGCcAuAGdTsdT 
               
               
                   
               
               
                 119 
                 AAGUGACUAAAGUAAGUUA 
                 352 
                 UAACUUACUUUAGUCACUU 
                 590 
                 AaGuGAcuAAAGuAAGuuAdTsdT 
                 769 
                 puAACUuACUUuAGUcACUUdTsdT 
               
               
                   
               
               
                 120 
                 UGACUAAAGUAAGUUAAAC 
                 353 
                 GUUUAACUUACUUUAGUCA 
                 591 
                 ugAcuAAAGuAAGuuAAAcdTsdT 
                 771 
                 pGUUuAACUuACUUuAGUcAdTsdT 
               
               
                   
               
               
                 121 
                 UGCUGUUCGGAUAGAACAG 
                 354 
                 CUGUUCUAUCCGAACAGCA 
                 592 
                 ugcuGuucGGAuAGAAcAGdTsdT 
                 731 
                 pCUGUUCuAUCCGAAcAGcAdTsdT 
               
               
                   
               
               
                 122 
                 GCGAGUAUCAGAGGAUGGG 
                 355 
                 CCCAUCCUCUGAUACUCGC 
                 593 
                 GcGAGuAucAGAGGAuGGGdTsdT 
                 895 
                 pCCcAUCCUCUGAuACUCGCdTsdT 
               
               
                   
               
               
                 123 
                 GGGCCUUGCGCUGGAUUGG 
                 356 
                 CCAAUCCAGCGCAAGGCCC 
                 594 
                 GgGccuuGcGcuGGAuuGGdTsdT 
                 848 
                 pCCAAUCcAGCGcAAGGCCCdTsdT 
               
               
                   
               
               
                 124 
                 ACCUCACAACCAGUCCUGU 
                 357 
                 ACAGGACUGGUUGUGAGGU 
                 595 
                 AccucAcAAccAGuccuGudTsdT 
                 899 
                 pACAGGACUGGUUGUGAGGUdTsdT 
               
               
                   
               
               
                 124 
                 ACCUCACAACCAGUCCUGU 
                 357 
                 ACAGGACUGGUUGUGAGGU 
                 595 
                 AccucAcAAccAGuccuGudTsdT 
                 956 
                 pAcAGGACUGGUUGUGAGGUdTsdT 
               
               
                   
               
               
                 125 
                 ACUAAGUGACUAAAGUAAG 
                 358 
                 CUUACUUUAGUCACUUAGU 
                 596 
                 AcuAAGuGAcuAAAGuAAGdTsdT 
                 768 
                 pCUuACUUuAGUcACUuAGUdTsdT 
               
               
                   
               
               
                 126 
                 AUUACAGAAGCCCGCUGUU 
                 359 
                 AACAGCGGGCUUCUGUAAU 
                 597 
                 AuuAcAGAAGcccGcuGuudTsdT 
                 830 
                 pAAcAGCGGGCUUCUGuAAUdTsdT 
               
               
                   
               
               
                 127 
                 GAGUAGGCGAGUAUCAGAG 
                 360 
                 CUCUGAUACUCGCCUACUC 
                 598 
                 GaGuAGGcGAGuAucAGAGdTsdT 
                 890 
                 pCUCUGAuACUCGCCuACUCdTsdT 
               
               
                   
               
               
                 128 
                 CAGUGACAAUGGCAGUCUU 
                 361 
                 AAGACUGCCAUUGUCACUG 
                 599 
                 caGuGAcAAuGGcAGucuudTsdT 
                 904 
                 pAAGACUGCcAUUGUcACUGdTsdT 
               
               
                   
               
               
                 129 
                 GGCCUUGCGCUGGAUUGGG 
                 362 
                 CCCAAUCCAGCGCAAGGCC 
                 600 
                 GgccuuGcGcuGGAuuGGGdTsdT 
                 849 
                 pCCcAAUCcAGCGcAAGGCCdTsdT 
               
               
                   
               
               
                 130 
                 UUCUUAUUGACACUUACAU 
                 363 
                 AUGUAAGUGUCAAUAAGAA 
                 601 
                 uucuuAuuGAcAcuuAcAudTsdT 
                 843 
                 pAUGuAAGUGUcAAuAAGAAdTsdT 
               
               
                   
               
               
                 131 
                 UUCACUAAGUGACUAAAGU 
                 364 
                 ACUUUAGUCACUUAGUGAA 
                 602 
                 uucAcuAAGuGAcuAAAGudTsdT 
                 765 
                 pACUUuAGUcACUuAGUGAAdTsdT 
               
               
                   
               
               
                 132 
                 GUGUGAGUUAAUUCAUUUA 
                 365 
                 UAAAUGAAUUAACUCACAC 
                 603 
                 GuGuGAGuuAAuucAuuuAdTsdT 
                 791 
                 puAAAUGAAUuAACUcAcACdTsdT 
               
               
                   
               
               
                 133 
                 CCCGCUCGCGCCCAUCACG 
                 366 
                 CGUGAUGGGCGCGAGCGGG 
                 604 
                 cccGcucGcGcccAucAcGdTsdT 
                 813 
                 pCGUGAUGGGCGCGAGCGGGdTsdT 
               
               
                   
               
               
                 134 
                 GUAAGUUAAACUUGUGUAG 
                 367 
                 CUACACAAGUUUAACUUAC 
                 605 
                 GuAAGuuAAAcuuGuGuAGdTsdT 
                 775 
                 pCUAcAcAAGUUuAACUuACdTsdT 
               
               
                   
               
               
                 134 
                 GUAAGUUAAACUUGUGUAG 
                 367 
                 CUACACAAGUUUAACUUAC 
                 605 
                 GuAAGuuAAAcuuGuGuAGdTsdT 
                 943 
                 pCuAcAcAAGUUuAACUuACdTsdT 
               
               
                   
               
               
                 135 
                 CGGAAGUUGGAAUCAGGUU 
                 368 
                 AACCUGAUUCCAACUUCCG 
                 606 
                 cgGAAGuuGGAAucAGGuudTsdT 
                 931 
                 pAACCUGAUUCcAACUUCCGdTsdT 
               
               
                   
               
               
                 136 
                 AUGUGAGGAUUAACUUCUG 
                 369 
                 CAGAAGUUAAUCCUCACAU 
                 607 
                 AuGuGAGGAuuAAcuucuGdTsdT 
                 810 
                 pcAGAAGUuAAUCCUcAcAUdTsdT 
               
               
                   
               
               
                 137 
                 UUAAGUGGUGAAAUCAACU 
                 370 
                 AGUUGAUUUCACCACUUAA 
                 608 
                 uuAAGuGGuGAAAucAAcudTsdT 
                 919 
                 pAGUUGAUUUcACcACUuAAdTsdT 
               
               
                   
               
               
                 138 
                 UGUAGACUAAGCAUGUAAU 
                 371 
                 AUUACAUGCUUAGUCUACA 
                 609 
                 uguAGAcuAAGcAuGuAAudTsdT 
                 783 
                 pAUuAcAUGCUuAGUCuAcAdTsdT 
               
               
                   
               
               
                 139 
                 AUAAUGUGAGGAUUAACUU 
                 372 
                 AAGUUAAUCCUCACAUUAU 
                 610 
                 AuAAuGuGAGGAuuAAcuudTsdT 
                 934 
                 pAAGUuAAUCCUcAcAUuAUdTsdT 
               
               
                   
               
               
                 140 
                 GGCUGGCUGUGACUUACCA 
                 373 
                 UGGUAAGUCACAGCCAGCC 
                 611 
                 GgcuGGcuGuGAcuuAccAdTsdT 
                 901 
                 pUGGuAAGUcAcAGCcAGCCdTsdT 
               
               
                   
               
               
                 141 
                 AAGAGGCUACCUAUGGUGA 
                 374 
                 UCACCAUAGGUAGCCUCUU 
                 612 
                 AaGAGGcuAccuAuGGuGAdTsdT 
                 850 
                 pUCACcAuAGGuAGCCUCUUdTsdT 
               
               
                   
               
               
                 141 
                 AAGAGGCUACCUAUGGUGA 
                 374 
                 UCACCAUAGGUAGCCUCUU 
                 612 
                 AaGAGGcuAccuAuGGuGAdTsdT 
                 951 
                 pUcACcAuAGGuAGCCUCUUdTsdT 
               
               
                   
               
               
                 142 
                 CAGAUUACAGAAGCCCGCU 
                 375 
                 AGCGGGCUUCUGUAAUCUG 
                 613 
                 caGAuuAcAGAAGcccGcudTsdT 
                 829 
                 pAGCGGGCUUCUGuAAUCUGdTsdT 
               
               
                   
               
               
                 143 
                 UGAGGCCUUGCCUGUGAAG 
                 376 
                 CUUCACAGGCAAGGCCUCA 
                 614 
                 ugAGGccuuGccuGuGAAGdTsdT 
                 869 
                 pCUUcAcAGGcAAGGCCUcAdTsdT 
               
               
                   
               
               
                 144 
                 AUAAUUAUCAAUGCUGUUC 
                 377 
                 GAACAGCAUUGAUAAUUAU 
                 615 
                 AuAAuuAucAAuGcuGuucdTsdT 
                 726 
                 pGAAcAGcAUUGAuAAUuAUdTsdT 
               
               
                   
               
               
                 145 
                 GUGACUUACCAUAGCAGUG 
                 466 
                 CACUGCUAUGGUAAGUCAC 
                 616 
                 GuGAcuuAccAuAGcAGuGdTsdT 
                 753 
                 pcACUGCuAUGGuAAGUcACdTsdT 
               
               
                   
               
               
                 146 
                 UAGGGCUACUUUGAAUUAA 
                 378 
                 UUAAUUCAAAGUAGCCCUA 
                 617 
                 uaGGGcuAcuuuGAAuuAAdTsdT 
                 795 
                 pUUAAUUcAAAGuAGCCCuAdTsdT 
               
               
                   
               
               
                 146 
                 UAGGGCUACUUUGAAUUAA 
                 378 
                 UUAAUUCAAAGUAGCCCUA 
                 617 
                 uaGGGcuAcuuuGAAuuAAdTsdT 
                 946 
                 pUuAAUUcAAAGuAGCCCuAdTsdT 
               
               
                   
               
               
                 147 
                 UGGCAGAUGUAUAAGAAGG 
                 379 
                 CCUUCUUAUACAUCUGCCA 
                 618 
                 ugGcAGAuGuAuAAGAAGGdTsdT 
                 826 
                 pCCUUCUuAuAcAUCUGCcAdTsdT 
               
               
                   
               
               
                 148 
                 AUAGCUUGAUUUAUUUGGU 
                 380 
                 ACCAAAUAAAUCAAGCUAU 
                 619 
                 AuAGcuuGAuuuAuuuGGudTsdT 
                 759 
                 pACcAAAuAAAUcAAGCuAUdTsdT 
               
               
                   
               
               
                 149 
                 CAGCAAGACCGCGAGGAGG 
                 381 
                 CCUCCUCGCGGUCUUGCUG 
                 620 
                 caGcAAGAccGcGAGGAGGdTsdT 
                 707 
                 pCCUCCUCGCGGUCUUGCUGdTsdT 
               
               
                   
               
               
                 150 
                 GACUGAUGCCUGGCCUCAC 
                 382 
                 GUGAGGCCAGGCAUCAGUC 
                 621 
                 GacuGAuGccuGGccucAcdTsdT 
                 854 
                 pGUGAGGCcAGGcAUcAGUCdTsdT 
               
               
                   
               
               
                 151 
                 UUACCUUGGAUGCUGACUU 
                 383 
                 AAGUCAGCAUCCAAGGUAA 
                 622 
                 uuAccuuGGAuGcuGAcuudTsdT 
                 897 
                 pAAGUcAGcAUCcAAGGuAAdTsdT 
               
               
                   
               
               
                 152 
                 AUUCAGCACUGGGAAUCCC 
                 384 
                 GGGAUUCCCAGUGCUGAAU 
                 623 
                 AuucAGcAcuGGGAAucccdTsdT 
                 709 
                 pGGGAUUCCcAGUGCUGAAUdTsdT 
               
               
                   
               
               
                 153 
                 AGCAAGACCGCGAGGAGGA 
                 385 
                 UCCUCCUCGCGGUCUUGCU 
                 624 
                 AgcAAGAccGcGAGGAGGAdTsdT 
                 814 
                 pUCCUCCUCGCGGUCUUGCUdTsdT 
               
               
                   
               
               
                 154 
                 AGGGCUACUUUGAAUUAAU 
                 386 
                 AUUAAUUCAAAGUAGCCCU 
                 625 
                 AgGGcuAcuuuGAAuuAAudTsdT 
                 796 
                 pAUuAAUUcAAAGuAGCCCUdTsdT 
               
               
                   
               
               
                 155 
                 UAAGUUAUUGUUACCUAAA 
                 387 
                 UUUAGGUAACAAUAACUUA 
                 626 
                 uaAGuuAuuGuuAccuAAAdTsdT 
                 799 
                 pUUuAGGuAAcAAuAACUuAdTsdT 
               
               
                   
               
               
                 156 
                 UUUAUAGUGCUGGUAGUAU 
                 388 
                 AUACUACCAGCACUAUAAA 
                 627 
                 uuuAuAGuGcuGGuAGuAudTsdT 
                 900 
                 pAUACuACcAGcACuAuAAAdTsdT 
               
               
                   
               
               
                 156 
                 UUUAUAGUGCUGGUAGUAU 
                 388 
                 AUACUACCAGCACUAUAAA 
                 627 
                 uuuAuAGuGcuGGuAGuAudTsdT 
                 957 
                 pAuACuACcAGcACuAuAAAdTsdT 
               
               
                   
               
               
                 157 
                 GCAAGACCGCGAGGAGGAU 
                 389 
                 AUCCUCCUCGCGGUCUUGC 
                 628 
                 GcAAGAccGcGAGGAGGAudTsdT 
                 815 
                 pAUCCUCCUCGCGGUCUUGCdTsdT 
               
               
                   
               
               
                 158 
                 UCUAUGGCUUCCAAAUUGC 
                 390 
                 GCAAUUUGGAAGCCAUAGA 
                 629 
                 ucuAuGGcuuccAAAuuGcdTsdT 
                 836 
                 pGCAAUUUGGAAGCcAuAGAdTsdT 
               
               
                   
               
               
                 159 
                 AAAGACUAACUUCUUUGAG 
                 391 
                 CUCAAAGAAGUUAGUCUUU 
                 630 
                 AaAGAcuAAcuucuuuGAGdTsdT 
                 886 
                 pCUcAAAGAAGUuAGUCUUUdTsdT 
               
               
                   
               
               
                 160 
                 ACCAUGAUAUCUGGCAGAU 
                 392 
                 AUCUGCCAGAUAUCAUGGU 
                 631 
                 AccAuGAuAucuGGcAGAudTsdT 
                 822 
                 pAUCUGCcAGAuAUcAUGGUdTsdT 
               
               
                   
               
               
                 161 
                 GACCAUUUCCUAAUCAGUU 
                 393 
                 AACUGAUUAGGAAAUGGUC 
                 632 
                 GaccAuuuccuAAucAGuudTsdT 
                 811 
                 pAACUGAUuAGGAAAUGGUCdTsdT 
               
               
                   
               
               
                 162 
                 UUACCAUAGCAGUGACAAU 
                 394 
                 AUUGUCACUGCUAUGGUAA 
                 633 
                 uuAccAuAGcAGuGAcAAudTsdT 
                 754 
                 pAUUGUcACUGCuAUGGuAAdTsdT 
               
               
                   
               
               
                 163 
                 AAUGUGAGGAUUAACUUCU 
                 395 
                 AGAAGUUAAUCCUCACAUU 
                 634 
                 AauGuGAGGAuuAAcuucudTsdT 
                 809 
                 pAGAAGUuAAUCCUcAcAUUdTsdT 
               
               
                   
               
               
                 164 
                 UAGUGUCCUGGGAUUCUCU 
                 396 
                 AGAGAAUCCCAGGACACUA 
                 635 
                 uaGuGuccuGGGAuucucudTsdT 
                 916 
                 pAGAGAAUCCcAGGAcACuAdTsdT 
               
               
                   
               
               
                 165 
                 UGUUAAGUGGUGAAAUCAA 
                 397 
                 UUGAUUUCACCACUUAACA 
                 636 
                 uguuAAGuGGuGAAAucAAdTsdT 
                 918 
                 pUUGAUUUcACcACUuAAcAdTsdT 
               
               
                   
               
               
                 166 
                 ACAAAUAUUCUUAAUAGGG 
                 398 
                 CCCUAUUAAGAAUAUUUGU 
                 637 
                 AcAAAuAuucuuAAuAGGGdTsdT 
                 792 
                 pCCCuAUuAAGAAuAUUUGUdTsdT 
               
               
                   
               
               
                 167 
                 GCGGAAGUUGGAAUCAGGU 
                 399 
                 ACCUGAUUCCAACUUCCGC 
                 638 
                 GcGGAAGuuGGAAucAGGudTsdT 
                 930 
                 pACCUGAUUCcAACUUCCGCdTsdT 
               
               
                   
               
               
                 168 
                 AACUUGUGUAGACUAAGCA 
                 400 
                 UGCUUAGUCUACACAAGUU 
                 639 
                 AacuuGuGuAGAcuAAGcAdTsdT 
                 780 
                 pUGCUuAGUCuAcAcAAGUUdTsdT 
               
               
                   
               
               
                 169 
                 AUUCUUAAUAGGGCUACUU 
                 401 
                 AAGUAGCCCUAUUAAGAAU 
                 640 
                 AuucuuAAuAGGGcuAcuudTsdT 
                 794 
                 pAAGuAGCCCuAUuAAGAAUdTsdT 
               
               
                   
               
               
                 170 
                 CCUAAAGUUAAUCCAGAUU 
                 402 
                 AAUCUGGAUUAACUUUAGG 
                 641 
                 ccuAAAGuuAAuccAGAuudTsdT 
                 929 
                 pAAUCUGGAUuAACUUuAGGdTsdT 
               
               
                   
               
               
                 171 
                 UAUUGUUACCUAAAGUUAA 
                 403 
                 UUAACUUUAGGUAACAAUA 
                 642 
                 uauuGuuAccuAAAGuuAAdTsdT 
                 803 
                 pUUAACUUuAGGuAAcAAuAdTsdT 
               
               
                   
               
               
                 171 
                 UAUUGUUACCUAAAGUUAA 
                 403 
                 UUAACUUUAGGUAACAAUA 
                 642 
                 uauuGuuAccuAAAGuuAAdTsdT 
                 947 
                 pUuAACUUuAGGuAAcAAuAdTsdT 
               
               
                   
               
               
                 172 
                 GUGCUGGUAGUAUCACCUU 
                 404 
                 AAGGUGAUACUACCAGCAC 
                 643 
                 GuGcuGGuAGuAucAccuudTsdT 
                 750 
                 pAAGGUGAuACuACcAGcACdTsdT 
               
               
                   
               
               
                 173 
                 CUGUGACUUACCAUAGCAG 
                 405 
                 CUGCUAUGGUAAGUCACAG 
                 644 
                 cuGuGAcuuAccAuAGcAGdTsdT 
                 752 
                 pCUGCuAUGGuAAGUcAcAGdTsdT 
               
               
                   
               
               
                 174 
                 GAGCUUCUUAAGUUAAAUC 
                 406 
                 GAUUUAACUUAAGAAGCUC 
                 645 
                 GaGcuucuuAAGuuAAAucdTsdT 
                 917 
                 pGAUUuAACUuAAGAAGCUCdTsdT 
               
               
                   
               
               
                 175 
                 CUGUUCGGAUAGAACAGGA 
                 407 
                 UCCUGUUCUAUCCGAACAG 
                 646 
                 cuGuucGGAuAGAAcAGGAdTsdT 
                 732 
                 pUCCUGUUCuAUCCGAAcAGdTsdT 
               
               
                   
               
               
                 176 
                 GUUAUUGUUACCUAAAGUU 
                 408 
                 AACUUUAGGUAACAAUAAC 
                 647 
                 GuuAuuGuuAccuAAAGuudTsdT 
                 801 
                 pAACUUuAGGuAAcAAuAACdTsdT 
               
               
                   
               
               
                 177 
                 UAAUGUGAGGAUUAACUUC 
                 409 
                 GAAGUUAAUCCUCACAUUA 
                 648 
                 uaAuGuGAGGAuuAAcuucdTsdT 
                 935 
                 pGAAGUuAAUCCUcAcAUuAdTsdT 
               
               
                   
               
               
                 178 
                 ACCACUAAUGGGAGCCAAU 
                 410 
                 AUUGGCUCCCAUUAGUGGU 
                 649 
                 AccAcuAAuGGGAGccAAudTsdT 
                 764 
                 pAUUGGCUCCcAUuAGUGGUdTsdT 
               
               
                   
               
               
                 179 
                 UGUGUAGACUAAGCAUGUA 
                 411 
                 UACAUGCUUAGUCUACACA 
                 650 
                 uguGuAGAcuAAGcAuGuAdTsdT 
                 782 
                 puAcAUGCUuAGUCuAcAcAdTsdT 
               
               
                   
               
               
                 180 
                 UGGGCCUUGCGCUGGAUUG 
                 412 
                 CAAUCCAGCGCAAGGCCCA 
                 651 
                 ugGGccuuGcGcuGGAuuGdTsdT 
                 847 
                 pcAAUCcAGCGcAAGGCCcAdTsdT 
               
               
                   
               
               
                 181 
                 AGGAGCUUCUUAAGUUAAA 
                 413 
                 UUUAACUUAAGAAGCUCCU 
                 652 
                 AgGAGcuucuuAAGuuAAAdTsdT 
                 788 
                 pUUuAACUuAAGAAGCUCCUdTsdT 
               
               
                   
               
               
                 182 
                 GGUGACCCUUUAGUGAGCU 
                 414 
                 AGCUCACUAAAGGGUCACC 
                 653 
                 GguGAcccuuuAGuGAGcudTsdT 
                 757 
                 pAGCUcACuAAAGGGUcACCdTsdT 
               
               
                   
               
               
                 183 
                 AGAGUAGGCGAGUAUCAGA 
                 415 
                 UCUGAUACUCGCCUACUCU 
                 654 
                 AgAGuAGGcGAGuAucAGAdTsdT 
                 889 
                 pUCUGAuACUCGCCuACUCUdTsdT 
               
               
                   
               
               
                 184 
                 GCAGUGACAAUGGCAGUCU 
                 416 
                 AGACUGCCAUUGUCACUGC 
                 655 
                 GcAGuGAcAAuGGcAGucudTsdT 
                 903 
                 pAGACUGCcAUUGUcACUGCdTsdT 
               
               
                   
               
               
                 185 
                 AAACGAUGCCUUGUGUCAA 
                 417 
                 UUGACACAAGGCAUCGUUU 
                 656 
                 AaAcGAuGccuuGuGucAAdTsdT 
                 719 
                 pUUGAcAcAAGGcAUCGUUUdTsdT 
               
               
                   
               
               
                 186 
                 GGACUGAUGCCUGGCCUCA 
                 418 
                 UGAGGCCAGGCAUCAGUCC 
                 657 
                 GgAcuGAuGccuGGccucAdTsdT 
                 853 
                 pUGAGGCcAGGcAUcAGUCCdTsdT 
               
               
                   
               
               
                 187 
                 UGAGAGAUAAAUGUUGAUC 
                 419 
                 GAUCAACAUUUAUCUCUCA 
                 658 
                 ugAGAGAuAAAuGuuGAucdTsdT 
                 797 
                 pGAUcAAcAUUuAUCUCUcAdTsdT 
               
               
                   
               
               
                 188 
                 UGGUUUCUACACCAAAUAC 
                 420 
                 GUAUUUGGUGUAGAAACCA 
                 659 
                 ugGuuucuAcAccAAAuAcdTsdT 
                 760 
                 pGUAUUUGGUGuAGAAACcAdTsdT 
               
               
                   
               
               
                 188 
                 UGGUUUCUACACCAAAUAC 
                 420 
                 GUAUUUGGUGUAGAAACCA 
                 659 
                 ugGuuucuAcAccAAAuAcdTsdT 
                 941 
                 pGuAUUUGGUGuAGAAACcAdTsdT 
               
               
                   
               
               
                 189 
                 UCUCUGUAAUAUGAUACAU 
                 421 
                 AUGUAUCAUAUUACAGAGA 
                 660 
                 ucucuGuAAuAuGAuAcAudTsdT 
                 927 
                 pAUGuAUcAuAUuAcAGAGAdTsdT 
               
               
                   
               
               
                 190 
                 GAGAGAUAAAUGUUGAUCU 
                 422 
                 AGAUCAACAUUUAUCUCUC 
                 661 
                 GaGAGAuAAAuGuuGAucudTsdT 
                 926 
                 pAGAUcAAcAUUuAUCUCUCdTsdT 
               
               
                   
               
               
                 191 
                 ACUCUAAUGAAGCAAUACA 
                 423 
                 UGUAUUGCUUCAUUAGAGU 
                 662 
                 AcucuAAuGAAGcAAuAcAdTsdT 
                 736 
                 pUGuAUUGCUUcAUuAGAGUdTsdT 
               
               
                   
               
               
                 192 
                 UGAAGUGUUACCAACUAGC 
                 424 
                 GCUAGUUGGUAACACUUCA 
                 663 
                 ugAAGuGuuAccAAcuAGcdTsdT 
                 743 
                 pGCuAGUUGGuAAcACUUcAdTsdT 
               
               
                   
               
               
                 193 
                 AAUGAAGCAAUACAUUGAG 
                 425 
                 CUCAAUGUAUUGCUUCAUU 
                 664 
                 AauGAAGcAAuAcAuuGAGdTsdT 
                 873 
                 pCUcAAUGuAUUGCUUcAUUdTsdT 
               
               
                   
               
               
                 194 
                 ACGAUGCCUUGUGUCAAGA 
                 426 
                 UCUUGACACAAGGCAUCGU 
                 665 
                 AcGAuGccuuGuGucAAGAdTsdT 
                 720 
                 pUCUUGAcAcAAGGcAUCGUdTsdT 
               
               
                   
               
               
                 195 
                 AGACCGCGAGGAGGAUCUU 
                 427 
                 AAGAUCCUCCUCGCGGUCU 
                 666 
                 AgAccGcGAGGAGGAucuudTsdT 
                 817 
                 pAAGAUCCUCCUCGCGGUCUdTsdT 
               
               
                   
               
               
                 196 
                 UUGUUACCUAAAGUUAAUC 
                 428 
                 GAUUAACUUUAGGUAACAA 
                 667 
                 uuGuuAccuAAAGuuAAucdTsdT 
                 804 
                 pGAUuAACUUuAGGuAAcAAdTsdT 
               
               
                   
               
               
                 197 
                 CAGAAGCCCGCUGUUUCUA 
                 429 
                 UAGAAACAGCGGGCUUCUG 
                 668 
                 caGAAGcccGcuGuuucuAdTsdT 
                 833 
                 puAGAAAcAGCGGGCUUCUGdTsdT 
               
               
                   
               
               
                 198 
                 UUUGACUUUAUGGAGAAUA 
                 430 
                 UAUUCUCCAUAAAGUCAAA 
                 669 
                 uuuGAcuuuAuGGAGAAuAdTsdT 
                 883 
                 puAUUCUCcAuAAAGUcAAAdTsdT 
               
               
                   
               
               
                 199 
                 UACCUAAAGUUAAUCCAGA 
                 431 
                 UCUGGAUUAACUUUAGGUA 
                 670 
                 uaccuAAAGuuAAuccAGAdTsdT 
                 807 
                 pUCUGGAUuAACUUuAGGuAdTsdT 
               
               
                   
               
               
                 200 
                 UUCAAACACCUGGUACACA 
                 432 
                 UGUGUACCAGGUGUUUGAA 
                 671 
                 uucAAAcAccuGGuAcAcAdTsdT 
                 864 
                 pUGUGuACcAGGUGUUUGAAdTsdT 
               
               
                   
               
               
                 201 
                 UUGCACUCUAAUGAAGCAA 
                 433 
                 UUGCUUCAUUAGAGUGCAA 
                 672 
                 uuGcAcucuAAuGAAGcAAdTsdT 
                 870 
                 pUUGCUUcAUuAGAGUGcAAdTsdT 
               
               
                   
               
               
                 202 
                 UGUUACCUAAAGUUAAUCC 
                 434 
                 GGAUUAACUUUAGGUAACA 
                 673 
                 uguuAccuAAAGuuAAuccdTsdT 
                 805 
                 pGGAUuAACUUuAGGuAAcAdTsdT 
               
               
                   
               
               
                 203 
                 CACUAAGUGACUAAAGUAA 
                 435 
                 UUACUUUAGUCACUUAGUG 
                 674 
                 cacuAAGuGAcuAAAGuAAdTsdT 
                 767 
                 pUUACUUuAGUcACUuAGUGdTsdT 
               
               
                   
               
               
                 203 
                 CACUAAGUGACUAAAGUAA 
                 435 
                 UUACUUUAGUCACUUAGUG 
                 674 
                 cacuAAGuGAcuAAAGuAAdTsdT 
                 942 
                 pUuACUUuAGUcACUuAGUGdTsdT 
               
               
                   
               
               
                 204 
                 UGCCAGAUAGAAGACAGGU 
                 436 
                 ACCUGUCUUCUAUCUGGCA 
                 675 
                 ugccAGAuAGAAGAcAGGudTsdT 
                 786 
                 pACCUGUCUUCuAUCUGGcAdTsdT 
               
               
                   
               
               
                 205 
                 AAUGUAUAGUCUUCUUAUU 
                 437 
                 AAUAAGAAGACUAUACAUU 
                 676 
                 AauGuAuAGucuucuuAuudTsdT 
                 840 
                 pAAuAAGAAGACuAuAcAUUdTsdT 
               
               
                   
               
               
                 206 
                 GACCACUAAUGGGAGCCAA 
                 438 
                 UUGGCUCCCAUUAGUGGUC 
                 677 
                 GaccAcuAAuGGGAGccAAdTsdT 
                 914 
                 pUUGGCUCCcAUuAGUGGUCdTsdT 
               
               
                   
               
               
                 207 
                 GUUACCUAAAGUUAAUCCA 
                 439 
                 UGGAUUAACUUUAGGUAAC 
                 678 
                 GuuAccuAAAGuuAAuccAdTsdT 
                 928 
                 pUGGAUuAACUUuAGGuAACdTsdT 
               
               
                   
               
               
                 208 
                 UGAUGCCUGGCCUCACAUU 
                 440 
                 AAUGUGAGGCCAGGCAUCA 
                 679 
                 ugAuGccuGGccucAcAuudTsdT 
                 855 
                 pAAUGUGAGGCcAGGcAUcAdTsdT 
               
               
                   
               
               
                 209 
                 CCAACUUUAAAGUCAGUCC 
                 441 
                 GGACUGACUUUAAAGUUGG 
                 680 
                 ccAAcuuuAAAGucAGuccdTsdT 
                 915 
                 pGGACUGACUUuAAAGUUGGdTsdT 
               
               
                   
               
               
                 210 
                 UAAACUUGUGUAGACUAAG 
                 442 
                 CUUAGUCUACACAAGUUUA 
                 681 
                 uaAAcuuGuGuAGAcuAAGdTsdT 
                 778 
                 pCUuAGUCuAcAcAAGUUuAdTsdT 
               
               
                   
               
               
                 211 
                 AGUAGGUUGUGUGAGUUAA 
                 443 
                 UUAACUCACACAACCUACU 
                 682 
                 AguAGGuuGuGuGAGuuAAdTsdT 
                 920 
                 pUUAACUcAcAcAACCuACUdTsdT 
               
               
                   
               
               
                 211 
                 AGUAGGUUGUGUGAGUUAA 
                 443 
                 UUAACUCACACAACCUACU 
                 682 
                 AguAGGuuGuGuGAGuuAAdTsdT 
                 958 
                 pUuAACUcAcAcAACCuACUdTsdT 
               
               
                   
               
               
                 212 
                 GUUAAACUUGUGUAGACUA 
                 444 
                 UAGUCUACACAAGUUUAAC 
                 683 
                 GuuAAAcuuGuGuAGAcuAdTsdT 
                 776 
                 puAGUCuAcAcAAGUUuAACdTsdT 
               
               
                   
               
               
                 213 
                 CUGACCACUAAUGGGAGCC 
                 445 
                 GGCUCCCAUUAGUGGUCAG 
                 684 
                 cuGAccAcuAAuGGGAGccdTsdT 
                 762 
                 pGGCUCCcAUuAGUGGUcAGdTsdT 
               
               
                   
               
               
                 214 
                 UAUUCUUAAUAGGGCUACU 
                 446 
                 AGUAGCCCUAUUAAGAAUA 
                 685 
                 uauucuuAAuAGGGcuAcudTsdT 
                 793 
                 pAGuAGCCCuAUuAAGAAuAdTsdT 
               
               
                   
               
               
                 215 
                 GUAGUGUCCUGGGAUUCUC 
                 447 
                 GAGAAUCCCAGGACACUAC 
                 686 
                 GuAGuGuccuGGGAuucucdTsdT 
                 787 
                 pGAGAAUCCcAGGAcACuACdTsdT 
               
               
                   
               
               
                 216 
                 UAUCUGGCAGAUGUAUAAG 
                 448 
                 CUUAUACAUCUGCCAGAUA 
                 687 
                 uaucuGGcAGAuGuAuAAGdTsdT 
                 824 
                 pCUuAuAcAUCUGCcAGAuAdTsdT 
               
               
                   
               
               
                 217 
                 AGGCUACCUAUGGUGAACG 
                 449 
                 CGUUCACCAUAGGUAGCCU 
                 688 
                 AgGcuAccuAuGGuGAAcGdTsdT 
                 721 
                 pCGUUcACcAuAGGuAGCCUdTsdT 
               
               
                   
               
               
                 218 
                 UCAGACCAUUUCCUAAUCA 
                 450 
                 UGAUUAGGAAAUGGUCUGA 
                 689 
                 ucAGAccAuuuccuAAucAdTsdT 
                 936 
                 pUGAUuAGGAAAUGGUCUGAdTsdT 
               
               
                   
               
               
                 219 
                 UUACCUAAAGUUAAUCCAG 
                 451 
                 CUGGAUUAACUUUAGGUAA 
                 690 
                 uuAccuAAAGuuAAuccAGdTsdT 
                 806 
                 pCUGGAUuAACUUuAGGuAAdTsdT 
               
               
                   
               
               
                 220 
                 GGUUUCUACACCAAAUACA 
                 452 
                 UGUAUUUGGUGUAGAAACC 
                 691 
                 GguuucuAcAccAAAuAcAdTsdT 
                 761 
                 pUGuAUUUGGUGuAGAAACCdTsdT 
               
               
                   
               
               
                 221 
                 GUUGGUGCCAGAUAGAAGA 
                 453 
                 UCUUCUAUCUGGCACCAAC 
                 692 
                 GuuGGuGccAGAuAGAAGAdTsdT 
                 785 
                 pUCUUCuAUCUGGcACcAACdTsdT 
               
               
                   
               
               
                 222 
                 GCUACCUAUGGUGAACGUG 
                 454 
                 CACGUUCACCAUAGGUAGC 
                 693 
                 GcuAccuAuGGuGAAcGuGdTsdT 
                 723 
                 pcACGUUcACcAuAGGuAGCdTsdT 
               
               
                   
               
               
                 223 
                 UCACUAAGUGACUAAAGUA 
                 455 
                 UACUUUAGUCACUUAGUGA 
                 694 
                 ucAcuAAGuGAcuAAAGuAdTsdT 
                 766 
                 puACUUuAGUcACUuAGUGAdTsdT 
               
               
                   
               
               
                 224 
                 UUAUUGUUACCUAAAGUUA 
                 456 
                 UAACUUUAGGUAACAAUAA 
                 695 
                 uuAuuGuuAccuAAAGuuAdTsdT 
                 802 
                 puAACUUuAGGuAAcAAuAAdTsdT 
               
               
                   
               
               
                 225 
                 UAGCUGAAUAAUGUGAGGA 
                 457 
                 UCCUCACAUUAUUCAGCUA 
                 696 
                 uaGcuGAAuAAuGuGAGGAdTsdT 
                 808 
                 pUCCUcAcAUuAUUcAGCuAdTsdT 
               
               
                   
               
               
                 226 
                 UGACCACUAAUGGGAGCCA 
                 458 
                 UGGCUCCCAUUAGUGGUCA 
                 697 
                 ugAccAcuAAuGGGAGccAdTsdT 
                 763 
                 pUGGCUCCcAUuAGUGGUcAdTsdT 
               
               
                   
               
               
                 227 
                 GUAGCUACCUCACAACCAG 
                 459 
                 CUGGUUGUGAGGUAGCUAC 
                 698 
                 GuAGcuAccucAcAAccAGdTsdT 
                 898 
                 pCUGGUUGUGAGGuAGCuACdTsdT 
               
               
                   
               
               
                 228 
                 UCCCGCUCGCGCCCAUCAC 
                 460 
                 GUGAUGGGCGCGAGCGGGA 
                 699 
                 ucccGcucGcGcccAucAcdTsdT 
                 812 
                 pGUGAUGGGCGCGAGCGGGAdTsdT 
               
               
                   
               
               
                 229 
                 CUUGGCUUUAAAGUGAGGG 
                 461 
                 CCCUCACUUUAAAGCCAAG 
                 700 
                 cuuGGcuuuAAAGuGAGGGdTsdT 
                 906 
                 pCCCUcACUUuAAAGCcAAGdTsdT 
               
               
                   
               
               
                 230 
                 AGAAGCCCGCUGUUUCUAU 
                 462 
                 AUAGAAACAGCGGGCUUCU 
                 701 
                 AgAAGcccGcuGuuucuAudTsdT 
                 834 
                 pAUAGAAAcAGCGGGCUUCUdTsdT 
               
               
                   
               
               
                 230 
                 AGAAGCCCGCUGUUUCUAU 
                 462 
                 AUAGAAACAGCGGGCUUCU 
                 701 
                 AgAAGcccGcuGuuucuAudTsdT 
                 948 
                 pAuAGAAAcAGCGGGCUUCUdTsdT 
               
               
                   
               
               
                 231 
                 ACUAAAGUAAGUUAAACUU 
                 463 
                 AAGUUUAACUUACUUUAGU 
                 702 
                 AcuAAAGuAAGuuAAAcuudTsdT 
                 773 
                 pAAGUUuAACUuACUUuAGUdTsdT 
               
               
                   
               
               
                 232 
                 AGUAAGUUAAACUUGUGUA 
                 464 
                 UACACAAGUUUAACUUACU 
                 703 
                 AguAAGuuAAAcuuGuGuAdTsdT 
                 774 
                 puAcAcAAGUUuAACUuACUdTsdT 
               
               
                   
               
               
                 233 
                 AAUAAUUAUCAAUGCUGUU 
                 465 
                 AACAGCAUUGAUAAUUAUU 
                 704 
                 AauAAuuAucAAuGcuGuudTsdT 
                 725 
                 pAAcAGcAUUGAuAAUuAUUdTsdT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 6 
               
               
                   
               
               
                   
                   
                   
                 SEQ ID 
               
               
                 FPL Name 
                 Function 
                 Sequence 
                 No. 
               
               
                   
               
             
            
               
                 hsRRM001 
                 CE 
                 cgggtttcagggattcccagTTTTTctcttggaaagaaagt 
                  997 
               
               
                   
               
               
                 hsRRM002 
                 CE 
                 gcttgctgcaaagaaagccaTTTTTctcttggaaagaaagt 
                  998 
               
               
                   
               
               
                 hsRRM003 
                 CE 
                 cttcttggctaaatcgctccaTTTTTctcttggaaagaaagt 
                  999 
               
               
                   
               
               
                 hsRRM004 
                 CE 
                 agcgggcttctgtaatctgaaTTTTTctcttggaaagaaagt 
                 1000 
               
               
                   
               
               
                 hsRRM005 
                 CE 
                 gagaaattccctttctttgggaTTTTTctcttggaaagaaagt 
                 1001 
               
               
                   
               
               
                 hsRRM006 
                 CE 
                 ggtagcctctttgtccccaatTTTTTctcttggaaagaaagt 
                 1002 
               
               
                   
               
               
                 hsRRM007 
                 LE 
                 gaacatgggatataaaatatctctcctTTTTTaggcataggacccgtgtct 
                 1003 
               
               
                   
               
               
                 hsRRM008 
                 LE 
                 ccaagttttcatttactatgccatcTTTTTaggcataggacccgtgtct 
                 1004 
               
               
                   
               
               
                 hsRRM009 
                 LE 
                 catttcagaatgtatgttttccatgTTTTTaggcataggacccgtgtct 
                 1005 
               
               
                   
               
               
                 hsRRM010 
                 LE 
                 catcgtttcaatggcattgaaTTTTTaggcataggacccgtgtct 
                 1006 
               
               
                   
               
               
                 hsRRM011 
                 LE 
                 ccagcgcaaggcccagtTTTTTaggcataggacccgtgtct 
                 1007 
               
               
                   
               
               
                 hsRRM012 
                 LE 
                 aaggctacaacacgttcaccataTTTTTaggcataggacccgtgtct 
                 1008 
               
               
                   
               
               
                 hsRRM013 
                 LE 
                 aatgccttccactgcagcaTTTTTaggcataggacccgtgtct 
                 1009 
               
               
                   
               
               
                 hsRRM014 
                 BL 
                 gcaatttggaagccatagaaac 
                 1010 
               
               
                   
               
               
                 hsRRM015 
                 BL 
                 tcttttatgtaagtgtcaataagaagactata 
                 1011 
               
               
                   
               
               
                 hsRRM016 
                 BL 
                 ctgccttcttcttgacacaagg 
                 1012 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                   
                 SEQ ID 
               
               
                 FPL Name 
                 Function 
                 Sequence 
                 No. 
               
               
                   
               
             
            
               
                 hGAP001 
                 CE 
                 gaatttgccatgggtggaatTTTTTctcttggaaagaaagt 
                 986 
               
               
                   
               
               
                 hGAP002 
                 CE 
                 ggagggatctcgctcctggaTTTTTctcttggaaagaaagt 
                 987 
               
               
                   
               
               
                 hGAP003 
                 CE 
                 ccccagccttctccatggtTTTTTctcttggaaagaaagt 
                 988 
               
               
                   
               
               
                 hGAP004 
                 CE 
                 gctcccccctgcaaatgagTTTTTctcttggaaagaaagt 
                 989 
               
               
                   
               
               
                 hGAP005 
                 LE 
                 agccttgacggtgccatgTTTTTaggcataggacccgtgtct 
                 990 
               
               
                   
               
               
                 hGAP006 
                 LE 
                 gatgacaagatcccgttctcTTTTTaggcataggacccgtgtct 
                 991 
               
               
                   
               
               
                 hGAP007 
                 LE 
                 agatggtgatgggatttccattTTTTTaggcataggacccgtgtct 
                 992 
               
               
                   
               
               
                 hGAP008 
                 LE 
                 gcatcgccccacttgattttTTTTTaggcataggacccgtgtct 
                 993 
               
               
                   
               
               
                 hGAP009 
                 LE 
                 cacgacgtactcagcgccaTTTTTaggcataggacccgtgtct 
                 994 
               
               
                   
               
               
                 hGAP010 
                 LE 
                 ggcagagatgatgacccttttgTTTTTaggcataggacccgtgtct 
                 995 
               
               
                   
               
               
                 hGAP011 
                 BL 
                 ggtgaagacgccagtggactc 
                 996 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 8 
               
             
            
               
                   
                   
               
               
                   
                   
                   
                 Cell- 
                   
               
               
                   
                 p53 
                 bDNA 
                 Titer 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 status 
                 expt. 1 
                 expt. 2 
                 Glo 
                 xCELLigence 
               
               
                   
                   
               
            
           
           
               
            
               
                 SEQ ID 497/711 
               
            
           
           
               
               
               
               
               
               
            
               
                 HepG2 
                 wt 
                 10.1 
                 33 
                 540 
                 210 
               
               
                 HLF 
                 mutant 
                 4.7 
                 37 
                 180 
                 80 
               
               
                 A549 
                 wt 
                 5.2 
                 165 
                 520 
                 140 
               
            
           
           
               
            
               
                 SEQ ID 477/839 
               
            
           
           
               
               
               
               
               
               
            
               
                 HepG2 
                 wt 
                 3.6 
                 28 
                 380 
                 130 
               
               
                 HLF 
                 mutant 
                 0.73 
                 21 
                 120 
                 69 
               
               
                 A549 
                 wt 
                 0.73 
                 21 
                 190 
                 160 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 9 
               
               
                   
                   
               
               
                   
                 24 hr 
                 48 hr 
                 72 hr 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 SEQ ID 497/711 
               
            
           
           
               
               
               
               
               
            
               
                   
                 HepG2 
                 81 
                 85 
                 85 
               
               
                   
                 HLF 
                 90 
                 90 
                 83 
               
               
                   
                 A549 
                 84 
                 59 
                 ND 
               
            
           
           
               
            
               
                 SEQ ID 477/839 
               
            
           
           
               
               
               
               
               
            
               
                   
                 HepG2 
                 87 
                 76 
                 75 
               
               
                   
                 HLF 
                 96 
                 92 
                 62 
               
               
                   
                 A549 
                 91 
                 54 
                 ND