cdd4004a31b93ffff00183c5961edcc4 pmc_10000190.pdf c02b7f6fcff6632bf0eb1d655b88e773f7f74009 pmc_10000190.pdf 5d98f30fe444f0f8f314c685c6b107e500de90812a20726a79ffa1fbeba87fa1 pmc_10000190.pdf Title: Elucidating the Effects of the Lipids Regulators Fibrates and Statins on the Health Status of Finfish Species: A Review Subject: The most documented fibrates are gemfibrozil, clofibrate and bezafibrate, while for statins, the majority of the published literature focuses on atorvastatin and simvastatin. The present work reviews previously published research concerning the effects of these hypocholesterolaemic pharmaceuticals on fish, with a particular focus on commercially important species, commonly produced by the European aquaculture industry, specifically in recirculated aquaculture systems (RAS). Overall, results suggest that both acute and chronic exposures to lipid-lowering compounds may have adverse effects on fish, disrupting their capacity to excrete exogenous substances, as well as both lipid metabolism and homeostasis, causing severe ontogenetic and endocrinological abnormalities, leading to hampered reproductive success (e.g., gametogenesis, fecundity), and skeletal or muscular malformations, having serious repercussions on fish health and welfare. Nonetheless, the available literature focusing on the effects of statins or fibrates on commonly farmed fish is still limited, and further research is required to understand the implications of this matter on aquaculture production, global food security and, ultimately, human health. Keywords: lipid-lowering agents; fibrates; statins; fish; gemfibrozil; atorvastatin Author: Manuel Blonç, Jennifer Lima, Joan Carles Balasch, Lluis Tort, Carlos Gravato and Mariana Teles Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Feb 22 10:41:08 2023 CET ModDate: Wed Feb 22 10:47:02 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 29 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1105475 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YREJEZ+VnURWPalladioL Type 1 Custom yes yes no 10 0 NLHKIP+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 UEQLQH+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 YWEWOH+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 SZMRXJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 42 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 67 0 NOCEJF+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 80 0 NOCEJH+PalatinoLinotype TrueType WinAnsi yes yes no 83 0 NOCEJJ+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 86 0 XCUBZO+CMSY10 Type 1 Builtin yes yes no 97 0 IOLAWT+PazoMath-Italic Type 1 Builtin yes yes no 101 0 QMQJLY+PazoMath Type 1 Builtin yes yes no 108 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-03-23 02:38:28 CET RepresentationInformation: pmc_10000190.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-22 02:10:57 CET Size: 1105475 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 581 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Children: Item: Title: Fibrates Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Statins Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Methodology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Effects of Lipids Regulators on Fish Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Fibrates Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Gemfibrozil Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Clofibrate and Clofibric Acid Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Bezafibrate Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Overall Effects of Fibrates in Fishes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Statins Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Atorvastatin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Simvastatin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Overall Effects of Statins in Fishes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Concluding Remarks Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Elucidating the Effects of the Lipids Regulators Fibrates and Statins on the Health Status of Finfish Species: A Review Author: Manuel Blonç, Jennifer Lima, Joan Carles Balasch, Lluis Tort, Carlos Gravato and Mariana Teles Subject: The most documented fibrates are gemfibrozil, clofibrate and bezafibrate, while for statins, the majority of the published literature focuses on atorvastatin and simvastatin. The present work reviews previously published research concerning the effects of these hypocholesterolaemic pharmaceuticals on fish, with a particular focus on commercially important species, commonly produced by the European aquaculture industry, specifically in recirculated aquaculture systems (RAS). Overall, results suggest that both acute and chronic exposures to lipid-lowering compounds may have adverse effects on fish, disrupting their capacity to excrete exogenous substances, as well as both lipid metabolism and homeostasis, causing severe ontogenetic and endocrinological abnormalities, leading to hampered reproductive success (e.g., gametogenesis, fecundity), and skeletal or muscular malformations, having serious repercussions on fish health and welfare. Nonetheless, the available literature focusing on the effects of statins or fibrates on commonly farmed fish is still limited, and further research is required to understand the implications of this matter on aquaculture production, global food security and, ultimately, human health. Keywords: lipid-lowering agents; fibrates; statins; fish; gemfibrozil; atorvastatin Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Feb 22 10:41:08 CET 2023 ModDate: Wed Feb 22 10:47:02 CET 2023 ID: 0xa1bdaa2149d715876ff4a1c5d4d8e4b2, 0xa1bdaa2149d715876ff4a1c5d4d8e4b2 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: XCUBZO+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: XCUBZO+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: VVSYYB+EURM10 FontSubset: true FirstChar: 11 LastChar: 22 FontDescriptor: FontName: VVSYYB+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: UEQLQH+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: UEQLQH+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IOLAWT+PazoMath-Italic FontSubset: true FirstChar: 97 LastChar: 97 FontDescriptor: FontName: IOLAWT+PazoMath-Italic Flags: Symbolic FontBBox: -70, -277, 902, 733 FontFile: true Font: BaseFont: YWEWOH+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 150 FontDescriptor: FontName: YWEWOH+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YREJEZ+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 254 FontDescriptor: FontName: YREJEZ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QMQJLY+PazoMath FontSubset: true FirstChar: 85 LastChar: 85 FontDescriptor: FontName: QMQJLY+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true Font: BaseFont: NLHKIP+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 231 FontDescriptor: FontName: NLHKIP+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 281, 152, 290 Annotation: Subtype: Link Rect: 34, 271, 74, 278 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 165, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 437, 661, 448, 674 Annotation: Subtype: Link Rect: 375, 143, 382, 152 ActionDest: 159 Annotation: Subtype: Link Rect: 358, 130, 365, 139 ActionDest: 159 Annotation: Subtype: Link Rect: 365, 130, 372, 139 ActionDest: 159 Annotation: Subtype: Link Rect: 441, 118, 448, 127 ActionDest: 159 Annotation: Subtype: Link Rect: 451, 118, 458, 127 ActionDest: 159 Annotation: Subtype: Link Rect: 295, 93, 302, 102 ActionDest: 159 Annotation: Subtype: Link Rect: 302, 92, 309, 102 ActionDest: 159 Annotation: Subtype: Link Rect: 112, 17, 247, 28 Annotation: Subtype: Link Rect: 409, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 366, 87, 385 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 416, 736, 423, 744 ActionDest: 159 Annotation: Subtype: Link Rect: 423, 735, 430, 744 ActionDest: 159 Annotation: Subtype: Link Rect: 433, 735, 445, 744 ActionDest: 159 Annotation: Subtype: Link Rect: 309, 685, 321, 694 ActionDest: 159 Annotation: Subtype: Link Rect: 324, 685, 336, 694 ActionDest: 159 Annotation: Subtype: Link Rect: 473, 648, 485, 657 ActionDest: 159 Annotation: Subtype: Link Rect: 488, 647, 500, 657 ActionDest: 162 Annotation: Subtype: Link Rect: 216, 635, 228, 644 ActionDest: 159 Annotation: Subtype: Link Rect: 228, 635, 240, 644 ActionDest: 162 Annotation: Subtype: Link Rect: 495, 622, 507, 631 ActionDest: 162 Annotation: Subtype: Link Rect: 507, 623, 519, 631 ActionDest: 162 Annotation: Subtype: Link Rect: 522, 623, 534, 631 ActionDest: 162 Annotation: Subtype: Link Rect: 514, 597, 526, 606 ActionDest: 162 Annotation: Subtype: Link Rect: 510, 522, 522, 531 ActionDest: 162 Annotation: Subtype: Link Rect: 525, 522, 537, 531 ActionDest: 162 Annotation: Subtype: Link Rect: 475, 484, 487, 493 ActionDest: 162 Annotation: Subtype: Link Rect: 417, 447, 429, 456 ActionDest: 162 Annotation: Subtype: Link Rect: 430, 447, 442, 456 ActionDest: 162 Annotation: Subtype: Link Rect: 281, 422, 292, 431 ActionDest: 162 Annotation: Subtype: Link Rect: 293, 422, 305, 431 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 384, 556, 393 ActionDest: 162 Annotation: Subtype: Link Rect: 216, 334, 228, 343 ActionDest: 162 Annotation: Subtype: Link Rect: 229, 334, 241, 343 ActionDest: 162 Annotation: Subtype: Link Rect: 241, 334, 253, 343 ActionDest: 162 Annotation: Subtype: Link Rect: 205, 296, 217, 305 ActionDest: 162 Annotation: Subtype: Link Rect: 531, 259, 543, 267 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 258, 556, 267 ActionDest: 162 Annotation: Subtype: Link Rect: 313, 221, 325, 230 ActionDest: 162 Annotation: Subtype: Link Rect: 326, 221, 338, 230 ActionDest: 162 Annotation: Subtype: Link Rect: 400, 208, 412, 217 ActionDest: 162 Annotation: Subtype: Link Rect: 413, 208, 424, 217 ActionDest: 162 Annotation: Subtype: Link Rect: 382, 183, 394, 192 ActionDest: 162 Annotation: Subtype: Link Rect: 394, 183, 406, 192 ActionDest: 162 Annotation: Subtype: Link Rect: 316, 170, 328, 180 ActionDest: 162 Annotation: Subtype: Link Rect: 208, 146, 219, 154 ActionDest: 162 Annotation: Subtype: Link Rect: 220, 145, 232, 154 ActionDest: 162 Annotation: Subtype: Link Rect: 232, 145, 244, 154 ActionDest: 162 Annotation: Subtype: Link Rect: 364, 120, 376, 129 ActionDest: 162 Annotation: Subtype: Link Rect: 388, 70, 400, 79 ActionDest: 162 Annotation: Subtype: Link Rect: 401, 70, 412, 79 ActionDest: 162 Annotation: Subtype: Link Rect: 415, 70, 427, 79 ActionDest: 162 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 346, 723, 358, 732 ActionDest: 162 Annotation: Subtype: Link Rect: 458, 685, 470, 694 ActionDest: 162 Annotation: Subtype: Link Rect: 502, 673, 514, 682 ActionDest: 162 Annotation: Subtype: Link Rect: 444, 660, 456, 669 ActionDest: 162 Annotation: Subtype: Link Rect: 484, 610, 496, 619 ActionDest: 162 Annotation: Subtype: Link Rect: 496, 610, 508, 619 ActionDest: 162 Annotation: Subtype: Link Rect: 521, 560, 533, 569 ActionDest: 162 Annotation: Subtype: Link Rect: 205, 535, 217, 544 ActionDest: 162 Annotation: Subtype: Link Rect: 519, 522, 531, 531 ActionDest: 162 Annotation: Subtype: Link Rect: 531, 522, 543, 531 ActionDest: 162 Annotation: Subtype: Link Rect: 544, 522, 556, 531 ActionDest: 162 Annotation: Subtype: Link Rect: 354, 484, 366, 493 ActionDest: 162 Annotation: Subtype: Link Rect: 253, 472, 265, 481 ActionDest: 162 Annotation: Subtype: Link Rect: 306, 459, 318, 468 ActionDest: 162 Annotation: Subtype: Link Rect: 348, 358, 360, 368 ActionDest: 162 Annotation: Subtype: Link Rect: 283, 333, 295, 342 ActionDest: 162 Annotation: Subtype: Link Rect: 337, 308, 349, 317 ActionDest: 162 Annotation: Subtype: Link Rect: 454, 271, 466, 280 ActionDest: 162 Annotation: Subtype: Link Rect: 456, 208, 468, 217 ActionDest: 162 Annotation: Subtype: Link Rect: 469, 208, 481, 217 ActionDest: 165 Annotation: Subtype: Link Rect: 484, 208, 496, 217 ActionDest: 165 Annotation: Subtype: Link Rect: 263, 183, 275, 192 ActionDest: 165 Annotation: Subtype: Link Rect: 442, 170, 453, 179 ActionDest: 165 Annotation: Subtype: Link Rect: 493, 158, 505, 167 ActionDest: 165 Annotation: Subtype: Link Rect: 498, 133, 510, 142 ActionDest: 165 Annotation: Subtype: Link Rect: 445, 120, 457, 129 ActionDest: 162 Annotation: Subtype: Link Rect: 475, 107, 487, 117 ActionDest: 165 Annotation: Subtype: Link Rect: 493, 95, 505, 104 ActionDest: 165 Annotation: Subtype: Link Rect: 290, 82, 302, 91 ActionDest: 165 Annotation: Subtype: Link Rect: 365, 70, 377, 79 ActionDest: 165 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 315, 735, 327, 744 ActionDest: 165 Annotation: Subtype: Link Rect: 447, 723, 459, 732 ActionDest: 165 Annotation: Subtype: Link Rect: 460, 723, 472, 732 ActionDest: 165 Annotation: Subtype: Link Rect: 318, 685, 330, 694 ActionDest: 165 Annotation: Subtype: Link Rect: 495, 673, 507, 682 ActionDest: 165 Annotation: Subtype: Link Rect: 291, 635, 303, 644 ActionDest: 162 Annotation: Subtype: Link Rect: 347, 622, 359, 631 ActionDest: 165 Annotation: Subtype: Link Rect: 359, 622, 371, 631 ActionDest: 165 Annotation: Subtype: Link Rect: 509, 559, 521, 568 ActionDest: 162 Annotation: Subtype: Link Rect: 422, 534, 434, 543 ActionDest: 165 Annotation: Subtype: Link Rect: 434, 534, 446, 543 ActionDest: 165 Annotation: Subtype: Link Rect: 444, 509, 456, 518 ActionDest: 165 Annotation: Subtype: Link Rect: 456, 509, 468, 518 ActionDest: 165 Annotation: Subtype: Link Rect: 544, 459, 556, 468 ActionDest: 165 Annotation: Subtype: Link Rect: 506, 396, 518, 405 ActionDest: 165 Annotation: Subtype: Link Rect: 233, 293, 240, 305 ActionDest: 74 Page: Sequence: 5 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 496, 590, 503, 603 ActionDest: 118 Annotation: Subtype: Link Rect: 229, 543, 241, 552 ActionDest: 162 Annotation: Subtype: Link Rect: 487, 530, 499, 539 ActionDest: 165 Annotation: Subtype: Link Rect: 405, 505, 417, 514 ActionDest: 162 Annotation: Subtype: Link Rect: 452, 442, 464, 452 ActionDest: 165 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 746, 437, 757, 446 ActionDest: 162 Annotation: Subtype: Link Rect: 746, 376, 757, 384 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 295, 757, 303 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 221, 757, 229 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 157, 757, 165 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 103, 757, 111 ActionDest: 165 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 746, 440, 757, 448 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 395, 757, 403 ActionDest: 162 Annotation: Subtype: Link Rect: 746, 344, 757, 352 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 305, 757, 314 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 276, 757, 285 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 248, 757, 256 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 214, 757, 223 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 185, 757, 194 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 143, 757, 151 ActionDest: 165 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 746, 425, 757, 433 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 362, 757, 370 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 315, 757, 323 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 278, 757, 286 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 236, 757, 245 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 198, 757, 206 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 159, 757, 167 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 109, 757, 118 ActionDest: 168 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 746, 434, 757, 443 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 376, 757, 385 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 310, 757, 318 ActionDest: 165 Annotation: Subtype: Link Rect: 746, 263, 757, 271 ActionDest: 168 Annotation: Subtype: Link Rect: 746, 216, 757, 224 ActionDest: 168 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 746, 421, 757, 430 ActionDest: 168 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 218, 720, 230, 729 ActionDest: 165 Annotation: Subtype: Link Rect: 230, 720, 242, 729 ActionDest: 168 Annotation: Subtype: Link Rect: 478, 683, 490, 692 ActionDest: 165 Annotation: Subtype: Link Rect: 216, 658, 228, 667 ActionDest: 168 Annotation: Subtype: Link Rect: 341, 620, 353, 629 ActionDest: 165 Annotation: Subtype: Link Rect: 461, 582, 473, 591 ActionDest: 168 Annotation: Subtype: Link Rect: 255, 494, 267, 503 ActionDest: 165 Annotation: Subtype: Link Rect: 349, 494, 361, 503 ActionDest: 162 Annotation: Subtype: Link Rect: 464, 419, 476, 428 ActionDest: 162 Annotation: Subtype: Link Rect: 451, 369, 463, 378 ActionDest: 162 Annotation: Subtype: Link Rect: 464, 369, 476, 378 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 369, 556, 378 ActionDest: 168 Annotation: Subtype: Link Rect: 294, 281, 306, 290 ActionDest: 168 Annotation: Subtype: Link Rect: 339, 268, 351, 277 ActionDest: 168 Annotation: Subtype: Link Rect: 283, 243, 295, 252 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 168, 556, 177 ActionDest: 168 Annotation: Subtype: Link Rect: 253, 105, 265, 114 ActionDest: 171 Annotation: Subtype: Link Rect: 214, 67, 226, 77 ActionDest: 165 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 509, 700, 521, 709 ActionDest: 171 Annotation: Subtype: Link Rect: 255, 662, 267, 671 ActionDest: 168 Annotation: Subtype: Link Rect: 418, 624, 430, 633 ActionDest: 165 Annotation: Subtype: Link Rect: 431, 624, 443, 633 ActionDest: 165 Annotation: Subtype: Link Rect: 405, 587, 417, 596 ActionDest: 165 Annotation: Subtype: Link Rect: 330, 574, 342, 583 ActionDest: 168 Annotation: Subtype: Link Rect: 287, 511, 299, 521 ActionDest: 168 Annotation: Subtype: Link Rect: 364, 474, 376, 483 ActionDest: 168 Annotation: Subtype: Link Rect: 376, 449, 388, 458 ActionDest: 168 Annotation: Subtype: Link Rect: 253, 273, 265, 282 ActionDest: 165 Annotation: Subtype: Link Rect: 265, 273, 277, 282 ActionDest: 168 Annotation: Subtype: Link Rect: 361, 246, 368, 257 ActionDest: 118 Annotation: Subtype: Link Rect: 398, 185, 410, 194 ActionDest: 168 Annotation: Subtype: Link Rect: 485, 109, 497, 119 ActionDest: 168 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 244, 737, 256, 746 ActionDest: 168 Annotation: Subtype: Link Rect: 288, 624, 300, 633 ActionDest: 168 Annotation: Subtype: Link Rect: 260, 599, 272, 608 ActionDest: 168 Annotation: Subtype: Link Rect: 428, 574, 440, 583 ActionDest: 168 Annotation: Subtype: Link Rect: 544, 499, 556, 508 ActionDest: 168 Annotation: Subtype: Link Rect: 300, 424, 312, 433 ActionDest: 168 Annotation: Subtype: Link Rect: 525, 373, 537, 382 ActionDest: 168 Annotation: Subtype: Link Rect: 280, 311, 292, 320 ActionDest: 168 Annotation: Subtype: Link Rect: 418, 298, 430, 307 ActionDest: 168 Annotation: Subtype: Link Rect: 352, 273, 364, 282 ActionDest: 171 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 496, 672, 503, 684 ActionDest: 118 Annotation: Subtype: Link Rect: 270, 637, 282, 646 ActionDest: 168 Annotation: Subtype: Link Rect: 214, 398, 226, 407 ActionDest: 171 Annotation: Subtype: Link Rect: 407, 348, 419, 357 ActionDest: 168 Annotation: Subtype: Link Rect: 390, 285, 407, 294 ActionDest: 171 Annotation: Subtype: Link Rect: 410, 285, 427, 294 ActionDest: 171 Annotation: Subtype: Link Rect: 412, 247, 429, 257 ActionDest: 171 Annotation: Subtype: Link Rect: 432, 247, 449, 257 ActionDest: 171 Annotation: Subtype: Link Rect: 469, 197, 481, 206 ActionDest: 168 Annotation: Subtype: Link Rect: 481, 197, 493, 206 ActionDest: 168 Annotation: Subtype: Link Rect: 377, 147, 394, 156 ActionDest: 171 Annotation: Subtype: Link Rect: 449, 109, 466, 119 ActionDest: 171 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 255, 697, 262, 709 ActionDest: 74 Annotation: Subtype: Link Rect: 539, 624, 556, 633 ActionDest: 171 Annotation: Subtype: Link Rect: 216, 586, 228, 596 ActionDest: 162 Annotation: Subtype: Link Rect: 228, 586, 240, 596 ActionDest: 165 Annotation: Subtype: Link Rect: 429, 549, 446, 558 ActionDest: 171 Annotation: Subtype: Link Rect: 299, 521, 306, 533 ActionDest: 146 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 746, 442, 761, 450 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 400, 757, 408 ActionDest: 162 Annotation: Subtype: Link Rect: 746, 324, 761, 332 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 257, 761, 266 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 210, 761, 218 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 142, 761, 151 ActionDest: 171 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 746, 411, 761, 419 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 330, 761, 338 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 254, 761, 262 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 187, 761, 196 ActionDest: 171 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 746, 396, 761, 404 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 310, 761, 318 ActionDest: 171 Annotation: Subtype: Link Rect: 746, 212, 761, 221 ActionDest: 171 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 746, 429, 761, 438 ActionDest: 174 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 404, 708, 416, 717 ActionDest: 162 Annotation: Subtype: Link Rect: 417, 708, 434, 717 ActionDest: 174 Annotation: Subtype: Link Rect: 325, 695, 342, 704 ActionDest: 174 Annotation: Subtype: Link Rect: 324, 633, 341, 642 ActionDest: 171 Annotation: Subtype: Link Rect: 355, 607, 372, 616 ActionDest: 171 Annotation: Subtype: Link Rect: 306, 545, 317, 554 ActionDest: 162 Annotation: Subtype: Link Rect: 511, 507, 523, 516 ActionDest: 162 Annotation: Subtype: Link Rect: 401, 482, 418, 491 ActionDest: 171 Annotation: Subtype: Link Rect: 296, 432, 313, 441 ActionDest: 171 Annotation: Subtype: Link Rect: 539, 306, 556, 315 ActionDest: 171 Annotation: Subtype: Link Rect: 477, 281, 494, 290 ActionDest: 171 Annotation: Subtype: Link Rect: 495, 281, 511, 290 ActionDest: 171 Annotation: Subtype: Link Rect: 445, 218, 462, 227 ActionDest: 171 Annotation: Subtype: Link Rect: 296, 180, 313, 189 ActionDest: 171 Annotation: Subtype: Link Rect: 313, 180, 330, 189 ActionDest: 171 Annotation: Subtype: Link Rect: 280, 143, 297, 152 ActionDest: 171 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 468, 712, 484, 721 ActionDest: 171 Annotation: Subtype: Link Rect: 493, 700, 510, 709 ActionDest: 171 Annotation: Subtype: Link Rect: 451, 637, 468, 646 ActionDest: 171 Annotation: Subtype: Link Rect: 366, 599, 383, 608 ActionDest: 171 Annotation: Subtype: Link Rect: 415, 562, 432, 571 ActionDest: 171 Annotation: Subtype: Link Rect: 333, 549, 350, 558 ActionDest: 171 Annotation: Subtype: Link Rect: 524, 461, 541, 470 ActionDest: 171 Annotation: Subtype: Link Rect: 221, 424, 238, 433 ActionDest: 171 Annotation: Subtype: Link Rect: 284, 348, 301, 357 ActionDest: 171 Annotation: Subtype: Link Rect: 423, 348, 440, 357 ActionDest: 174 Annotation: Subtype: Link Rect: 538, 222, 555, 231 ActionDest: 174 Annotation: Subtype: Link Rect: 452, 135, 469, 144 ActionDest: 174 Annotation: Subtype: Link Rect: 264, 109, 281, 119 ActionDest: 171 Annotation: Subtype: Link Rect: 212, 97, 229, 106 ActionDest: 174 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 259, 496, 276, 505 ActionDest: 174 Annotation: Subtype: Link Rect: 483, 471, 500, 480 ActionDest: 174 Annotation: Subtype: Link Rect: 195, 446, 212, 455 ActionDest: 174 Annotation: Subtype: Link Rect: 296, 370, 313, 379 ActionDest: 174 Annotation: Subtype: Link Rect: 275, 320, 292, 329 ActionDest: 174 Annotation: Subtype: Link Rect: 290, 245, 306, 254 ActionDest: 174 Page: Sequence: 24 Annotations: Annotation: Subtype: Link Rect: 59, 459, 96, 469 Annotation: Subtype: Link Rect: 409, 435, 447, 446 Annotation: Subtype: Link Rect: 454, 412, 492, 423 Annotation: Subtype: Link Rect: 202, 390, 239, 400 Annotation: Subtype: Link Rect: 166, 366, 204, 377 Annotation: Subtype: Link Rect: 233, 344, 270, 354 Annotation: Subtype: Link Rect: 283, 309, 321, 320 Annotation: Subtype: Link Rect: 271, 286, 309, 297 Annotation: Subtype: Link Rect: 494, 263, 531, 274 Annotation: Subtype: Link Rect: 59, 229, 96, 239 Annotation: Subtype: Link Rect: 348, 205, 386, 216 Annotation: Subtype: Link Rect: 323, 182, 361, 193 Annotation: Subtype: Link Rect: 520, 159, 557, 170 Annotation: Subtype: Link Rect: 479, 136, 517, 147 Annotation: Subtype: Link Rect: 374, 113, 411, 124 Annotation: Subtype: Link Rect: 395, 90, 433, 101 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 95, 713, 133, 723 Annotation: Subtype: Link Rect: 385, 689, 423, 700 Annotation: Subtype: Link Rect: 419, 666, 456, 677 Annotation: Subtype: Link Rect: 290, 643, 328, 654 Annotation: Subtype: Link Rect: 452, 620, 489, 631 Annotation: Subtype: Link Rect: 59, 598, 96, 608 Annotation: Subtype: Link Rect: 102, 598, 138, 608 Annotation: Subtype: Link Rect: 478, 574, 515, 585 Annotation: Subtype: Link Rect: 170, 552, 208, 562 Annotation: Subtype: Link Rect: 249, 528, 286, 539 Annotation: Subtype: Link Rect: 187, 506, 224, 516 Annotation: Subtype: Link Rect: 503, 493, 560, 504 Annotation: Subtype: Link Rect: 56, 482, 424, 493 Annotation: Subtype: Link Rect: 217, 459, 254, 470 Annotation: Subtype: Link Rect: 169, 367, 207, 378 Annotation: Subtype: Link Rect: 160, 321, 197, 332 Annotation: Subtype: Link Rect: 202, 298, 239, 309 Annotation: Subtype: Link Rect: 259, 275, 296, 286 Annotation: Subtype: Link Rect: 517, 263, 555, 274 Annotation: Subtype: Link Rect: 342, 252, 380, 263 Annotation: Subtype: Link Rect: 341, 229, 379, 240 Annotation: Subtype: Link Rect: 405, 206, 442, 217 Annotation: Subtype: Link Rect: 331, 183, 368, 194 Annotation: Subtype: Link Rect: 254, 160, 291, 171 Annotation: Subtype: Link Rect: 450, 137, 488, 148 Annotation: Subtype: Link Rect: 351, 114, 389, 125 Annotation: Subtype: Link Rect: 193, 92, 230, 102 Page: Sequence: 26 Annotations: Annotation: Subtype: Link Rect: 222, 712, 260, 723 Annotation: Subtype: Link Rect: 104, 678, 142, 689 Annotation: Subtype: Link Rect: 473, 654, 510, 665 Annotation: Subtype: Link Rect: 59, 621, 96, 631 Annotation: Subtype: Link Rect: 260, 598, 298, 608 Annotation: Subtype: Link Rect: 394, 574, 431, 585 Annotation: Subtype: Link Rect: 437, 574, 473, 585 Annotation: Subtype: Link Rect: 190, 551, 227, 562 Annotation: Subtype: Link Rect: 233, 551, 269, 562 Annotation: Subtype: Link Rect: 264, 529, 301, 539 Annotation: Subtype: Link Rect: 463, 505, 500, 516 Annotation: Subtype: Link Rect: 287, 470, 325, 481 Annotation: Subtype: Link Rect: 306, 436, 344, 447 Annotation: Subtype: Link Rect: 501, 413, 539, 424 Annotation: Subtype: Link Rect: 198, 379, 235, 389 Annotation: Subtype: Link Rect: 193, 344, 231, 355 Annotation: Subtype: Link Rect: 509, 332, 546, 343 Annotation: Subtype: Link Rect: 253, 309, 290, 320 Annotation: Subtype: Link Rect: 59, 287, 96, 297 Annotation: Subtype: Link Rect: 473, 263, 511, 274 Annotation: Subtype: Link Rect: 404, 240, 441, 251 Annotation: Subtype: Link Rect: 201, 218, 239, 228 Annotation: Subtype: Link Rect: 351, 194, 388, 205 Annotation: Subtype: Link Rect: 59, 161, 96, 171 Annotation: Subtype: Link Rect: 59, 126, 96, 136 Annotation: Subtype: Link Rect: 323, 102, 361, 113 Annotation: Subtype: Link Rect: 243, 79, 280, 90 Page: Sequence: 27 Annotations: Annotation: Subtype: Link Rect: 246, 712, 284, 723 Annotation: Subtype: Link Rect: 479, 689, 516, 700 Annotation: Subtype: Link Rect: 86, 655, 124, 665 Annotation: Subtype: Link Rect: 175, 632, 213, 642 Annotation: Subtype: Link Rect: 395, 609, 432, 619 Annotation: Subtype: Link Rect: 364, 585, 401, 596 Annotation: Subtype: Link Rect: 186, 551, 224, 562 Annotation: Subtype: Link Rect: 235, 528, 272, 539 Annotation: Subtype: Link Rect: 520, 505, 557, 516 Annotation: Subtype: Link Rect: 166, 471, 204, 481 Annotation: Subtype: Link Rect: 113, 437, 150, 447 Annotation: Subtype: Link Rect: 516, 413, 554, 424 Annotation: Subtype: Link Rect: 390, 390, 428, 401 Annotation: Subtype: Link Rect: 59, 356, 96, 366 Annotation: Subtype: Link Rect: 59, 322, 96, 332 Annotation: Subtype: Link Rect: 491, 298, 528, 309 Annotation: Subtype: Link Rect: 104, 264, 142, 274 Annotation: Subtype: Link Rect: 435, 240, 472, 251 Annotation: Subtype: Link Rect: 340, 206, 378, 217 Annotation: Subtype: Link Rect: 365, 160, 403, 171 Annotation: Subtype: Link Rect: 95, 126, 132, 136 Annotation: Subtype: Link Rect: 104, 92, 141, 102 Annotation: Subtype: Link Rect: 286, 68, 324, 79 Page: Sequence: 28 Annotations: Annotation: Subtype: Link Rect: 399, 724, 436, 735 Annotation: Subtype: Link Rect: 163, 701, 200, 712 Annotation: Subtype: Link Rect: 297, 666, 334, 677 Annotation: Subtype: Link Rect: 513, 643, 551, 654 Annotation: Subtype: Link Rect: 108, 621, 146, 631 Annotation: Subtype: Link Rect: 249, 597, 286, 608 Annotation: Subtype: Link Rect: 490, 574, 528, 585 Annotation: Subtype: Link Rect: 481, 551, 519, 562 Annotation: Subtype: Link Rect: 247, 528, 284, 539 Annotation: Subtype: Link Rect: 473, 516, 511, 527 Annotation: Subtype: Link Rect: 305, 493, 342, 504 Annotation: Subtype: Link Rect: 284, 470, 321, 481 Annotation: Subtype: Link Rect: 514, 447, 551, 458 Annotation: Subtype: Link Rect: 298, 424, 336, 435 Annotation: Subtype: Link Rect: 358, 390, 396, 401 Annotation: Subtype: Link Rect: 214, 367, 251, 378 Annotation: Subtype: Link Rect: 174, 345, 212, 355 Annotation: Subtype: Link Rect: 475, 321, 512, 332 Annotation: Subtype: Link Rect: 172, 286, 209, 297 Annotation: Subtype: Link Rect: 286, 252, 324, 263 Annotation: Subtype: Link Rect: 301, 229, 338, 240 Annotation: Subtype: Link Rect: 345, 206, 383, 217 Annotation: Subtype: Link Rect: 389, 206, 425, 217 Annotation: Subtype: Link Rect: 209, 171, 247, 182 Annotation: Subtype: Link Rect: 370, 148, 408, 159 Annotation: Subtype: Link Rect: 278, 125, 316, 136 Annotation: Subtype: Link Rect: 158, 92, 195, 102 Annotation: Subtype: Link Rect: 287, 68, 325, 79 Page: Sequence: 29 Annotations: Annotation: Subtype: Link Rect: 520, 724, 557, 735 Annotation: Subtype: Link Rect: 95, 690, 133, 700 Annotation: Subtype: Link Rect: 127, 667, 164, 677 Annotation: Subtype: Link Rect: 520, 654, 557, 665 Annotation: Subtype: Link Rect: 353, 631, 391, 642 Annotation: Subtype: Link Rect: 251, 597, 289, 608 Annotation: Subtype: Link Rect: 501, 574, 538, 585 Annotation: Subtype: Link Rect: 95, 540, 133, 550 Annotation: Subtype: Link Rect: 345, 505, 382, 516 Annotation: Subtype: Link Rect: 519, 482, 557, 493 Annotation: Subtype: Link Rect: 459, 459, 496, 470 Checksum: a4cb3453 Type: CRC32 Checksum: cdd4004a31b93ffff00183c5961edcc4 Type: MD5 Checksum: c02b7f6fcff6632bf0eb1d655b88e773f7f74009 Type: SHA-1