fd6ef65370bb12801b30646c5504050c medicina-62-01134.pdf 6d355e9249536be4d8e4b49d48a67da48c2a1ce2 medicina-62-01134.pdf e09c5af4a837b95c9ddd62192d911c4594e13d62accf90c03f28ad2c5aac3d19 medicina-62-01134.pdf Title: Statin-Associated Muscle Symptoms and Myotoxicity: A Clinically Oriented Narrative Review with a Practical Prevention, Evaluation, and Management Algorithm Subject: Background and Objectives: Muscle symptoms are the most visible adverse event attributed to statins, but terminology is often imprecise. Most patients report myalgia or nonspecific aches, whereas objective myopathy, inflammatory or necrotizing myositis, rhabdomyolysis, and anti-HMGCR immune-mediated necrotizing myopathy are uncommon and clinically distinct entities. To provide a clinically oriented narrative synthesis of statin-associated muscle symptoms (SAMS) and severe statin-associated myotoxicity, and to propose a practical prevention, evaluation, and management algorithm. The classification of muscle events is used to standardize terminology and avoid diagnostic confusion, not to create a new formal taxonomy. Materials and Methods: A clinically oriented narrative review was performed using PubMed, Google Scholar, and major society documents published from January 2021 to April 2026. Eligible sources addressed SAMS, statin myopathy/myositis, rhabdomyolysis, anti-HMGCR immune-mediated necrotizing myopathy, nocebo/drucebo effects, pharmacogenetics, drug interactions, diagnosis, or management. The final evidence set comprised 55 verifiable sources, including blinded randomized or n-of-1/crossover evidence; meta-analyses; clinical statements and reviews; pharmacovigilance analyses; pharmacogenetic guidance; mechanism-focused reviews; anti-HMGCR series; and lipid-lowering guideline/treatment studies. Because the review was narrative, no pooled estimate or formal PRISMA screening log was generated. Results: Blinded evidence indicates only a small absolute excess of muscle pain with statins, concentrated mainly in the first year of therapy, and that most muscle symptoms reported during statin therapy are not pharmacologically caused by the statin. N-of-1 and crossover trials show that symptom intensity is often similar during statin and placebo periods, consistent with an important nocebo/drucebo contribution. Severe muscle toxicity can nevertheless occur, especially when systemic statin exposure is increased by a high dose, interacting drugs, frailty, renal or hepatic impairment, hypothyroidism, transporter or metabolic genotypes, or intense unaccustomed exercise. Statin choice matters chiefly through dose, pharmacokinetics, and interaction burden. Conclusions: SAMS are common as reported clinical problems, but confirmed statin-caused muscle injury is substantially less frequent than routine clinical attribution suggests. Permanent discontinuation should be reserved for carefully assessed cases. A structured approach—baseline risk assessment, selective CK measurement, exclusion of alternative causes, correction of modifiable risks, dechallenge/rechallenge, statin switching, dose reduction, and combination with non-statin therapy—preserves cardiovascular benefit while protecting the rare patient with genuine toxicity. Keywords: statins; statin-associated muscle symptoms; SAMS; myopathy; myositis; rhabdomyolysis; nocebo effect; drucebo; statin intolerance; anti-HMGCR myopathy; creatine kinase Author: Francisco Epelde Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Wed Jun 10 11:50:12 2026 CEST ModDate: Wed Jun 10 11:55:13 2026 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1360909 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IKCMWB+URWPalladioL-Roma Type 1 Custom yes yes yes 97 0 OQELLH+URWPalladioL-Ital Type 1 Custom yes yes yes 98 0 MIKRSI+VnURWPalladioL Type 1 Custom yes yes yes 99 0 NNMABV+URWPalladioL-Bold Type 1 Custom yes yes yes 100 0 WGMTAF+CMSY10 Type 1 Builtin yes yes yes 169 0 CPMKOC+PalatinoLinotype TrueType WinAnsi yes yes no 207 0 CPMKOC+PalatinoLinotype TrueType WinAnsi yes yes no 337 0 CPMKOC+PalatinoLinotype TrueType WinAnsi yes yes no 435 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-07-28 04:22:42 CEST RepresentationInformation: medicina-62-01134.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-07-27 15:54:22 CEST Size: 1360909 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 627 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction: Scope, Definitions, and Epidemiology Item: Title: Methodology Item: Title: Frequency and Causal Attribution of Statin-Associated Muscle Disease Item: Title: Diagnostic Uncertainty in SAMS Item: Title: Statin-Specific Differences in Muscle-Safety Risk Item: Title: Mechanisms of Statin-Associated Muscle Symptoms and Muscle Injury Item: Title: Risk Profiles for Reported Symptoms and Objective Muscle Injury Item: Title: Prevention of Unnecessary Statin Withdrawal Item: Title: Proposed Prevention, Evaluation, and Management Algorithm Item: Title: Implications for Clinical Communication and Manuscript Framing Item: Title: Limitations Item: Title: Conclusions Item: Title: References Info: Title: Statin-Associated Muscle Symptoms and Myotoxicity: A Clinically Oriented Narrative Review with a Practical Prevention, Evaluation, and Management Algorithm Author: Francisco Epelde Subject: Background and Objectives: Muscle symptoms are the most visible adverse event attributed to statins, but terminology is often imprecise. Most patients report myalgia or nonspecific aches, whereas objective myopathy, inflammatory or necrotizing myositis, rhabdomyolysis, and anti-HMGCR immune-mediated necrotizing myopathy are uncommon and clinically distinct entities. To provide a clinically oriented narrative synthesis of statin-associated muscle symptoms (SAMS) and severe statin-associated myotoxicity, and to propose a practical prevention, evaluation, and management algorithm. The classification of muscle events is used to standardize terminology and avoid diagnostic confusion, not to create a new formal taxonomy. Materials and Methods: A clinically oriented narrative review was performed using PubMed, Google Scholar, and major society documents published from January 2021 to April 2026. Eligible sources addressed SAMS, statin myopathy/myositis, rhabdomyolysis, anti-HMGCR immune-mediated necrotizing myopathy, nocebo/drucebo effects, pharmacogenetics, drug interactions, diagnosis, or management. The final evidence set comprised 55 verifiable sources, including blinded randomized or n-of-1/crossover evidence; meta-analyses; clinical statements and reviews; pharmacovigilance analyses; pharmacogenetic guidance; mechanism-focused reviews; anti-HMGCR series; and lipid-lowering guideline/treatment studies. Because the review was narrative, no pooled estimate or formal PRISMA screening log was generated. Results: Blinded evidence indicates only a small absolute excess of muscle pain with statins, concentrated mainly in the first year of therapy, and that most muscle symptoms reported during statin therapy are not pharmacologically caused by the statin. N-of-1 and crossover trials show that symptom intensity is often similar during statin and placebo periods, consistent with an important nocebo/drucebo contribution. Severe muscle toxicity can nevertheless occur, especially when systemic statin exposure is increased by a high dose, interacting drugs, frailty, renal or hepatic impairment, hypothyroidism, transporter or metabolic genotypes, or intense unaccustomed exercise. Statin choice matters chiefly through dose, pharmacokinetics, and interaction burden. Conclusions: SAMS are common as reported clinical problems, but confirmed statin-caused muscle injury is substantially less frequent than routine clinical attribution suggests. Permanent discontinuation should be reserved for carefully assessed cases. A structured approach—baseline risk assessment, selective CK measurement, exclusion of alternative causes, correction of modifiable risks, dechallenge/rechallenge, statin switching, dose reduction, and combination with non-statin therapy—preserves cardiovascular benefit while protecting the rare patient with genuine toxicity. Keywords: statins; statin-associated muscle symptoms; SAMS; myopathy; myositis; rhabdomyolysis; nocebo effect; drucebo; statin intolerance; anti-HMGCR myopathy; creatine kinase Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Wed Jun 10 11:50:12 CEST 2026 ModDate: Wed Jun 10 11:55:13 CEST 2026 ID: 0x61058f1dd5ddf38daa782b141856e22a, 0xd25143c4d0710c8de8bd840a6d082397 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: IKCMWB+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: IKCMWB+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: OQELLH+URWPalladioL-Ital FontSubset: true FirstChar: 46 LastChar: 121 FontDescriptor: FontName: OQELLH+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: MIKRSI+VnURWPalladioL FontSubset: true FirstChar: 225 LastChar: 225 FontDescriptor: FontName: MIKRSI+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NNMABV+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: NNMABV+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: WGMTAF+CMSY10 FontSubset: true FirstChar: 2 LastChar: 35 FontDescriptor: FontName: WGMTAF+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 239, 124, 258 Annotation: Subtype: Link Rect: 120, 87, 152, 95 Annotation: Subtype: Link Rect: 34, 74, 152, 83 Annotation: Subtype: Link Rect: 34, 773, 142, 809 Annotation: Subtype: Link Rect: 515, 773, 560, 809 Annotation: Subtype: Link Rect: 124, 643, 135, 656 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 539, 524, 546, 533 ActionDest: 62 Annotation: Subtype: Link Rect: 549, 524, 556, 533 ActionDest: 62 Annotation: Subtype: Link Rect: 439, 455, 446, 464 ActionDest: 62 Annotation: Subtype: Link Rect: 386, 413, 393, 422 ActionDest: 62 Annotation: Subtype: Link Rect: 331, 329, 338, 338 ActionDest: 62 Annotation: Subtype: Link Rect: 338, 329, 345, 338 ActionDest: 62 Annotation: Subtype: Link Rect: 389, 315, 396, 324 ActionDest: 62 Annotation: Subtype: Link Rect: 396, 315, 403, 324 ActionDest: 62 Annotation: Subtype: Link Rect: 329, 187, 336, 199 ActionDest: 13 Annotation: Subtype: Link Rect: 347, 134, 354, 143 ActionDest: 62 Annotation: Subtype: Link Rect: 355, 134, 362, 143 ActionDest: 62 Annotation: Subtype: Link Rect: 362, 134, 374, 143 ActionDest: 62 Annotation: Subtype: Link Rect: 377, 134, 389, 143 ActionDest: 166 Annotation: Subtype: Link Rect: 278, 90, 285, 102 ActionDest: 13 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 378, 677, 384, 685 ActionDest: 62 Annotation: Subtype: Link Rect: 387, 677, 393, 685 ActionDest: 62 Annotation: Subtype: Link Rect: 382, 617, 388, 625 ActionDest: 62 Annotation: Subtype: Link Rect: 391, 617, 397, 625 ActionDest: 62 Annotation: Subtype: Link Rect: 397, 617, 408, 625 ActionDest: 62 Annotation: Subtype: Link Rect: 373, 552, 384, 560 ActionDest: 166 Annotation: Subtype: Link Rect: 386, 552, 397, 560 ActionDest: 166 Annotation: Subtype: Link Rect: 406, 493, 417, 501 ActionDest: 166 Annotation: Subtype: Link Rect: 419, 492, 430, 501 ActionDest: 166 Annotation: Subtype: Link Rect: 377, 427, 388, 436 ActionDest: 166 Annotation: Subtype: Link Rect: 391, 427, 401, 436 ActionDest: 166 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 282, 647, 289, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 292, 647, 299, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 206, 633, 213, 642 ActionDest: 62 Annotation: Subtype: Link Rect: 216, 633, 223, 642 ActionDest: 62 Annotation: Subtype: Link Rect: 223, 633, 230, 642 ActionDest: 62 Annotation: Subtype: Link Rect: 233, 633, 245, 642 ActionDest: 166 Annotation: Subtype: Link Rect: 246, 633, 258, 642 ActionDest: 166 Annotation: Subtype: Link Rect: 258, 633, 270, 642 ActionDest: 222 Annotation: Subtype: Link Rect: 243, 619, 255, 628 ActionDest: 166 Annotation: Subtype: Link Rect: 258, 619, 270, 628 ActionDest: 166 Annotation: Subtype: Link Rect: 270, 619, 282, 628 ActionDest: 222 Annotation: Subtype: Link Rect: 285, 619, 297, 628 ActionDest: 222 Annotation: Subtype: Link Rect: 495, 619, 507, 628 ActionDest: 166 Annotation: Subtype: Link Rect: 510, 619, 522, 628 ActionDest: 166 Annotation: Subtype: Link Rect: 265, 605, 277, 614 ActionDest: 222 Annotation: Subtype: Link Rect: 280, 605, 292, 614 ActionDest: 222 Annotation: Subtype: Link Rect: 442, 605, 454, 614 ActionDest: 166 Annotation: Subtype: Link Rect: 454, 605, 466, 614 ActionDest: 222 Annotation: Subtype: Link Rect: 469, 605, 481, 614 ActionDest: 222 Annotation: Subtype: Link Rect: 385, 591, 397, 600 ActionDest: 166 Annotation: Subtype: Link Rect: 400, 591, 411, 600 ActionDest: 166 Annotation: Subtype: Link Rect: 371, 577, 383, 586 ActionDest: 222 Annotation: Subtype: Link Rect: 386, 577, 398, 586 ActionDest: 232 Annotation: Subtype: Link Rect: 462, 408, 469, 420 ActionDest: 117 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 493, 700, 500, 709 ActionDest: 62 Annotation: Subtype: Link Rect: 503, 700, 510, 709 ActionDest: 62 Annotation: Subtype: Link Rect: 209, 602, 216, 611 ActionDest: 62 Annotation: Subtype: Link Rect: 463, 546, 470, 556 ActionDest: 62 Annotation: Subtype: Link Rect: 549, 379, 556, 388 ActionDest: 62 Annotation: Subtype: Link Rect: 549, 352, 556, 361 ActionDest: 62 Annotation: Subtype: Link Rect: 541, 282, 548, 291 ActionDest: 62 Annotation: Subtype: Link Rect: 549, 282, 556, 291 ActionDest: 62 Annotation: Subtype: Link Rect: 256, 212, 263, 221 ActionDest: 62 Annotation: Subtype: Link Rect: 264, 212, 271, 221 ActionDest: 62 Annotation: Subtype: Link Rect: 272, 212, 283, 221 ActionDest: 62 Annotation: Subtype: Link Rect: 287, 212, 299, 221 ActionDest: 166 Annotation: Subtype: Link Rect: 510, 184, 522, 193 ActionDest: 232 Annotation: Subtype: Link Rect: 522, 184, 534, 193 ActionDest: 232 Annotation: Subtype: Link Rect: 194, 155, 201, 166 ActionDest: 23 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 139, 689, 146, 698 ActionDest: 62 Annotation: Subtype: Link Rect: 149, 689, 156, 698 ActionDest: 62 Annotation: Subtype: Link Rect: 156, 689, 168, 698 ActionDest: 222 Annotation: Subtype: Link Rect: 107, 613, 114, 622 ActionDest: 62 Annotation: Subtype: Link Rect: 90, 554, 97, 563 ActionDest: 62 Annotation: Subtype: Link Rect: 97, 554, 104, 563 ActionDest: 62 Annotation: Subtype: Link Rect: 80, 501, 87, 510 ActionDest: 62 Annotation: Subtype: Link Rect: 88, 501, 95, 510 ActionDest: 62 Annotation: Subtype: Link Rect: 95, 501, 107, 510 ActionDest: 62 Annotation: Subtype: Link Rect: 110, 501, 122, 510 ActionDest: 166 Annotation: Subtype: Link Rect: 91, 437, 103, 446 ActionDest: 166 Annotation: Subtype: Link Rect: 106, 437, 118, 446 ActionDest: 166 Annotation: Subtype: Link Rect: 119, 437, 131, 446 ActionDest: 166 Annotation: Subtype: Link Rect: 134, 437, 146, 446 ActionDest: 166 Annotation: Subtype: Link Rect: 142, 402, 154, 411 ActionDest: 232 Annotation: Subtype: Link Rect: 155, 402, 166, 411 ActionDest: 232 Annotation: Subtype: Link Rect: 87, 361, 94, 370 ActionDest: 62 Annotation: Subtype: Link Rect: 87, 315, 93, 324 ActionDest: 62 Annotation: Subtype: Link Rect: 94, 315, 101, 324 ActionDest: 62 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 205, 730, 212, 740 ActionDest: 62 Annotation: Subtype: Link Rect: 213, 731, 220, 740 ActionDest: 62 Annotation: Subtype: Link Rect: 220, 730, 232, 740 ActionDest: 166 Annotation: Subtype: Link Rect: 392, 647, 399, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 399, 647, 406, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 407, 647, 414, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 414, 647, 426, 656 ActionDest: 62 Annotation: Subtype: Link Rect: 427, 647, 439, 656 ActionDest: 166 Annotation: Subtype: Link Rect: 442, 647, 453, 656 ActionDest: 166 Annotation: Subtype: Link Rect: 268, 563, 280, 572 ActionDest: 166 Annotation: Subtype: Link Rect: 283, 563, 295, 572 ActionDest: 166 Annotation: Subtype: Link Rect: 351, 326, 363, 335 ActionDest: 166 Annotation: Subtype: Link Rect: 366, 326, 378, 335 ActionDest: 166 Annotation: Subtype: Link Rect: 378, 326, 390, 335 ActionDest: 166 Annotation: Subtype: Link Rect: 391, 326, 403, 335 ActionDest: 222 Annotation: Subtype: Link Rect: 406, 326, 418, 335 ActionDest: 222 Annotation: Subtype: Link Rect: 318, 242, 330, 251 ActionDest: 222 Annotation: Subtype: Link Rect: 382, 173, 394, 181 ActionDest: 166 Annotation: Subtype: Link Rect: 397, 173, 409, 181 ActionDest: 166 Annotation: Subtype: Link Rect: 487, 75, 499, 84 ActionDest: 222 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 340, 730, 352, 740 ActionDest: 222 Annotation: Subtype: Link Rect: 355, 730, 366, 740 ActionDest: 222 Annotation: Subtype: Link Rect: 399, 729, 406, 740 ActionDest: 33 Annotation: Subtype: Link Rect: 317, 605, 329, 614 ActionDest: 166 Annotation: Subtype: Link Rect: 332, 605, 344, 614 ActionDest: 166 Annotation: Subtype: Link Rect: 288, 541, 300, 550 ActionDest: 166 Annotation: Subtype: Link Rect: 303, 541, 314, 550 ActionDest: 166 Annotation: Subtype: Link Rect: 281, 476, 293, 485 ActionDest: 166 Annotation: Subtype: Link Rect: 294, 476, 306, 485 ActionDest: 222 Annotation: Subtype: Link Rect: 203, 158, 215, 167 ActionDest: 166 Annotation: Subtype: Link Rect: 215, 158, 227, 167 ActionDest: 222 Annotation: Subtype: Link Rect: 230, 158, 242, 167 ActionDest: 222 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 319, 410, 331, 419 ActionDest: 166 Annotation: Subtype: Link Rect: 334, 410, 346, 419 ActionDest: 166 Annotation: Subtype: Link Rect: 347, 410, 359, 419 ActionDest: 166 Annotation: Subtype: Link Rect: 359, 410, 371, 419 ActionDest: 222 Annotation: Subtype: Link Rect: 374, 410, 386, 419 ActionDest: 222 Annotation: Subtype: Link Rect: 282, 271, 294, 280 ActionDest: 166 Annotation: Subtype: Link Rect: 297, 271, 309, 280 ActionDest: 166 Annotation: Subtype: Link Rect: 281, 240, 288, 252 ActionDest: 38 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 199, 218, 206, 226 ActionDest: 62 Annotation: Subtype: Link Rect: 209, 217, 216, 226 ActionDest: 62 Annotation: Subtype: Link Rect: 216, 217, 223, 226 ActionDest: 62 Annotation: Subtype: Link Rect: 224, 217, 235, 226 ActionDest: 62 Annotation: Subtype: Link Rect: 236, 217, 248, 226 ActionDest: 166 Annotation: Subtype: Link Rect: 248, 217, 260, 226 ActionDest: 222 Annotation: Subtype: Link Rect: 529, 134, 541, 143 ActionDest: 166 Annotation: Subtype: Link Rect: 544, 134, 556, 143 ActionDest: 166 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 418, 689, 430, 698 ActionDest: 166 Annotation: Subtype: Link Rect: 433, 689, 445, 698 ActionDest: 166 Annotation: Subtype: Link Rect: 484, 619, 496, 628 ActionDest: 222 Annotation: Subtype: Link Rect: 462, 536, 474, 545 ActionDest: 222 Annotation: Subtype: Link Rect: 290, 505, 297, 517 ActionDest: 43 Annotation: Subtype: Link Rect: 457, 366, 464, 375 ActionDest: 62 Annotation: Subtype: Link Rect: 467, 366, 474, 375 ActionDest: 62 Annotation: Subtype: Link Rect: 475, 366, 487, 375 ActionDest: 62 Annotation: Subtype: Link Rect: 487, 366, 499, 375 ActionDest: 166 Annotation: Subtype: Link Rect: 468, 325, 480, 334 ActionDest: 166 Annotation: Subtype: Link Rect: 483, 325, 495, 334 ActionDest: 166 Annotation: Subtype: Link Rect: 442, 238, 454, 247 ActionDest: 166 Annotation: Subtype: Link Rect: 457, 238, 469, 247 ActionDest: 166 Annotation: Subtype: Link Rect: 446, 191, 458, 200 ActionDest: 222 Annotation: Subtype: Link Rect: 461, 191, 473, 200 ActionDest: 222 Annotation: Subtype: Link Rect: 416, 139, 428, 148 ActionDest: 222 Annotation: Subtype: Link Rect: 431, 139, 443, 148 ActionDest: 222 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 434, 683, 441, 692 ActionDest: 62 Annotation: Subtype: Link Rect: 444, 683, 451, 692 ActionDest: 62 Annotation: Subtype: Link Rect: 452, 683, 464, 692 ActionDest: 166 Annotation: Subtype: Link Rect: 464, 683, 476, 692 ActionDest: 222 Annotation: Subtype: Link Rect: 501, 577, 508, 585 ActionDest: 62 Annotation: Subtype: Link Rect: 509, 576, 516, 585 ActionDest: 62 Annotation: Subtype: Link Rect: 516, 576, 528, 585 ActionDest: 62 Annotation: Subtype: Link Rect: 529, 576, 541, 585 ActionDest: 166 Annotation: Subtype: Link Rect: 544, 576, 556, 585 ActionDest: 166 Annotation: Subtype: Link Rect: 262, 284, 269, 293 ActionDest: 62 Annotation: Subtype: Link Rect: 269, 284, 276, 293 ActionDest: 62 Annotation: Subtype: Link Rect: 276, 284, 288, 293 ActionDest: 62 Annotation: Subtype: Link Rect: 289, 284, 301, 293 ActionDest: 166 Annotation: Subtype: Link Rect: 304, 284, 316, 293 ActionDest: 166 Annotation: Subtype: Link Rect: 544, 228, 556, 237 ActionDest: 222 Annotation: Subtype: Link Rect: 383, 200, 394, 209 ActionDest: 222 Annotation: Subtype: Link Rect: 395, 117, 407, 126 ActionDest: 222 Annotation: Subtype: Link Rect: 407, 117, 419, 126 ActionDest: 222 Annotation: Subtype: Link Rect: 397, 75, 409, 84 ActionDest: 222 Annotation: Subtype: Link Rect: 412, 75, 424, 84 ActionDest: 222 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 281, 703, 293, 712 ActionDest: 166 Annotation: Subtype: Link Rect: 296, 703, 308, 712 ActionDest: 166 Annotation: Subtype: Link Rect: 260, 228, 272, 237 ActionDest: 222 Annotation: Subtype: Link Rect: 275, 228, 287, 237 ActionDest: 222 Annotation: Subtype: Link Rect: 325, 225, 332, 237 ActionDest: 456 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 316, 672, 323, 681 ActionDest: 62 Annotation: Subtype: Link Rect: 326, 672, 333, 681 ActionDest: 62 Annotation: Subtype: Link Rect: 324, 533, 331, 542 ActionDest: 62 Annotation: Subtype: Link Rect: 332, 533, 339, 542 ActionDest: 62 Annotation: Subtype: Link Rect: 339, 533, 351, 542 ActionDest: 62 Annotation: Subtype: Link Rect: 352, 533, 364, 542 ActionDest: 222 Annotation: Subtype: Link Rect: 367, 533, 378, 542 ActionDest: 222 Annotation: Subtype: Link Rect: 521, 421, 528, 430 ActionDest: 62 Annotation: Subtype: Link Rect: 531, 421, 538, 430 ActionDest: 62 Annotation: Subtype: Link Rect: 538, 421, 550, 430 ActionDest: 166 Annotation: Subtype: Link Rect: 248, 296, 260, 305 ActionDest: 166 Annotation: Subtype: Link Rect: 263, 296, 275, 305 ActionDest: 166 Annotation: Subtype: Link Rect: 276, 296, 288, 305 ActionDest: 222 Annotation: Subtype: Link Rect: 291, 296, 303, 305 ActionDest: 222 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 283, 483, 366, 494 Annotation: Subtype: Link Rect: 422, 371, 459, 382 Annotation: Subtype: Link Rect: 161, 332, 199, 343 Annotation: Subtype: Link Rect: 152, 294, 190, 305 Annotation: Subtype: Link Rect: 406, 269, 444, 280 Annotation: Subtype: Link Rect: 409, 243, 446, 254 Annotation: Subtype: Link Rect: 59, 206, 96, 216 Annotation: Subtype: Link Rect: 104, 167, 141, 177 Annotation: Subtype: Link Rect: 147, 167, 183, 177 Annotation: Subtype: Link Rect: 519, 128, 557, 139 Annotation: Subtype: Link Rect: 59, 116, 95, 126 Annotation: Subtype: Link Rect: 117, 91, 155, 101 Annotation: Subtype: Link Rect: 161, 91, 197, 101 Annotation: Subtype: Link Rect: 283, 64, 321, 75 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 150, 743, 187, 754 Annotation: Subtype: Link Rect: 300, 718, 338, 729 Annotation: Subtype: Link Rect: 135, 693, 173, 703 Annotation: Subtype: Link Rect: 59, 655, 96, 665 Annotation: Subtype: Link Rect: 102, 655, 138, 665 Annotation: Subtype: Link Rect: 59, 629, 96, 639 Annotation: Subtype: Link Rect: 102, 629, 138, 639 Annotation: Subtype: Link Rect: 459, 616, 496, 627 Annotation: Subtype: Link Rect: 104, 591, 142, 601 Annotation: Subtype: Link Rect: 148, 591, 184, 601 Annotation: Subtype: Link Rect: 259, 565, 297, 576 Annotation: Subtype: Link Rect: 317, 539, 354, 550 Annotation: Subtype: Link Rect: 140, 450, 177, 461 Annotation: Subtype: Link Rect: 172, 411, 209, 422 Annotation: Subtype: Link Rect: 215, 411, 252, 422 Annotation: Subtype: Link Rect: 407, 386, 444, 397 Annotation: Subtype: Link Rect: 140, 348, 177, 358 Annotation: Subtype: Link Rect: 174, 310, 212, 320 Annotation: Subtype: Link Rect: 218, 310, 254, 320 Annotation: Subtype: Link Rect: 299, 271, 336, 282 Annotation: Subtype: Link Rect: 354, 245, 391, 256 Annotation: Subtype: Link Rect: 398, 245, 434, 256 Annotation: Subtype: Link Rect: 167, 208, 205, 218 Annotation: Subtype: Link Rect: 194, 169, 232, 180 Annotation: Subtype: Link Rect: 59, 131, 96, 141 Annotation: Subtype: Link Rect: 415, 105, 453, 116 Annotation: Subtype: Link Rect: 95, 67, 133, 78 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 145, 731, 182, 742 Annotation: Subtype: Link Rect: 520, 705, 557, 716 Annotation: Subtype: Link Rect: 337, 667, 375, 678 Annotation: Subtype: Link Rect: 104, 629, 142, 639 Annotation: Subtype: Link Rect: 472, 590, 509, 601 Annotation: Subtype: Link Rect: 254, 552, 291, 563 Annotation: Subtype: Link Rect: 297, 552, 333, 563 Annotation: Subtype: Link Rect: 458, 513, 495, 524 Annotation: Subtype: Link Rect: 501, 513, 537, 524 Annotation: Subtype: Link Rect: 359, 488, 396, 499 Annotation: Subtype: Link Rect: 104, 450, 142, 461 Annotation: Subtype: Link Rect: 148, 450, 184, 461 Annotation: Subtype: Link Rect: 315, 424, 353, 435 Annotation: Subtype: Link Rect: 149, 387, 186, 397 Annotation: Subtype: Link Rect: 178, 336, 216, 346 Annotation: Subtype: Link Rect: 222, 336, 258, 346 Annotation: Subtype: Link Rect: 464, 296, 502, 307 Annotation: Subtype: Link Rect: 520, 271, 557, 282 Annotation: Subtype: Link Rect: 59, 259, 95, 269 Annotation: Subtype: Link Rect: 95, 208, 133, 218 Annotation: Subtype: Link Rect: 59, 170, 96, 180 Annotation: Subtype: Link Rect: 154, 131, 192, 141 Annotation: Subtype: Link Rect: 519, 105, 557, 116 Annotation: Subtype: Link Rect: 59, 93, 95, 103 Annotation: Subtype: Link Rect: 520, 67, 557, 78 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 457, 743, 494, 754 Annotation: Subtype: Link Rect: 501, 743, 537, 754 Annotation: Subtype: Link Rect: 519, 718, 557, 729 Annotation: Subtype: Link Rect: 59, 706, 95, 716 Annotation: Subtype: Link Rect: 95, 680, 132, 690 Annotation: Subtype: Link Rect: 138, 680, 174, 690 Annotation: Subtype: Link Rect: 403, 27, 560, 37 Checksum: b44bd765 Type: CRC32 Checksum: fd6ef65370bb12801b30646c5504050c Type: MD5 Checksum: 6d355e9249536be4d8e4b49d48a67da48c2a1ce2 Type: SHA-1 Checksum: e09c5af4a837b95c9ddd62192d911c4594e13d62accf90c03f28ad2c5aac3d19 Type: SHA-256