240e49d37ff6237288cb6f7ac1dbcc16 269694.pdf 5490b11c947c23bb5d4abefddfc1d30a9d790596 269694.pdf 82cc3012fac81113230bb231b0c36bf8b1c1c5671038855b112f3fc359dabdf4 269694.pdf Title: From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment Subject: The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural—containing a SEFIR/TILL domain—and functional—requiring ACT-1 for signaling—properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments. Keywords: psoriasis; Th17; IL-17; IL-17R; monoclonal antibodies; secukinumab; ixekizumab; bimekizumab; brodalumab Author: Silvia Vidal, Lluís Puig, José-Manuel Carrascosa-Carrillo, Álvaro González-Cantero, José-Carlos Ruiz-Carrascosa and Antonio-Manuel Velasco-Pastor Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Feb 28 10:21:06 2022 CET ModDate: Mon Feb 28 10:23:00 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 741872 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CMFVHJ+VnURWPalladioL Type 1 Custom yes yes no 10 0 ZODHIU+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 NCNJID+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 ZAUHJL+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 ILUGHX+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 DGCGUO+PazoMath-Italic Type 1 Builtin yes yes no 81 0 CVVLUV+CMSY10 Type 1 Builtin yes yes no 85 0 YQLUTS+EURM10 Type 1 Builtin yes yes no 89 0 WABLSD+SFRM1000 Type 1 Custom yes yes no 93 0 BCDEEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 106 0 BCDFEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 110 0 BCDGEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 114 0 BCDHEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 118 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 122 0 BCDJEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 129 0 BOLMEN+SFRM0900 Type 1 Custom yes yes no 179 0 BBETNX+PazoMath Type 1 Builtin yes yes no 189 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:15:17 CEST RepresentationInformation: 269694.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:04:42 CEST Size: 741872 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 614 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Psoriasis Pathogenesis in Context Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: The IL-17 Pathogenic Route in Psoriasis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: IL-17 Family Overview Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: IL-17 Isoforms and Their Roles in Psoriasis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Children: Item: Title: IL-17A Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: IL-17F Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: IL-17C Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: IL-17E Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: IL-17B Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: IL-17D Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: IL-17 Isoforms beyond Psoriasis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: IL-17R as Unique Receptors in Cytokine Signaling: Focus on IL-17RA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Targeting IL-17 Pathway in Psoriasis Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Treatments Acting by Ligand Inhibition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Children: Item: Title: Secukinumab Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Ixekizumab Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Bimekizumab Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Treatments Acting by Receptor Blockade Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Potential Role of IL-17A/IL-17RA Blockade in Psoriasis Comorbid Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Info: Title: From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment Author: Silvia Vidal, Lluís Puig, José-Manuel Carrascosa-Carrillo, Álvaro González-Cantero, José-Carlos Ruiz-Carrascosa and Antonio-Manuel Velasco-Pastor Subject: The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural containing a SEFIR/TILL domain and functional requiring ACT-1 for signaling properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments. Keywords: psoriasis; Th17; IL-17; IL-17R; monoclonal antibodies; secukinumab; ixekizumab; bimekizumab; brodalumab Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Feb 28 10:21:06 CET 2022 ModDate: Mon Feb 28 10:23:00 CET 2022 ID: 0xc49b6218cc73cf706d5917f9025618ab, 0xc49b6218cc73cf706d5917f9025618ab Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: DGCGUO+PazoMath-Italic FontSubset: true FirstChar: 97 LastChar: 107 FontDescriptor: FontName: DGCGUO+PazoMath-Italic Flags: Symbolic FontBBox: -70, -277, 902, 733 FontFile: true Font: BaseFont: BOLMEN+SFRM0900 FontSubset: true FirstChar: 180 LastChar: 180 FontDescriptor: FontName: BOLMEN+SFRM0900 Flags: Symbolic FontBBox: -196, -322, 1502, 937 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NCNJID+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: NCNJID+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CVVLUV+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: CVVLUV+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: ZAUHJL+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: ZAUHJL+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YQLUTS+EURM10 FontSubset: true FirstChar: 11 LastChar: 22 FontDescriptor: FontName: YQLUTS+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: CMFVHJ+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 226 FontDescriptor: FontName: CMFVHJ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ILUGHX+VnURWPalladioL-Bold FontSubset: true FirstChar: 129 LastChar: 189 FontDescriptor: FontName: ILUGHX+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WABLSD+SFRM1000 FontSubset: true FirstChar: 180 LastChar: 180 FontDescriptor: FontName: WABLSD+SFRM1000 Flags: Symbolic FontBBox: -189, -321, 1456, 937 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BBETNX+PazoMath FontSubset: true FirstChar: 71 LastChar: 71 FontDescriptor: FontName: BBETNX+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true Font: BaseFont: ZODHIU+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: ZODHIU+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 181, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 161, 662, 172, 675 Annotation: Subtype: Link Rect: 82, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 346, 104, 355 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 436, 243, 443, 252 ActionDest: 176 Annotation: Subtype: Link Rect: 218, 218, 225, 227 ActionDest: 176 Annotation: Subtype: Link Rect: 225, 218, 232, 227 ActionDest: 176 Annotation: Subtype: Link Rect: 459, 193, 466, 202 ActionDest: 183 Annotation: Subtype: Link Rect: 390, 168, 397, 177 ActionDest: 183 Annotation: Subtype: Link Rect: 400, 168, 407, 177 ActionDest: 183 Annotation: Subtype: Link Rect: 179, 143, 186, 152 ActionDest: 183 Annotation: Subtype: Link Rect: 186, 143, 193, 152 ActionDest: 183 Annotation: Subtype: Link Rect: 268, 143, 280, 152 ActionDest: 183 Annotation: Subtype: Link Rect: 438, 130, 449, 139 ActionDest: 183 Annotation: Subtype: Link Rect: 286, 118, 297, 127 ActionDest: 183 Annotation: Subtype: Link Rect: 444, 92, 456, 102 ActionDest: 183 Annotation: Subtype: Link Rect: 139, 17, 278, 28 Annotation: Subtype: Link Rect: 420, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 458, 87, 477 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 423, 724, 435, 733 ActionDest: 183 Annotation: Subtype: Link Rect: 438, 724, 450, 733 ActionDest: 183 Annotation: Subtype: Link Rect: 279, 699, 291, 708 ActionDest: 183 Annotation: Subtype: Link Rect: 313, 661, 325, 670 ActionDest: 183 Annotation: Subtype: Link Rect: 491, 649, 503, 658 ActionDest: 183 Annotation: Subtype: Link Rect: 209, 624, 220, 633 ActionDest: 183 Annotation: Subtype: Link Rect: 221, 624, 233, 633 ActionDest: 183 Annotation: Subtype: Link Rect: 369, 599, 381, 608 ActionDest: 183 Annotation: Subtype: Link Rect: 384, 599, 395, 608 ActionDest: 183 Annotation: Subtype: Link Rect: 230, 511, 242, 520 ActionDest: 183 Annotation: Subtype: Link Rect: 501, 498, 513, 507 ActionDest: 183 Annotation: Subtype: Link Rect: 283, 410, 295, 419 ActionDest: 183 Annotation: Subtype: Link Rect: 312, 373, 324, 382 ActionDest: 183 Annotation: Subtype: Link Rect: 534, 309, 546, 318 ActionDest: 183 Annotation: Subtype: Link Rect: 477, 258, 489, 267 ActionDest: 183 Annotation: Subtype: Link Rect: 544, 246, 556, 255 ActionDest: 183 Annotation: Subtype: Link Rect: 200, 208, 212, 217 ActionDest: 183 Annotation: Subtype: Link Rect: 201, 170, 213, 180 ActionDest: 183 Annotation: Subtype: Link Rect: 274, 170, 286, 180 ActionDest: 186 Annotation: Subtype: Link Rect: 294, 95, 306, 104 ActionDest: 183 Annotation: Subtype: Link Rect: 307, 95, 318, 104 ActionDest: 186 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 203, 735, 215, 744 ActionDest: 183 Annotation: Subtype: Link Rect: 423, 710, 435, 719 ActionDest: 186 Annotation: Subtype: Link Rect: 435, 710, 447, 719 ActionDest: 186 Annotation: Subtype: Link Rect: 398, 697, 410, 706 ActionDest: 186 Annotation: Subtype: Link Rect: 304, 682, 311, 694 ActionDest: 142 Annotation: Subtype: Link Rect: 503, 669, 510, 681 ActionDest: 98 Annotation: Subtype: Link Rect: 220, 150, 231, 158 ActionDest: 183 Annotation: Subtype: Link Rect: 231, 150, 242, 158 ActionDest: 183 Annotation: Subtype: Link Rect: 242, 150, 253, 158 ActionDest: 183 Annotation: Subtype: Link Rect: 253, 150, 264, 158 ActionDest: 186 Page: Sequence: 4 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 238, 703, 249, 712 ActionDest: 183 Annotation: Subtype: Link Rect: 282, 700, 289, 712 ActionDest: 142 Annotation: Subtype: Link Rect: 234, 552, 246, 561 ActionDest: 186 Annotation: Subtype: Link Rect: 246, 552, 258, 561 ActionDest: 186 Annotation: Subtype: Link Rect: 258, 552, 270, 561 ActionDest: 186 Annotation: Subtype: Link Rect: 482, 452, 494, 461 ActionDest: 186 Annotation: Subtype: Link Rect: 495, 452, 506, 461 ActionDest: 186 Annotation: Subtype: Link Rect: 507, 452, 519, 461 ActionDest: 186 Annotation: Subtype: Link Rect: 407, 402, 419, 411 ActionDest: 186 Annotation: Subtype: Link Rect: 215, 364, 227, 373 ActionDest: 186 Annotation: Subtype: Link Rect: 236, 313, 248, 323 ActionDest: 183 Annotation: Subtype: Link Rect: 279, 311, 286, 323 ActionDest: 142 Annotation: Subtype: Link Rect: 343, 288, 355, 297 ActionDest: 183 Annotation: Subtype: Link Rect: 544, 276, 556, 285 ActionDest: 186 Annotation: Subtype: Link Rect: 452, 238, 464, 247 ActionDest: 186 Annotation: Subtype: Link Rect: 271, 213, 283, 222 ActionDest: 186 Annotation: Subtype: Link Rect: 338, 163, 350, 172 ActionDest: 186 Annotation: Subtype: Link Rect: 288, 138, 300, 147 ActionDest: 186 Annotation: Subtype: Link Rect: 301, 138, 313, 147 ActionDest: 186 Annotation: Subtype: Link Rect: 435, 125, 447, 134 ActionDest: 186 Annotation: Subtype: Link Rect: 428, 75, 440, 84 ActionDest: 186 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 247, 707, 259, 716 ActionDest: 183 Annotation: Subtype: Link Rect: 295, 704, 302, 716 ActionDest: 142 Annotation: Subtype: Link Rect: 423, 694, 435, 703 ActionDest: 186 Annotation: Subtype: Link Rect: 436, 694, 448, 703 ActionDest: 186 Annotation: Subtype: Link Rect: 289, 669, 301, 678 ActionDest: 186 Annotation: Subtype: Link Rect: 456, 644, 468, 653 ActionDest: 186 Annotation: Subtype: Link Rect: 468, 644, 480, 653 ActionDest: 186 Annotation: Subtype: Link Rect: 431, 594, 443, 603 ActionDest: 186 Annotation: Subtype: Link Rect: 309, 581, 321, 590 ActionDest: 186 Annotation: Subtype: Link Rect: 302, 544, 314, 553 ActionDest: 186 Annotation: Subtype: Link Rect: 314, 543, 326, 553 ActionDest: 186 Annotation: Subtype: Link Rect: 327, 543, 339, 553 ActionDest: 186 Annotation: Subtype: Link Rect: 531, 519, 543, 527 ActionDest: 186 Annotation: Subtype: Link Rect: 544, 518, 556, 527 ActionDest: 186 Annotation: Subtype: Link Rect: 199, 456, 211, 465 ActionDest: 186 Annotation: Subtype: Link Rect: 346, 367, 357, 377 ActionDest: 183 Annotation: Subtype: Link Rect: 394, 365, 401, 377 ActionDest: 142 Annotation: Subtype: Link Rect: 436, 342, 448, 351 ActionDest: 183 Annotation: Subtype: Link Rect: 427, 330, 439, 339 ActionDest: 183 Annotation: Subtype: Link Rect: 439, 330, 451, 339 ActionDest: 186 Annotation: Subtype: Link Rect: 392, 292, 404, 301 ActionDest: 186 Annotation: Subtype: Link Rect: 281, 280, 293, 289 ActionDest: 186 Annotation: Subtype: Link Rect: 225, 104, 236, 113 ActionDest: 186 Annotation: Subtype: Link Rect: 430, 104, 442, 113 ActionDest: 186 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 544, 685, 556, 694 ActionDest: 186 Annotation: Subtype: Link Rect: 328, 672, 340, 681 ActionDest: 186 Annotation: Subtype: Link Rect: 497, 559, 509, 568 ActionDest: 186 Annotation: Subtype: Link Rect: 252, 508, 264, 518 ActionDest: 183 Annotation: Subtype: Link Rect: 297, 506, 304, 518 ActionDest: 142 Annotation: Subtype: Link Rect: 374, 483, 386, 492 ActionDest: 186 Annotation: Subtype: Link Rect: 544, 458, 556, 467 ActionDest: 186 Annotation: Subtype: Link Rect: 354, 358, 366, 367 ActionDest: 186 Annotation: Subtype: Link Rect: 298, 308, 310, 317 ActionDest: 186 Annotation: Subtype: Link Rect: 255, 257, 267, 266 ActionDest: 183 Annotation: Subtype: Link Rect: 300, 255, 307, 267 ActionDest: 142 Annotation: Subtype: Link Rect: 256, 207, 268, 216 ActionDest: 186 Annotation: Subtype: Link Rect: 440, 169, 452, 178 ActionDest: 186 Annotation: Subtype: Link Rect: 241, 144, 253, 153 ActionDest: 186 Annotation: Subtype: Link Rect: 235, 69, 247, 78 ActionDest: 186 Annotation: Subtype: Link Rect: 248, 69, 260, 78 ActionDest: 193 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 227, 710, 239, 719 ActionDest: 193 Annotation: Subtype: Link Rect: 451, 659, 463, 669 ActionDest: 193 Annotation: Subtype: Link Rect: 414, 634, 426, 643 ActionDest: 193 Annotation: Subtype: Link Rect: 427, 634, 439, 643 ActionDest: 193 Annotation: Subtype: Link Rect: 498, 572, 510, 581 ActionDest: 193 Annotation: Subtype: Link Rect: 253, 446, 265, 455 ActionDest: 193 Annotation: Subtype: Link Rect: 483, 433, 495, 443 ActionDest: 193 Annotation: Subtype: Link Rect: 273, 421, 285, 430 ActionDest: 193 Annotation: Subtype: Link Rect: 285, 421, 297, 430 ActionDest: 193 Annotation: Subtype: Link Rect: 516, 383, 528, 392 ActionDest: 193 Annotation: Subtype: Link Rect: 202, 270, 214, 279 ActionDest: 186 Annotation: Subtype: Link Rect: 232, 182, 244, 192 ActionDest: 193 Annotation: Subtype: Link Rect: 247, 183, 259, 192 ActionDest: 193 Annotation: Subtype: Link Rect: 271, 170, 283, 179 ActionDest: 193 Annotation: Subtype: Link Rect: 419, 145, 431, 154 ActionDest: 193 Annotation: Subtype: Link Rect: 434, 145, 446, 154 ActionDest: 193 Annotation: Subtype: Link Rect: 297, 95, 309, 104 ActionDest: 193 Annotation: Subtype: Link Rect: 309, 95, 321, 104 ActionDest: 193 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 430, 735, 442, 744 ActionDest: 193 Annotation: Subtype: Link Rect: 408, 710, 420, 719 ActionDest: 193 Annotation: Subtype: Link Rect: 421, 710, 433, 719 ActionDest: 193 Annotation: Subtype: Link Rect: 532, 697, 544, 706 ActionDest: 193 Annotation: Subtype: Link Rect: 544, 647, 556, 656 ActionDest: 183 Annotation: Subtype: Link Rect: 357, 584, 369, 593 ActionDest: 193 Annotation: Subtype: Link Rect: 193, 571, 205, 580 ActionDest: 186 Annotation: Subtype: Link Rect: 384, 559, 396, 568 ActionDest: 193 Annotation: Subtype: Link Rect: 512, 433, 524, 442 ActionDest: 183 Annotation: Subtype: Link Rect: 524, 433, 536, 442 ActionDest: 193 Annotation: Subtype: Link Rect: 544, 383, 556, 392 ActionDest: 193 Annotation: Subtype: Link Rect: 369, 320, 381, 329 ActionDest: 193 Annotation: Subtype: Link Rect: 214, 295, 226, 304 ActionDest: 193 Annotation: Subtype: Link Rect: 227, 295, 239, 304 ActionDest: 196 Annotation: Subtype: Link Rect: 209, 207, 221, 216 ActionDest: 183 Annotation: Subtype: Link Rect: 221, 207, 233, 216 ActionDest: 186 Annotation: Subtype: Link Rect: 507, 157, 519, 166 ActionDest: 186 Annotation: Subtype: Link Rect: 519, 157, 531, 166 ActionDest: 186 Annotation: Subtype: Link Rect: 531, 157, 543, 166 ActionDest: 196 Annotation: Subtype: Link Rect: 544, 157, 556, 166 ActionDest: 196 Annotation: Subtype: Link Rect: 512, 119, 524, 128 ActionDest: 196 Annotation: Subtype: Link Rect: 365, 82, 377, 91 ActionDest: 183 Annotation: Subtype: Link Rect: 526, 69, 538, 78 ActionDest: 196 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 293, 710, 305, 719 ActionDest: 186 Annotation: Subtype: Link Rect: 324, 647, 336, 656 ActionDest: 186 Annotation: Subtype: Link Rect: 448, 622, 460, 631 ActionDest: 186 Annotation: Subtype: Link Rect: 230, 584, 242, 593 ActionDest: 196 Annotation: Subtype: Link Rect: 189, 559, 201, 568 ActionDest: 186 Annotation: Subtype: Link Rect: 202, 559, 214, 568 ActionDest: 196 Annotation: Subtype: Link Rect: 214, 559, 226, 568 ActionDest: 196 Annotation: Subtype: Link Rect: 543, 546, 555, 556 ActionDest: 196 Annotation: Subtype: Link Rect: 262, 521, 274, 530 ActionDest: 196 Annotation: Subtype: Link Rect: 311, 496, 323, 505 ActionDest: 186 Annotation: Subtype: Link Rect: 377, 471, 389, 480 ActionDest: 186 Annotation: Subtype: Link Rect: 177, 433, 189, 443 ActionDest: 196 Annotation: Subtype: Link Rect: 525, 421, 537, 430 ActionDest: 196 Annotation: Subtype: Link Rect: 373, 371, 385, 380 ActionDest: 196 Annotation: Subtype: Link Rect: 515, 205, 527, 215 ActionDest: 196 Annotation: Subtype: Link Rect: 274, 180, 286, 189 ActionDest: 196 Annotation: Subtype: Link Rect: 345, 143, 357, 152 ActionDest: 196 Annotation: Subtype: Link Rect: 365, 118, 377, 127 ActionDest: 196 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 531, 659, 543, 669 ActionDest: 196 Annotation: Subtype: Link Rect: 544, 659, 556, 669 ActionDest: 196 Annotation: Subtype: Link Rect: 311, 609, 323, 618 ActionDest: 196 Annotation: Subtype: Link Rect: 526, 597, 538, 606 ActionDest: 196 Annotation: Subtype: Link Rect: 539, 597, 556, 606 ActionDest: 196 Annotation: Subtype: Link Rect: 213, 546, 225, 556 ActionDest: 196 Annotation: Subtype: Link Rect: 217, 509, 234, 518 ActionDest: 196 Annotation: Subtype: Link Rect: 293, 433, 310, 442 ActionDest: 196 Annotation: Subtype: Link Rect: 232, 408, 249, 417 ActionDest: 196 Annotation: Subtype: Link Rect: 287, 182, 299, 191 ActionDest: 196 Annotation: Subtype: Link Rect: 300, 182, 317, 191 ActionDest: 196 Annotation: Subtype: Link Rect: 228, 144, 245, 154 ActionDest: 196 Annotation: Subtype: Link Rect: 187, 132, 199, 141 ActionDest: 196 Annotation: Subtype: Link Rect: 199, 132, 216, 141 ActionDest: 196 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 215, 722, 232, 731 ActionDest: 196 Annotation: Subtype: Link Rect: 232, 722, 249, 731 ActionDest: 196 Annotation: Subtype: Link Rect: 202, 534, 219, 543 ActionDest: 196 Annotation: Subtype: Link Rect: 285, 509, 301, 518 ActionDest: 196 Annotation: Subtype: Link Rect: 539, 509, 556, 518 ActionDest: 196 Annotation: Subtype: Link Rect: 206, 484, 223, 493 ActionDest: 196 Annotation: Subtype: Link Rect: 362, 471, 379, 480 ActionDest: 196 Annotation: Subtype: Link Rect: 539, 371, 556, 380 ActionDest: 196 Annotation: Subtype: Link Rect: 354, 320, 371, 330 ActionDest: 199 Annotation: Subtype: Link Rect: 520, 308, 537, 317 ActionDest: 199 Annotation: Subtype: Link Rect: 231, 295, 247, 304 ActionDest: 199 Annotation: Subtype: Link Rect: 504, 206, 520, 215 ActionDest: 199 Annotation: Subtype: Link Rect: 268, 156, 285, 165 ActionDest: 199 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 258, 710, 275, 719 ActionDest: 199 Annotation: Subtype: Link Rect: 339, 660, 356, 669 ActionDest: 199 Annotation: Subtype: Link Rect: 307, 496, 324, 505 ActionDest: 199 Annotation: Subtype: Link Rect: 263, 408, 280, 417 ActionDest: 199 Annotation: Subtype: Link Rect: 466, 371, 478, 380 ActionDest: 196 Annotation: Subtype: Link Rect: 478, 371, 495, 380 ActionDest: 199 Annotation: Subtype: Link Rect: 539, 195, 556, 204 ActionDest: 199 Annotation: Subtype: Link Rect: 337, 145, 354, 154 ActionDest: 199 Annotation: Subtype: Link Rect: 196, 107, 208, 116 ActionDest: 196 Annotation: Subtype: Link Rect: 419, 69, 436, 79 ActionDest: 199 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 229, 685, 246, 694 ActionDest: 199 Annotation: Subtype: Link Rect: 247, 685, 264, 694 ActionDest: 199 Annotation: Subtype: Link Rect: 289, 609, 306, 618 ActionDest: 199 Annotation: Subtype: Link Rect: 217, 571, 234, 580 ActionDest: 199 Annotation: Subtype: Link Rect: 419, 509, 436, 518 ActionDest: 199 Annotation: Subtype: Link Rect: 329, 458, 345, 467 ActionDest: 199 Annotation: Subtype: Link Rect: 346, 458, 363, 467 ActionDest: 199 Annotation: Subtype: Link Rect: 277, 446, 294, 455 ActionDest: 199 Annotation: Subtype: Link Rect: 234, 408, 246, 417 ActionDest: 193 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 520, 107, 557, 118 Annotation: Subtype: Link Rect: 59, 96, 95, 106 Annotation: Subtype: Link Rect: 426, 84, 464, 95 Annotation: Subtype: Link Rect: 470, 84, 506, 95 Annotation: Subtype: Link Rect: 104, 62, 141, 72 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 382, 733, 420, 743 Annotation: Subtype: Link Rect: 186, 710, 222, 720 Annotation: Subtype: Link Rect: 223, 653, 261, 663 Annotation: Subtype: Link Rect: 400, 640, 438, 651 Annotation: Subtype: Link Rect: 486, 617, 523, 628 Annotation: Subtype: Link Rect: 316, 595, 353, 605 Annotation: Subtype: Link Rect: 104, 561, 141, 571 Annotation: Subtype: Link Rect: 470, 537, 506, 548 Annotation: Subtype: Link Rect: 198, 515, 236, 525 Annotation: Subtype: Link Rect: 287, 492, 324, 502 Annotation: Subtype: Link Rect: 361, 468, 399, 479 Annotation: Subtype: Link Rect: 157, 434, 194, 444 Annotation: Subtype: Link Rect: 95, 400, 133, 410 Annotation: Subtype: Link Rect: 410, 376, 447, 387 Annotation: Subtype: Link Rect: 95, 342, 133, 352 Annotation: Subtype: Link Rect: 139, 342, 175, 352 Annotation: Subtype: Link Rect: 520, 318, 557, 329 Annotation: Subtype: Link Rect: 183, 296, 221, 306 Annotation: Subtype: Link Rect: 227, 296, 263, 306 Annotation: Subtype: Link Rect: 508, 272, 545, 283 Annotation: Subtype: Link Rect: 348, 249, 386, 260 Annotation: Subtype: Link Rect: 392, 249, 428, 260 Annotation: Subtype: Link Rect: 519, 226, 557, 237 Annotation: Subtype: Link Rect: 59, 215, 95, 226 Annotation: Subtype: Link Rect: 152, 192, 189, 203 Annotation: Subtype: Link Rect: 250, 169, 287, 180 Annotation: Subtype: Link Rect: 466, 157, 503, 168 Annotation: Subtype: Link Rect: 462, 146, 500, 157 Annotation: Subtype: Link Rect: 59, 100, 97, 111 Annotation: Subtype: Link Rect: 104, 66, 142, 76 Annotation: Subtype: Link Rect: 148, 66, 184, 76 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 303, 721, 341, 732 Annotation: Subtype: Link Rect: 347, 721, 383, 732 Annotation: Subtype: Link Rect: 91, 699, 128, 709 Annotation: Subtype: Link Rect: 245, 675, 282, 686 Annotation: Subtype: Link Rect: 289, 675, 325, 686 Annotation: Subtype: Link Rect: 59, 641, 97, 651 Annotation: Subtype: Link Rect: 59, 618, 97, 628 Annotation: Subtype: Link Rect: 323, 606, 361, 617 Annotation: Subtype: Link Rect: 95, 584, 133, 594 Annotation: Subtype: Link Rect: 59, 561, 97, 571 Annotation: Subtype: Link Rect: 59, 538, 97, 548 Annotation: Subtype: Link Rect: 86, 503, 124, 513 Annotation: Subtype: Link Rect: 130, 503, 166, 513 Annotation: Subtype: Link Rect: 217, 468, 254, 479 Annotation: Subtype: Link Rect: 471, 445, 509, 456 Annotation: Subtype: Link Rect: 397, 422, 434, 433 Annotation: Subtype: Link Rect: 440, 422, 476, 433 Annotation: Subtype: Link Rect: 346, 399, 384, 410 Annotation: Subtype: Link Rect: 390, 399, 426, 410 Annotation: Subtype: Link Rect: 413, 376, 451, 387 Annotation: Subtype: Link Rect: 457, 376, 493, 387 Annotation: Subtype: Link Rect: 520, 353, 557, 364 Annotation: Subtype: Link Rect: 519, 330, 557, 341 Annotation: Subtype: Link Rect: 519, 318, 557, 329 Annotation: Subtype: Link Rect: 59, 308, 95, 318 Annotation: Subtype: Link Rect: 59, 273, 97, 283 Annotation: Subtype: Link Rect: 170, 238, 208, 249 Annotation: Subtype: Link Rect: 214, 238, 250, 249 Annotation: Subtype: Link Rect: 170, 215, 208, 226 Annotation: Subtype: Link Rect: 214, 215, 250, 226 Annotation: Subtype: Link Rect: 59, 181, 97, 191 Annotation: Subtype: Link Rect: 322, 158, 360, 168 Annotation: Subtype: Link Rect: 119, 123, 157, 134 Annotation: Subtype: Link Rect: 163, 123, 199, 134 Annotation: Subtype: Link Rect: 518, 111, 556, 122 Annotation: Subtype: Link Rect: 295, 88, 333, 99 Annotation: Subtype: Link Rect: 339, 88, 375, 99 Annotation: Subtype: Link Rect: 520, 77, 557, 88 Annotation: Subtype: Link Rect: 320, 66, 358, 76 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 147, 722, 185, 732 Annotation: Subtype: Link Rect: 191, 722, 227, 732 Annotation: Subtype: Link Rect: 419, 698, 456, 709 Annotation: Subtype: Link Rect: 477, 675, 515, 686 Annotation: Subtype: Link Rect: 166, 652, 203, 663 Annotation: Subtype: Link Rect: 209, 652, 245, 663 Annotation: Subtype: Link Rect: 358, 629, 395, 640 Annotation: Subtype: Link Rect: 239, 595, 277, 605 Annotation: Subtype: Link Rect: 131, 572, 169, 582 Annotation: Subtype: Link Rect: 175, 572, 211, 582 Annotation: Subtype: Link Rect: 302, 537, 340, 548 Annotation: Subtype: Link Rect: 346, 537, 382, 548 Annotation: Subtype: Link Rect: 136, 503, 173, 513 Annotation: Subtype: Link Rect: 163, 469, 200, 479 Annotation: Subtype: Link Rect: 86, 446, 124, 456 Annotation: Subtype: Link Rect: 289, 422, 326, 433 Annotation: Subtype: Link Rect: 332, 422, 368, 433 Annotation: Subtype: Link Rect: 519, 399, 557, 410 Annotation: Subtype: Link Rect: 59, 388, 95, 398 Annotation: Subtype: Link Rect: 59, 354, 97, 364 Annotation: Subtype: Link Rect: 103, 354, 139, 364 Annotation: Subtype: Link Rect: 449, 330, 487, 341 Annotation: Subtype: Link Rect: 91, 285, 128, 295 Annotation: Subtype: Link Rect: 118, 250, 155, 260 Annotation: Subtype: Link Rect: 265, 226, 302, 237 Annotation: Subtype: Link Rect: 507, 203, 545, 214 Annotation: Subtype: Link Rect: 59, 169, 97, 180 Annotation: Subtype: Link Rect: 104, 146, 141, 157 Annotation: Subtype: Link Rect: 90, 112, 127, 122 Annotation: Subtype: Link Rect: 127, 77, 164, 88 Annotation: Subtype: Link Rect: 171, 77, 207, 88 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 326, 721, 364, 732 Annotation: Subtype: Link Rect: 161, 687, 199, 697 Annotation: Subtype: Link Rect: 371, 663, 409, 674 Annotation: Subtype: Link Rect: 122, 641, 158, 651 Annotation: Subtype: Link Rect: 519, 617, 557, 628 Annotation: Subtype: Link Rect: 59, 607, 95, 617 Annotation: Subtype: Link Rect: 405, 583, 442, 594 Annotation: Subtype: Link Rect: 449, 583, 485, 594 Annotation: Subtype: Link Rect: 459, 548, 497, 559 Annotation: Subtype: Link Rect: 236, 526, 274, 536 Annotation: Subtype: Link Rect: 494, 502, 532, 513 Annotation: Subtype: Link Rect: 476, 479, 513, 490 Annotation: Subtype: Link Rect: 520, 479, 556, 490 Annotation: Subtype: Link Rect: 478, 456, 516, 467 Annotation: Subtype: Link Rect: 143, 400, 180, 410 Annotation: Subtype: Link Rect: 187, 400, 223, 410 Annotation: Subtype: Link Rect: 156, 377, 193, 387 Annotation: Subtype: Link Rect: 104, 354, 141, 364 Annotation: Subtype: Link Rect: 148, 354, 184, 364 Annotation: Subtype: Link Rect: 491, 330, 529, 341 Annotation: Subtype: Link Rect: 467, 307, 505, 318 Annotation: Subtype: Link Rect: 511, 307, 547, 318 Annotation: Subtype: Link Rect: 442, 272, 479, 283 Annotation: Subtype: Link Rect: 486, 272, 522, 283 Annotation: Subtype: Link Rect: 185, 227, 223, 237 Annotation: Subtype: Link Rect: 511, 215, 548, 226 Annotation: Subtype: Link Rect: 193, 181, 230, 191 Annotation: Subtype: Link Rect: 268, 146, 306, 157 Annotation: Subtype: Link Rect: 312, 146, 348, 157 Annotation: Subtype: Link Rect: 131, 100, 169, 111 Annotation: Subtype: Link Rect: 175, 100, 211, 111 Annotation: Subtype: Link Rect: 481, 66, 519, 76 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 400, 721, 437, 732 Annotation: Subtype: Link Rect: 443, 721, 479, 732 Annotation: Subtype: Link Rect: 95, 676, 133, 686 Annotation: Subtype: Link Rect: 401, 652, 438, 663 Annotation: Subtype: Link Rect: 423, 595, 461, 605 Annotation: Subtype: Link Rect: 467, 595, 503, 605 Annotation: Subtype: Link Rect: 506, 571, 543, 582 Annotation: Subtype: Link Rect: 265, 537, 303, 548 Annotation: Subtype: Link Rect: 136, 503, 173, 513 Annotation: Subtype: Link Rect: 59, 480, 97, 490 Annotation: Subtype: Link Rect: 443, 468, 481, 479 Annotation: Subtype: Link Rect: 131, 434, 169, 444 Annotation: Subtype: Link Rect: 175, 434, 211, 444 Annotation: Subtype: Link Rect: 158, 411, 195, 421 Annotation: Subtype: Link Rect: 201, 411, 237, 421 Annotation: Subtype: Link Rect: 520, 387, 557, 398 Annotation: Subtype: Link Rect: 59, 377, 95, 387 Annotation: Subtype: Link Rect: 95, 354, 132, 364 Annotation: Subtype: Link Rect: 139, 354, 175, 364 Annotation: Subtype: Link Rect: 198, 319, 236, 329 Annotation: Subtype: Link Rect: 340, 284, 378, 295 Annotation: Subtype: Link Rect: 384, 284, 420, 295 Annotation: Subtype: Link Rect: 324, 261, 361, 272 Annotation: Subtype: Link Rect: 368, 261, 404, 272 Annotation: Subtype: Link Rect: 519, 238, 557, 249 Annotation: Subtype: Link Rect: 59, 227, 95, 237 Checksum: cde1b389 Type: CRC32 Checksum: 240e49d37ff6237288cb6f7ac1dbcc16 Type: MD5 Checksum: 5490b11c947c23bb5d4abefddfc1d30a9d790596 Type: SHA-1