a3421c5b1d9b3e5675043d6852ec9387 pmc_32671036.pdf c79da434f465bfaa6b2c7c300968709f4fab0be5 pmc_32671036.pdf a029b5740ca5186497e2f363bd84100b62a8b3b4f8891ec2260329de3ec3b212 pmc_32671036.pdf Title: Continuous Cultivation as a Tool Toward the Rational Bioprocess Development With Pichia Pastoris Cell Factory Subject: The methylotrophic yeast Pichia pastoris (Komagataella phaffii) is currently considered one of the most promising hosts for recombinant protein production (RPP) and metabolites due to the availability of several tools to efficiently regulate the recombinant expression, its ability to perform eukaryotic post-translational modifications and to secrete the product in the extracellular media. Keywords: Pichia pastoris, continuous cultivation, steady-state omics, physiological characterization, rational bioprocess development, bioreaction kinetics, heterologous protein production, systems microbiology Author: Francisco Valero Creator: LaTeX with hyperref package + hypdvips Producer: dvips + MiKTeX GPL Ghostscript 9.0 CreationDate: Tue Jun 23 07:00:44 2020 CEST ModDate: Tue Jun 23 10:15:31 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.26 x 779.52 pts Page rot: 0 File size: 2850749 bytes Optimized: no PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PITPOK+HelveticaNeueLTStd-Bd Type 1C WinAnsi yes yes no 35 0 VNQBVA+HelveticaNeueLTStd-Lt Type 1C Custom yes yes no 40 0 PQCETC+HelveticaNeueLTStd-BdIt Type 1C WinAnsi yes yes no 53 0 XKSDWH+HelveticaNeueLTStd-LtIt Type 1C Custom yes yes no 55 0 QKBRQT+HelveticaNeueLTStd-MdIt Type 1C WinAnsi yes yes no 62 0 YPRKAH+RMTMI Type 1C Custom yes yes no 158 0 NBAMYR+MinionPro-Regular Type 1C Custom yes yes no 73 0 BBPIOV+MinionPro-It Type 1C Custom yes yes no 83 0 TXAPVB+MinionPro-Bold Type 1C Custom yes yes no 176 0 QEAWJI+MTSY Type 1C Custom yes yes yes 276 0 MJPKHX+RMTMIB Type 1C Custom yes yes no 623 0 IWRFRS+MTSYB Type 1C Custom yes yes no 625 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:41:53 CEST RepresentationInformation: pmc_32671036.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:47:00 CEST Size: 2850749 Format: PDF Version: 1.6 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 979 FreeObjects: 28 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: UseOutlines Language: en Outlines: Item: Title: Continuous Cultivation as a Tool Toward the Rational Bioprocess Development With Pichia Pastoris Cell Factory Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Children: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Continuous Cultivation Provides an Excellent Tool for Systems Biology Research Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: Steady-State Omics, a Key Issue in the Renaissance of Research Into Continuous Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Transcriptional Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Proteomic Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Metabolic Fluxes as Key Physiological Indicators Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Metabolic Flux Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Bioprocess Characterization With Chemostat Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Children: Item: Title: Microbial Physiology Studies/Physiological Characterization of the Cell Factory Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Operating Conditions and Media Optimization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Carbon Sources Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Bioreaction Kinetics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Bioprocess Optimization and Process Development Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: Is Continuous Cultivation a Real Alternative for its Use in Industrial Pichia Pastoris Processes? Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Children: Item: Title: The Transition of Industrial Biotechnology From Batch/Fed-Batch Mode to Continuous Manufacturing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Challenges to Be Addressed in Pichia Pastoris Continuous Cultivations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: How Far Is the Implementation of Pichia pastoris Continuous Manufacturing Processes? Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d Item: Title: Author Contributions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89 Item: Title: Funding Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9 Item: Title: Acknowledgments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b Info: Title: Continuous Cultivation as a Tool Toward the Rational Bioprocess Development With Pichia Pastoris Cell Factory Author: Francisco Valero Subject: The methylotrophic yeast Pichia pastoris (Komagataella phaffii) is currently considered one of the most promising hosts for recombinant protein production (RPP) and metabolites due to the availability of several tools to efficiently regulate the recombinant expression, its ability to perform eukaryotic post-translational modifications and to secrete the product in the extracellular media. 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Francisco Valero Continuous Cultivation as a Tool Toward the Rational Bioprocess Development With Pichia Pastoris Cell Factory Pichia pastoris continuous cultivation steady-state omics physiological characterization rational bioprocess development bioreaction kinetics heterologous protein production systems microbiology Pichia pastoris, continuous cultivation, steady-state omics, physiological characterization, rational bioprocess development, bioreaction kinetics, heterologous protein production, systems microbiology dvips + MiKTeX GPL Ghostscript 9.0 uuid:f4eeba52-c6e6-47ea-8026-ed58c7489e8a uuid:acfecf87-3cc9-4595-b3dd-9e91173be306 Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 43, 719, 290, 755 Annotation: Subtype: Link Rect: 522, 736, 551, 744 Annotation: Subtype: Link Rect: 474, 728, 517, 736 Annotation: Subtype: Link Rect: 517, 729, 533, 736 Annotation: Subtype: Link Rect: 533, 728, 551, 736 Annotation: Subtype: Link Rect: 455, 720, 551, 728 Annotation: 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Link Rect: 156, 193, 235, 204 Destination: External Annotation: Subtype: Link Rect: 239, 193, 259, 204 Destination: External Annotation: Subtype: Link Rect: 47, 170, 110, 181 Destination: External Annotation: Subtype: Link Rect: 114, 170, 134, 181 Destination: External Annotation: Subtype: Link Rect: 188, 113, 257, 124 Destination: External Annotation: Subtype: Link Rect: 265, 113, 285, 124 Destination: External Annotation: Subtype: Link Rect: 91, 78, 157, 90 Destination: External Annotation: Subtype: Link Rect: 162, 78, 182, 90 Destination: External Annotation: Subtype: Link Rect: 187, 78, 260, 90 Destination: External Annotation: Subtype: Link Rect: 265, 78, 285, 90 Destination: External Annotation: Subtype: Link Rect: 398, 628, 464, 640 Destination: External Annotation: Subtype: Link Rect: 471, 628, 492, 640 Destination: External Annotation: Subtype: Link Rect: 304, 468, 367, 479 Destination: External Annotation: Subtype: Link Rect: 371, 468, 391, 479 Destination: External Annotation: Subtype: Link Rect: 511, 239, 326, 239 Destination: External Annotation: Subtype: Link Rect: 331, 227, 351, 239 Destination: External Annotation: Subtype: Link Rect: 357, 227, 446, 239 Destination: External Annotation: Subtype: Link Rect: 452, 227, 472, 239 Destination: External Annotation: Subtype: Link Rect: 493, 147, 350, 147 Destination: External Annotation: Subtype: Link Rect: 352, 135, 373, 147 Destination: External Annotation: Subtype: Link Rect: 379, 113, 436, 124 Destination: External Annotation: Subtype: Link Rect: 440, 113, 460, 124 Destination: External Annotation: Subtype: Link Rect: 464, 113, 525, 124 Destination: External Annotation: Subtype: Link Rect: 529, 113, 549, 124 Destination: External Annotation: Subtype: Link Rect: 304, 101, 349, 113 Destination: External Annotation: Subtype: Link Rect: 352, 101, 372, 113 Destination: External Annotation: Subtype: Link Rect: 375, 101, 434, 113 Destination: External Annotation: Subtype: Link Rect: 437, 101, 457, 113 Destination: External Annotation: Subtype: Link Rect: 512, 78, 326, 78 Destination: External Annotation: Subtype: Link Rect: 331, 67, 351, 78 Destination: External Annotation: Subtype: Link Rect: 356, 67, 419, 78 Destination: External Annotation: Subtype: Link Rect: 423, 67, 444, 78 Destination: External Annotation: Subtype: Link Rect: 448, 67, 500, 78 Destination: External Annotation: Subtype: Link Rect: 505, 67, 525, 78 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 7 Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 70, 708, 90, 720 Destination: External Annotation: Subtype: Link Rect: 94, 708, 115, 720 Destination: External Annotation: Subtype: Link Rect: 119, 708, 158, 720 Destination: External Annotation: Subtype: Link Rect: 163, 708, 183, 720 Destination: External Annotation: Subtype: Link Rect: 109, 662, 167, 674 Destination: External Annotation: Subtype: Link Rect: 170, 662, 190, 674 Destination: External Annotation: Subtype: Link Rect: 55, 514, 113, 525 Destination: External Annotation: Subtype: Link Rect: 116, 514, 137, 525 Destination: External Annotation: Subtype: Link Rect: 55, 330, 119, 342 Destination: External Annotation: Subtype: Link Rect: 124, 330, 144, 342 Destination: External Annotation: Subtype: Link Rect: 116, 261, 157, 273 Destination: External Annotation: Subtype: Link Rect: 164, 261, 184, 273 Destination: External Annotation: Subtype: Link Rect: 252, 147, 66, 147 Destination: External Annotation: Subtype: Link Rect: 73, 135, 93, 147 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 8 Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 47, 697, 114, 708 Destination: External Annotation: Subtype: Link Rect: 117, 697, 141, 708 Destination: External Annotation: Subtype: Link Rect: 141, 697, 148, 708 Destination: External Annotation: Subtype: Link Rect: 195, 628, 236, 640 Destination: External Annotation: Subtype: Link Rect: 238, 628, 259, 640 Destination: External Annotation: Subtype: Link Rect: 47, 571, 68, 582 Destination: External Annotation: Subtype: Link Rect: 70, 571, 91, 582 Destination: External Annotation: Subtype: Link Rect: 237, 491, 289, 502 Destination: External Annotation: Subtype: Link Rect: 43, 479, 64, 491 Destination: External Annotation: Subtype: Link Rect: 68, 479, 113, 491 Destination: External Annotation: Subtype: Link Rect: 118, 479, 138, 491 Destination: External Annotation: Subtype: Link Rect: 230, 468, 265, 479 Destination: External Annotation: Subtype: Link Rect: 268, 468, 289, 479 Destination: External Annotation: Subtype: Link Rect: 43, 456, 136, 468 Destination: External Annotation: Subtype: Link Rect: 140, 456, 160, 468 Destination: External Annotation: Subtype: Link Rect: 167, 170, 262, 181 Destination: External Annotation: Subtype: Link Rect: 267, 170, 287, 181 Destination: External Annotation: Subtype: Link Rect: 47, 147, 105, 158 Destination: External Annotation: Subtype: Link Rect: 109, 147, 129, 158 Destination: External Annotation: Subtype: Link Rect: 133, 147, 179, 158 Destination: External Annotation: Subtype: Link Rect: 184, 147, 204, 158 Destination: External Annotation: Subtype: Link Rect: 208, 147, 233, 158 Destination: External Annotation: Subtype: Link Rect: 237, 147, 289, 158 Destination: External Annotation: Subtype: Link Rect: 43, 135, 64, 147 Destination: External Annotation: Subtype: Link Rect: 77, 67, 169, 78 Destination: External Annotation: Subtype: Link Rect: 172, 67, 192, 78 Destination: External Annotation: Subtype: Link Rect: 507, 594, 549, 605 Destination: External Annotation: Subtype: Link Rect: 304, 582, 328, 594 Destination: External Annotation: Subtype: Link Rect: 330, 582, 419, 594 Destination: External Annotation: Subtype: Link Rect: 421, 582, 442, 594 Destination: External Annotation: Subtype: Link Rect: 307, 479, 399, 491 Destination: External Annotation: Subtype: Link Rect: 403, 479, 423, 491 Destination: External Annotation: Subtype: Link Rect: 448, 445, 495, 456 Destination: External Annotation: Subtype: Link Rect: 500, 445, 520, 456 Destination: External Annotation: Subtype: Link Rect: 524, 445, 549, 456 Destination: External Annotation: Subtype: Link Rect: 304, 433, 370, 445 Destination: External Annotation: Subtype: Link Rect: 375, 433, 395, 445 Destination: External Annotation: Subtype: Link Rect: 502, 319, 549, 330 Destination: External Annotation: Subtype: Link Rect: 304, 307, 328, 319 Destination: External Annotation: Subtype: Link Rect: 331, 307, 421, 319 Destination: External Annotation: Subtype: Link Rect: 425, 307, 445, 319 Destination: External Annotation: Subtype: Link Rect: 348, 239, 425, 250 Destination: External Annotation: Subtype: Link Rect: 431, 239, 451, 250 Destination: External Annotation: Subtype: Link Rect: 457, 239, 523, 250 Destination: External Annotation: Subtype: Link Rect: 529, 239, 549, 250 Destination: External Annotation: Subtype: Link Rect: 304, 227, 363, 239 Destination: External Annotation: Subtype: Link Rect: 365, 227, 385, 239 Destination: External Annotation: Subtype: Link Rect: 387, 227, 443, 239 Destination: External Annotation: Subtype: Link Rect: 445, 227, 465, 239 Destination: External Annotation: Subtype: Link Rect: 330, 67, 388, 78 Destination: External Annotation: Subtype: Link Rect: 393, 67, 413, 78 Destination: External Annotation: Subtype: Link Rect: 417, 67, 464, 78 Destination: External Annotation: Subtype: Link Rect: 469, 67, 489, 78 Destination: External Annotation: Subtype: Link Rect: 494, 67, 519, 78 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 9 Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 66, 708, 86, 720 Destination: External Annotation: Subtype: Link Rect: 213, 674, 259, 685 Destination: External Annotation: Subtype: Link Rect: 265, 674, 285, 685 Destination: External Annotation: Subtype: Link Rect: 231, 408, 70, 408 Destination: External Annotation: Subtype: Link Rect: 76, 397, 96, 408 Destination: External Annotation: Subtype: Link Rect: 413, 591, 458, 603 Destination: External Annotation: Subtype: Link Rect: 462, 591, 482, 603 Destination: External Annotation: Subtype: Link Rect: 340, 557, 392, 568 Destination: External Annotation: Subtype: Link Rect: 394, 557, 414, 568 Destination: External Annotation: Subtype: Link Rect: 307, 477, 350, 488 Destination: External Annotation: Subtype: Link Rect: 353, 477, 374, 488 Destination: External Annotation: Subtype: Link Rect: 408, 419, 470, 431 Destination: External Annotation: Subtype: Link Rect: 474, 419, 494, 431 Destination: External Annotation: Subtype: Link Rect: 315, 362, 364, 373 Destination: External Annotation: Subtype: Link Rect: 368, 362, 388, 373 Destination: External Annotation: Subtype: Link Rect: 307, 236, 357, 247 Destination: External Annotation: Subtype: Link Rect: 360, 236, 381, 247 Destination: External Annotation: Subtype: Link Rect: 479, 225, 522, 236 Destination: External Annotation: Subtype: Link Rect: 525, 225, 546, 236 Destination: External Annotation: Subtype: Link Rect: 378, 133, 415, 144 Destination: External Annotation: Subtype: Link Rect: 417, 133, 437, 144 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 10 Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 80, 697, 157, 708 Destination: External Annotation: Subtype: Link Rect: 160, 697, 180, 708 Destination: External Annotation: Subtype: Link Rect: 106, 617, 146, 628 Destination: External Annotation: Subtype: Link Rect: 150, 617, 170, 628 Destination: External Annotation: Subtype: Link Rect: 174, 617, 221, 628 Destination: External Annotation: Subtype: Link Rect: 225, 617, 245, 628 Destination: External Annotation: Subtype: Link Rect: 184, 491, 219, 502 Destination: External Annotation: Subtype: Link Rect: 222, 491, 242, 502 Destination: External Annotation: Subtype: Link Rect: 244, 491, 289, 502 Destination: External Annotation: Subtype: Link Rect: 43, 479, 64, 491 Destination: External Annotation: Subtype: Link Rect: 55, 468, 156, 479 Destination: External Annotation: Subtype: Link Rect: 159, 468, 179, 479 Destination: External Annotation: Subtype: Link Rect: 266, 307, 63, 307 Destination: External Annotation: Subtype: Link Rect: 65, 296, 90, 307 Destination: External Annotation: Subtype: Link Rect: 138, 273, 202, 284 Destination: External Annotation: Subtype: Link Rect: 208, 273, 228, 284 Destination: External Annotation: Subtype: Link Rect: 260, 78, 91, 78 Destination: External Annotation: Subtype: Link Rect: 93, 67, 113, 78 Destination: External Annotation: Subtype: Link Rect: 307, 697, 363, 708 Destination: External Annotation: Subtype: Link Rect: 365, 697, 385, 708 Destination: External Annotation: Subtype: Link Rect: 307, 617, 354, 628 Destination: External Annotation: Subtype: Link Rect: 356, 617, 377, 628 Destination: External Annotation: Subtype: Link Rect: 379, 617, 399, 628 Destination: External Annotation: Subtype: Link Rect: 346, 559, 392, 571 Destination: External Annotation: Subtype: Link Rect: 395, 559, 420, 571 Destination: External Annotation: Subtype: Link Rect: 420, 559, 426, 571 Destination: External Annotation: Subtype: Link Rect: 307, 536, 359, 548 Destination: External Annotation: Subtype: Link Rect: 365, 536, 385, 548 Destination: External Annotation: Subtype: Link Rect: 390, 536, 444, 548 Destination: External Annotation: Subtype: Link Rect: 449, 536, 469, 548 Destination: External Annotation: Subtype: Link Rect: 521, 514, 352, 514 Destination: External Annotation: Subtype: Link Rect: 354, 502, 374, 514 Destination: External Annotation: Subtype: Link Rect: 315, 399, 407, 410 Destination: External Annotation: Subtype: Link Rect: 412, 399, 433, 410 Destination: External Annotation: Subtype: Link Rect: 506, 342, 551, 353 Destination: External Annotation: Subtype: Link Rect: 307, 330, 327, 342 Destination: External Annotation: Subtype: Link Rect: 315, 261, 363, 273 Destination: External Annotation: Subtype: Link Rect: 369, 261, 393, 273 Destination: External Annotation: Subtype: Link Rect: 315, 181, 368, 193 Destination: External Annotation: Subtype: Link Rect: 372, 181, 392, 193 Destination: External Annotation: Subtype: Link Rect: 499, 90, 551, 101 Destination: External Annotation: Subtype: Link Rect: 307, 78, 327, 90 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 11 Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 55, 674, 107, 685 Destination: External Annotation: Subtype: Link Rect: 111, 674, 131, 685 Destination: External Annotation: Subtype: Link Rect: 55, 594, 99, 605 Destination: External Annotation: Subtype: Link Rect: 107, 594, 127, 605 Destination: External Annotation: Subtype: Link Rect: 47, 261, 106, 273 Destination: External Annotation: Subtype: Link Rect: 108, 261, 128, 273 Destination: External Annotation: Subtype: Link Rect: 130, 261, 173, 273 Destination: External Annotation: Subtype: Link Rect: 176, 261, 196, 273 Destination: External Annotation: Subtype: Link Rect: 92, 204, 171, 216 Destination: External Annotation: Subtype: Link Rect: 174, 204, 195, 216 Destination: External Annotation: Subtype: Link Rect: 210, 135, 262, 147 Destination: External Annotation: Subtype: Link Rect: 265, 135, 285, 147 Destination: External Annotation: Subtype: Link Rect: 47, 90, 91, 101 Destination: External Annotation: Subtype: Link Rect: 93, 90, 118, 101 Destination: External Annotation: Subtype: Link Rect: 55, 78, 85, 87 Destination: External Annotation: Subtype: Link Rect: 307, 662, 358, 674 Destination: External Annotation: Subtype: Link Rect: 360, 662, 381, 674 Destination: External Annotation: Subtype: Link Rect: 489, 662, 549, 674 Destination: External Annotation: Subtype: Link Rect: 304, 651, 324, 662 Destination: External Annotation: Subtype: Link Rect: 407, 559, 463, 571 Destination: External Annotation: Subtype: Link Rect: 465, 559, 486, 571 Destination: External Annotation: Subtype: Link Rect: 475, 502, 526, 514 Destination: External Annotation: Subtype: Link Rect: 529, 502, 549, 514 Destination: External Annotation: Subtype: Link Rect: 304, 491, 368, 502 Destination: External Annotation: Subtype: Link Rect: 371, 491, 391, 502 Destination: External Annotation: Subtype: Link Rect: 394, 491, 444, 502 Destination: External Annotation: Subtype: Link Rect: 447, 491, 467, 502 Destination: External Annotation: Subtype: Link Rect: 471, 491, 549, 502 Destination: External Annotation: Subtype: Link Rect: 304, 479, 324, 491 Destination: External Annotation: Subtype: Link Rect: 446, 399, 500, 410 Destination: External Annotation: Subtype: Link Rect: 505, 399, 525, 410 Destination: External Annotation: Subtype: Link Rect: 336, 387, 367, 396 Destination: External Annotation: Subtype: Link Rect: 375, 284, 454, 296 Destination: External Annotation: Subtype: Link Rect: 457, 284, 477, 296 Destination: External Annotation: Subtype: Link Rect: 387, 227, 448, 239 Destination: External Annotation: Subtype: Link Rect: 451, 227, 471, 239 Destination: External Annotation: Subtype: Link Rect: 473, 227, 549, 239 Destination: External Annotation: Subtype: Link Rect: 304, 216, 324, 227 Destination: External Annotation: Subtype: Link Rect: 326, 216, 419, 227 Destination: External Annotation: Subtype: Link Rect: 421, 216, 441, 227 Destination: External Annotation: Subtype: Link Rect: 412, 204, 464, 216 Destination: External Annotation: Subtype: Link Rect: 468, 204, 488, 216 Destination: External Annotation: Subtype: Link Rect: 440, 170, 527, 181 Destination: External Annotation: Subtype: Link Rect: 529, 170, 549, 181 Destination: External Annotation: Subtype: Link Rect: 304, 158, 370, 170 Destination: External Annotation: Subtype: Link Rect: 375, 158, 395, 170 Destination: External Annotation: Subtype: Link Rect: 399, 158, 480, 170 Destination: External Annotation: Subtype: Link Rect: 485, 158, 505, 170 Destination: External Annotation: Subtype: Link Rect: 519, 147, 325, 147 Destination: External Annotation: Subtype: Link Rect: 329, 135, 349, 147 Destination: External Annotation: Subtype: Link Rect: 353, 135, 401, 147 Destination: External Annotation: Subtype: Link Rect: 405, 135, 425, 147 Destination: External Annotation: Subtype: Link Rect: 429, 135, 477, 147 Destination: External Annotation: Subtype: Link Rect: 481, 135, 501, 147 Destination: External Annotation: Subtype: Link Rect: 505, 135, 549, 147 Destination: External Annotation: Subtype: Link Rect: 304, 124, 324, 135 Destination: External Annotation: Subtype: Link Rect: 384, 113, 436, 124 Destination: External Annotation: Subtype: Link Rect: 440, 113, 460, 124 Destination: External Annotation: Subtype: Link Rect: 463, 113, 524, 124 Destination: External Annotation: Subtype: Link Rect: 527, 113, 548, 124 Destination: External Annotation: Subtype: Link Rect: 408, 101, 470, 113 Destination: External Annotation: Subtype: Link Rect: 473, 101, 493, 113 Destination: External Annotation: Subtype: Link Rect: 304, 90, 368, 101 Destination: External Annotation: Subtype: Link Rect: 374, 90, 394, 101 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 12 Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 478, 662, 518, 671 Destination: External Annotation: Subtype: Link Rect: 519, 662, 537, 671 Destination: External Annotation: Subtype: Link Rect: 478, 631, 526, 640 Destination: External Annotation: Subtype: Link Rect: 528, 631, 546, 640 Destination: External Annotation: Subtype: Link Rect: 478, 600, 539, 610 Destination: External Annotation: Subtype: Link Rect: 478, 591, 496, 600 Destination: External Annotation: Subtype: Link Rect: 478, 570, 515, 579 Destination: External Annotation: Subtype: Link Rect: 517, 570, 535, 579 Destination: External Annotation: Subtype: Link Rect: 478, 548, 511, 558 Destination: External Annotation: Subtype: Link Rect: 513, 548, 530, 558 Destination: External Annotation: Subtype: Link Rect: 478, 527, 545, 537 Destination: External Annotation: Subtype: Link Rect: 478, 518, 496, 527 Destination: External Annotation: Subtype: Link Rect: 478, 506, 527, 516 Destination: External Annotation: Subtype: Link Rect: 529, 506, 546, 516 Destination: External Annotation: Subtype: Link Rect: 478, 475, 520, 485 Destination: External Annotation: Subtype: Link Rect: 522, 475, 539, 485 Destination: External Annotation: Subtype: Link Rect: 478, 454, 530, 464 Destination: External Annotation: Subtype: Link Rect: 532, 454, 549, 464 Destination: External Annotation: Subtype: Link Rect: 478, 433, 520, 442 Destination: External Annotation: Subtype: Link Rect: 522, 433, 540, 442 Destination: External Annotation: Subtype: Link Rect: 478, 412, 515, 421 Destination: External Annotation: Subtype: Link Rect: 517, 412, 535, 421 Destination: External Annotation: Subtype: Link Rect: 478, 402, 499, 412 Destination: External Annotation: Subtype: Link Rect: 499, 402, 505, 412 Destination: External Annotation: Subtype: Link Rect: 478, 391, 495, 391 Destination: External Annotation: Subtype: Link Rect: 496, 381, 514, 391 Destination: External Annotation: Subtype: Link Rect: 478, 360, 519, 369 Destination: External Annotation: Subtype: Link Rect: 520, 360, 538, 369 Destination: External Annotation: Subtype: Link Rect: 259, 320, 66, 320 Destination: External Annotation: Subtype: Link Rect: 71, 309, 92, 320 Destination: External Annotation: Subtype: Link Rect: 191, 309, 263, 320 Destination: External Annotation: Subtype: Link Rect: 268, 309, 289, 320 Destination: External Annotation: Subtype: Link Rect: 43, 297, 90, 309 Destination: External Annotation: Subtype: Link Rect: 93, 297, 113, 309 Destination: External Annotation: Subtype: Link Rect: 66, 274, 96, 283 Destination: External Annotation: Subtype: Link Rect: 262, 194, 65, 194 Destination: External Annotation: Subtype: Link Rect: 69, 183, 90, 194 Destination: External Annotation: Subtype: Link Rect: 519, 206, 549, 214 Destination: External Annotation: Subtype: Link Rect: 476, 114, 323, 114 Destination: External Annotation: Subtype: Link Rect: 326, 103, 346, 114 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 13 Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 487, 638, 541, 647 Destination: External Annotation: Subtype: Link Rect: 487, 628, 504, 638 Destination: External Annotation: Subtype: Link Rect: 487, 607, 503, 607 Destination: External Annotation: Subtype: Link Rect: 505, 598, 522, 607 Destination: External Annotation: Subtype: Link Rect: 487, 576, 503, 576 Destination: External Annotation: Subtype: Link Rect: 505, 567, 522, 576 Destination: External Annotation: Subtype: Link Rect: 487, 546, 519, 555 Destination: External Annotation: Subtype: Link Rect: 521, 546, 539, 555 Destination: External Annotation: Subtype: Link Rect: 487, 480, 547, 489 Destination: External Annotation: Subtype: Link Rect: 487, 471, 504, 480 Destination: External Annotation: Subtype: Link Rect: 506, 471, 523, 480 Destination: External Annotation: Subtype: Link Rect: 487, 449, 526, 459 Destination: External Annotation: Subtype: Link Rect: 528, 449, 545, 459 Destination: External Annotation: Subtype: Link Rect: 487, 400, 535, 410 Destination: External Annotation: Subtype: Link Rect: 487, 391, 504, 400 Destination: External Annotation: Subtype: Link Rect: 487, 373, 538, 377 Destination: External Annotation: Subtype: Link Rect: 487, 358, 504, 368 Destination: External Annotation: Subtype: Link Rect: 487, 326, 527, 336 Destination: External Annotation: Subtype: Link Rect: 529, 326, 546, 336 Destination: External Annotation: Subtype: Link Rect: 487, 266, 524, 276 Destination: External Annotation: Subtype: Link Rect: 526, 266, 547, 276 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 14 Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 55, 662, 85, 671 Destination: External Annotation: Subtype: Link Rect: 173, 594, 230, 605 Destination: External Annotation: Subtype: Link Rect: 234, 594, 254, 605 Destination: External Annotation: Subtype: Link Rect: 259, 594, 65, 594 Destination: External Annotation: Subtype: Link Rect: 69, 582, 89, 594 Destination: External Annotation: Subtype: Link Rect: 225, 559, 289, 571 Destination: External Annotation: Subtype: Link Rect: 43, 548, 64, 559 Destination: External Annotation: Subtype: Link Rect: 139, 514, 210, 525 Destination: External Annotation: Subtype: Link Rect: 214, 514, 234, 525 Destination: External Annotation: Subtype: Link Rect: 239, 514, 289, 525 Destination: External Annotation: Subtype: Link Rect: 43, 502, 68, 514 Destination: External Annotation: Subtype: Link Rect: 68, 502, 74, 514 Destination: External Annotation: Subtype: Link Rect: 76, 502, 121, 514 Destination: External Annotation: Subtype: Link Rect: 124, 502, 144, 514 Destination: External Annotation: Subtype: Link Rect: 146, 502, 187, 514 Destination: External Annotation: Subtype: Link Rect: 189, 502, 209, 514 Destination: External Annotation: Subtype: Link Rect: 55, 491, 136, 502 Destination: External Annotation: Subtype: Link Rect: 142, 491, 162, 502 Destination: External Annotation: Subtype: Link Rect: 55, 433, 148, 445 Destination: External Annotation: Subtype: Link Rect: 151, 433, 171, 445 Destination: External Annotation: Subtype: Link Rect: 145, 319, 199, 330 Destination: External Annotation: Subtype: Link Rect: 203, 319, 223, 330 Destination: External Annotation: Subtype: Link Rect: 227, 319, 289, 330 Destination: External Annotation: Subtype: Link Rect: 43, 307, 64, 319 Destination: External Annotation: Subtype: Link Rect: 176, 307, 225, 319 Destination: External Annotation: Subtype: Link Rect: 227, 307, 247, 319 Destination: External Annotation: Subtype: Link Rect: 55, 296, 154, 307 Destination: External Annotation: Subtype: Link Rect: 163, 296, 183, 307 Destination: External Annotation: Subtype: Link Rect: 453, 708, 502, 720 Destination: External Annotation: Subtype: Link Rect: 505, 708, 526, 720 Destination: External Annotation: Subtype: Link Rect: 502, 662, 549, 674 Destination: External Annotation: Subtype: Link Rect: 304, 651, 324, 662 Destination: External Annotation: Subtype: Link Rect: 328, 651, 380, 662 Destination: External Annotation: Subtype: Link Rect: 385, 651, 405, 662 Destination: External Annotation: Subtype: Link Rect: 390, 605, 450, 617 Destination: External Annotation: Subtype: Link Rect: 453, 605, 473, 617 Destination: External Annotation: Subtype: Link Rect: 473, 559, 522, 571 Destination: External Annotation: Subtype: Link Rect: 528, 559, 548, 571 Destination: External Annotation: Subtype: Link Rect: 307, 491, 367, 502 Destination: External Annotation: Subtype: Link Rect: 370, 491, 390, 502 Destination: External Annotation: Subtype: Link Rect: 468, 468, 549, 479 Destination: External Annotation: Subtype: Link Rect: 304, 456, 324, 468 Destination: External Annotation: Subtype: Link Rect: 390, 422, 435, 433 Destination: External Annotation: Subtype: Link Rect: 437, 422, 458, 433 Destination: External Annotation: Subtype: Link Rect: 307, 365, 415, 376 Destination: External Annotation: Subtype: Link Rect: 421, 365, 441, 376 Destination: External Annotation: Subtype: Link Rect: 351, 330, 415, 342 Destination: External Annotation: Subtype: Link Rect: 417, 330, 437, 342 Destination: External Annotation: Subtype: Link Rect: 466, 250, 549, 261 Destination: External Annotation: Subtype: Link Rect: 304, 239, 324, 250 Destination: External Annotation: Subtype: Link Rect: 339, 101, 421, 113 Destination: External Annotation: Subtype: Link Rect: 423, 101, 443, 113 Destination: External Annotation: Subtype: Link Rect: 307, 55, 371, 67 Destination: External Annotation: Subtype: Link Rect: 376, 55, 396, 67 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 15 Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 156, 640, 261, 651 Destination: External Annotation: Subtype: Link Rect: 265, 640, 285, 651 Destination: External Annotation: Subtype: Link Rect: 67, 490, 173, 502 Destination: External Annotation: Subtype: Link Rect: 178, 490, 198, 502 Destination: External Annotation: Subtype: Link Rect: 232, 422, 289, 433 Destination: External Annotation: Subtype: Link Rect: 43, 410, 64, 422 Destination: External Annotation: Subtype: Link Rect: 55, 376, 154, 387 Destination: External Annotation: Subtype: Link Rect: 160, 376, 180, 387 Destination: External Annotation: Subtype: Link Rect: 357, 697, 403, 708 Destination: External Annotation: Subtype: Link Rect: 406, 697, 426, 708 Destination: External Annotation: Subtype: Link Rect: 507, 479, 551, 491 Destination: External Annotation: Subtype: Link Rect: 307, 468, 327, 479 Destination: External Annotation: Subtype: Link Rect: 307, 399, 385, 410 Destination: External Annotation: Subtype: Link Rect: 387, 399, 408, 410 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 16 Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 120, 674, 218, 685 Destination: External Annotation: Subtype: Link Rect: 221, 674, 242, 685 Destination: External Annotation: Subtype: Link Rect: 245, 674, 76, 674 Destination: External Annotation: Subtype: Link Rect: 81, 662, 101, 674 Destination: External Annotation: Subtype: Link Rect: 106, 662, 204, 674 Destination: External Annotation: Subtype: Link Rect: 210, 662, 230, 674 Destination: External Annotation: Subtype: Link Rect: 163, 605, 207, 617 Destination: External Annotation: Subtype: Link Rect: 209, 605, 234, 617 Destination: External Annotation: Subtype: Link Rect: 236, 605, 289, 617 Destination: External Annotation: Subtype: Link Rect: 43, 594, 64, 605 Destination: External Annotation: Subtype: Link Rect: 143, 473, 209, 484 Annotation: Subtype: Link Rect: 391, 628, 441, 640 Destination: External Annotation: Subtype: Link Rect: 444, 628, 464, 640 Destination: External Annotation: Subtype: Link Rect: 366, 594, 414, 605 Destination: External Annotation: Subtype: Link Rect: 419, 594, 439, 605 Destination: External Annotation: Subtype: Link Rect: 390, 491, 481, 502 Destination: External Annotation: Subtype: Link Rect: 483, 491, 503, 502 Destination: External Annotation: Subtype: Link Rect: 304, 443, 338, 453 Destination: External Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 17 Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 65, 477, 100, 487 Destination: External Annotation: Subtype: Link Rect: 66, 248, 134, 255 Annotation: Subtype: Link Rect: 166, 219, 251, 227 Annotation: Subtype: Link Rect: 66, 181, 152, 189 Annotation: Subtype: Link Rect: 172, 151, 249, 161 Annotation: Subtype: Link Rect: 133, 114, 232, 123 Annotation: Subtype: Link Rect: 157, 87, 239, 94 Annotation: Subtype: Link Rect: 435, 276, 490, 284 Annotation: Subtype: Link Rect: 552, 237, 313, 256 Annotation: Subtype: Link Rect: 400, 210, 489, 217 Annotation: Subtype: Link Rect: 327, 172, 382, 180 Annotation: Subtype: Link Rect: 452, 144, 531, 151 Annotation: Subtype: Link Rect: 327, 106, 409, 113 Annotation: Subtype: Link Rect: 356, 68, 411, 76 Annotation: Subtype: Link Rect: 43, 28, 183, 36 Annotation: Subtype: Link Rect: 186, 28, 246, 36 Annotation: Subtype: Link Rect: 446, 28, 551, 37 Page: Label: 18 Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 66, 670, 152, 678 Annotation: Subtype: Link Rect: 66, 631, 167, 640 Annotation: Subtype: Link Rect: 292, 592, 52, 612 Annotation: Subtype: Link Rect: 235, 566, 291, 574 Annotation: Subtype: Link Rect: 195, 547, 280, 554 Annotation: Subtype: Link Rect: 66, 498, 144, 508 Annotation: Subtype: Link Rect: 108, 460, 166, 469 Annotation: Subtype: Link Rect: 292, 414, 52, 433 Annotation: Subtype: Link Rect: 157, 375, 214, 384 Annotation: Subtype: Link Rect: 140, 339, 195, 347 Annotation: Subtype: Link Rect: 140, 301, 218, 308 Annotation: Subtype: Link Rect: 163, 281, 264, 290 Annotation: Subtype: Link Rect: 82, 244, 158, 252 Annotation: Subtype: Link Rect: 66, 214, 176, 224 Annotation: Subtype: Link Rect: 136, 178, 211, 185 Annotation: Subtype: Link Rect: 66, 150, 132, 157 Annotation: Subtype: Link Rect: 95, 121, 151, 129 Annotation: Subtype: Link Rect: 86, 82, 278, 91 Annotation: Subtype: Link Rect: 355, 688, 532, 697 Annotation: Subtype: Link Rect: 383, 640, 461, 649 Annotation: Subtype: Link Rect: 356, 613, 434, 621 Annotation: Subtype: Link Rect: 410, 574, 463, 583 Annotation: Subtype: Link Rect: 445, 546, 504, 554 Annotation: Subtype: Link Rect: 424, 519, 506, 526 Annotation: Subtype: Link Rect: 327, 489, 415, 498 Annotation: Subtype: Link Rect: 373, 452, 447, 460 Annotation: Subtype: Link Rect: 425, 424, 499, 431 Annotation: Subtype: Link Rect: 426, 386, 505, 394 Annotation: Subtype: Link Rect: 327, 347, 428, 356 Annotation: Subtype: Link Rect: 432, 319, 528, 327 Annotation: Subtype: Link Rect: 327, 282, 423, 289 Annotation: Subtype: Link Rect: 327, 252, 407, 261 Annotation: Subtype: Link Rect: 327, 205, 419, 214 Annotation: Subtype: Link Rect: 327, 157, 406, 167 Annotation: Subtype: Link Rect: 327, 120, 404, 129 Annotation: Subtype: Link Rect: 408, 82, 463, 91 Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Page: Label: 19 Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 66, 661, 152, 668 Annotation: Subtype: Link Rect: 93, 631, 163, 640 Annotation: Subtype: Link Rect: 66, 594, 145, 602 Annotation: Subtype: Link Rect: 292, 556, 52, 575 Annotation: Subtype: Link Rect: 89, 519, 175, 526 Annotation: Subtype: Link Rect: 102, 489, 206, 498 Annotation: Subtype: Link Rect: 191, 462, 270, 469 Annotation: Subtype: Link Rect: 66, 424, 152, 431 Annotation: Subtype: Link Rect: 66, 394, 153, 403 Annotation: Subtype: Link Rect: 66, 292, 152, 299 Annotation: Subtype: Link Rect: 66, 254, 122, 261 Annotation: Subtype: Link Rect: 102, 225, 158, 233 Annotation: Subtype: Link Rect: 167, 197, 223, 205 Annotation: Subtype: Link Rect: 157, 178, 227, 185 Annotation: Subtype: Link Rect: 66, 129, 145, 138 Annotation: Subtype: Link Rect: 66, 93, 145, 100 Annotation: Subtype: Link Rect: 327, 689, 402, 697 Annotation: Subtype: Link Rect: 437, 650, 526, 659 Annotation: Subtype: Link Rect: 417, 612, 517, 621 Annotation: Subtype: Link Rect: 348, 574, 437, 583 Annotation: Subtype: Link Rect: 327, 536, 416, 545 Annotation: Subtype: Link Rect: 327, 509, 401, 517 Annotation: Subtype: Link Rect: 393, 480, 494, 489 Annotation: Subtype: Link Rect: 423, 443, 508, 450 Annotation: Subtype: Link Rect: 473, 413, 538, 422 Annotation: Subtype: Link Rect: 435, 377, 490, 384 Annotation: Subtype: Link Rect: 395, 347, 475, 356 Annotation: Subtype: Link Rect: 425, 309, 509, 318 Annotation: Subtype: Link Rect: 457, 282, 542, 289 Annotation: Subtype: Link Rect: 446, 252, 548, 261 Annotation: Subtype: Link Rect: 552, 215, 313, 234 Annotation: Subtype: Link Rect: 431, 178, 505, 186 Annotation: Subtype: Link Rect: 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Annotation: Subtype: Link Rect: 362, 110, 390, 119 Annotation: Subtype: Link Rect: 43, 29, 183, 37 Annotation: Subtype: Link Rect: 186, 29, 246, 37 Annotation: Subtype: Link Rect: 446, 29, 551, 38 Checksum: 7e850435 Type: CRC32 Checksum: a3421c5b1d9b3e5675043d6852ec9387 Type: MD5 Checksum: c79da434f465bfaa6b2c7c300968709f4fab0be5 Type: SHA-1