[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

SG11201903252RA - Method for enhancing the incubation of samples, specimens and reagents using lasers - Google Patents

Method for enhancing the incubation of samples, specimens and reagents using lasers

Info

Publication number
SG11201903252RA
SG11201903252RA SG11201903252RA SG11201903252RA SG11201903252RA SG 11201903252R A SG11201903252R A SG 11201903252RA SG 11201903252R A SG11201903252R A SG 11201903252RA SG 11201903252R A SG11201903252R A SG 11201903252RA SG 11201903252R A SG11201903252R A SG 11201903252RA
Authority
SG
Singapore
Prior art keywords
international
biological product
pct
reagents
biological
Prior art date
Application number
SG11201903252RA
Inventor
Jim Manolios
Original Assignee
Haemokinesis Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2016904111A external-priority patent/AU2016904111A0/en
Application filed by Haemokinesis Pty Ltd filed Critical Haemokinesis Pty Ltd
Publication of SG11201903252RA publication Critical patent/SG11201903252RA/en

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/554—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being a biological cell or cell fragment, e.g. bacteria, yeast cells
    • G01N33/555—Red blood cell
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/36—Apparatus for enzymology or microbiology including condition or time responsive control, e.g. automatically controlled fermentors
    • C12M1/38—Temperature-responsive control
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/10—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by centrifugation ; Cyclones
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
    • C12M41/14—Incubators; Climatic chambers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
    • C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
    • C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
    • C12M41/24—Heat exchange systems, e.g. heat jackets or outer envelopes inside the vessel
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/07—Centrifugal type cuvettes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/80—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood groups or blood types or red blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1861—Means for temperature control using radiation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00346—Heating or cooling arrangements
    • G01N2035/00356—Holding samples at elevated temperature (incubation)
    • G01N2035/00415—Other radiation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00465—Separating and mixing arrangements
    • G01N2035/00495—Centrifuges
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/0332—Cuvette constructions with temperature control

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Cell Biology (AREA)
  • Sustainable Development (AREA)
  • Urology & Nephrology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Thermal Sciences (AREA)
  • Food Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Clinical Laboratory Science (AREA)
  • Mycology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property 111111411 0 11101 HOE 3E1 0 0111110111N 1110 HO HIDE 1111 011 Organization International Bureau (10) International Publication Number (43) International Publication Date .....0\"\" WO 2018/068077 Al 19 April 2018 (19.04.2018) WIP0 1 PCT (51) International Patent Classification: (71) Applicant (for all designated States except US): G01N 33/80 (2006.01) Cl 2M 1/38 (2006.01) HAEMOKINESIS PTY. LTD. [AU/AU]; 16 Technology G01N 33/537 (2006.01) G01N 21/00 (2006.01) Circuit, Hallam, Victoria 3803 (AU). G01N 33/555 (2006.01) G01N 21/07 (2006.01) G01N 33/559 (2006.01) BOOB 5/10 (2006.01) (72) Inventor; and GO1N 33/53 (2006.01) GO1N 33/49 (2006.01) (71) Applicant (for US only): MANOLIOS, Jim [AU/AU]; 205 C12M 1/34 (2006.01) Harrisons Road, Red Hill, Victoria 3937 (AU). (21) International Application Number: (74) Agent: WALSH & ASSOCIATES; Patent and Trade PCT/AU2017/000215 Mark Attorneys, Locked Bag 2011, Glebe, New South Wales 2037 (AU). (22) International Filing Date: 11 October 2017 (11.10.2017) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (26) Publication Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (30) Priority Data: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 2016904111 11 October 2016 (11.10.2016) AU KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, = (54) Title: METHOD FOR ENHANCING THE INCUBATION OF SAMPLES, SPECIMENS AND REAGENTS USING LASERS = 21 22 16 17 / I i ] 23 ( 24 25 26 V ' = !--- = = i ------ 1 = 33 34 35 = ______---/--- ---- I -- /w 30 31 32 _ = = 15 = - 0 — . it V e V V = = 3 4 5 = 6 7 8 _ Il 9 10 .4 IN IN 0 GO (57) : A method for incubating reagents, suspensions and/or biological products to a predetermined temperature for biological testing . ' the method comprising the steps of: a) providing a selected biological product in a receptacle and which is required to be 0 ---- incubated to a temperature which simulates a natural thermal GO or near the biological product using at least one laser emitting 1-1 © which simulates a target temperature of the natural thermal ei I 11 12 13 14 Figure 1 environment of the biological product; b) applying controlled heating to from a laser source for a time sufficient to reach a target temperature or environment in which the biological product exists. C [Continued on next page] WO 2018/068077 Al MIDEDIM01101 DIDIIMEN1111111111111111111111111111111111111110111111111111 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3))
SG11201903252RA 2016-10-11 2017-10-11 Method for enhancing the incubation of samples, specimens and reagents using lasers SG11201903252RA (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2016904111A AU2016904111A0 (en) 2016-10-11 Method for enhancing the incubation of samples, specimens and reagents for perfforming in vitro diagnostics.
PCT/AU2017/000215 WO2018068077A1 (en) 2016-10-11 2017-10-11 Method for enhancing the incubation of samples, specimens and reagents using lasers

Publications (1)

Publication Number Publication Date
SG11201903252RA true SG11201903252RA (en) 2019-05-30

Family

ID=61904920

Family Applications (2)

Application Number Title Priority Date Filing Date
SG11201903252RA SG11201903252RA (en) 2016-10-11 2017-10-11 Method for enhancing the incubation of samples, specimens and reagents using lasers
SG10202105651UA SG10202105651UA (en) 2016-10-11 2017-10-11 Method for enhancing the incubation of samples, specimens and reagents using lasers

Family Applications After (1)

Application Number Title Priority Date Filing Date
SG10202105651UA SG10202105651UA (en) 2016-10-11 2017-10-11 Method for enhancing the incubation of samples, specimens and reagents using lasers

Country Status (7)

Country Link
US (1) US20190242890A1 (en)
EP (1) EP3526608A4 (en)
JP (2) JP2019537000A (en)
AU (1) AU2017344050A1 (en)
CA (1) CA3044297A1 (en)
SG (2) SG11201903252RA (en)
WO (1) WO2018068077A1 (en)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552064A (en) * 1993-02-26 1996-09-03 Ortho Diagnostic Systems, Inc. Column agglutination assay and device using biphasic centrifugation
WO1996041864A1 (en) * 1995-06-13 1996-12-27 The Regents Of The University Of California Diode laser heated micro-reaction chamber with sample detection means
JPWO2003093835A1 (en) * 2002-04-30 2005-09-08 アークレイ株式会社 Temperature control method for analysis tool and analyzer with temperature control function
DE602004012161T2 (en) * 2003-12-22 2009-03-26 Micro Typing Systems, Inc., Pompano Beach REDUCING TIME TO SUBMISSION OF BLOOD BANK DIAGNOSTIC RESULTS
DK2249164T3 (en) * 2006-07-03 2013-01-07 Sebo Gmbh Process for processing a biological fluid for analyte determination
US7803101B2 (en) * 2007-01-30 2010-09-28 Ortho-Clinical Diagnostics, Inc. Random access multi-disc centrifuge
JP2011502264A (en) * 2007-10-29 2011-01-20 ベックマン コールター， インコーポレイテッド A method for rapid antibody-based analysis of platelet populations
EP2149793A1 (en) * 2008-07-25 2010-02-03 SeBo GmbH Disintegration of cellular components in body fluids
US10265696B2 (en) * 2012-12-27 2019-04-23 Research Business Foundation Sungkyunkwan University Nucleic acid amplification disk apparatus using temperature sensitive polymer synthesis and the analysis method using the same
KR101735083B1 (en) * 2015-02-05 2017-05-25 주식회사 씨디젠 DNA extractiion disc apparatus and DNA extraction method using the same

Also Published As

Publication number Publication date
JP2019537000A (en) 2019-12-19
WO2018068077A1 (en) 2018-04-19
JP2023002576A (en) 2023-01-10
AU2017344050A1 (en) 2019-05-02
EP3526608A4 (en) 2020-12-23
SG10202105651UA (en) 2021-07-29
US20190242890A1 (en) 2019-08-08
CA3044297A1 (en) 2018-04-19
EP3526608A1 (en) 2019-08-21

Similar Documents

Publication Publication Date Title
SG11201809913PA (en) Methods for detecting target nucleic acids in a sample
SG11201805592RA (en) Methods of producing patient-specific anti-cancer therapeutics and methods of treatment therefor
SG11201900907YA (en) Adenosine nucleobase editors and uses thereof
SG11201910019PA (en) Microorganisms and methods for producing cannabinoids and cannabinoid derivatives
SG11201810003UA (en) Using programmable dna binding proteins to enhance targeted genome modification
SG11201908127WA (en) Method for producing multispecific antibodies
SG11201903519UA (en) Methods and systems for barcoding nucleic acid molecules from individual cells or cell populations
SG11201807369UA (en) System and method for beam adjustment request
SG11201907679TA (en) Business verification method and apparatus
SG11201805532XA (en) Multivalent and multispecific 41bb-binding fusion proteins
SG11201805888SA (en) Cyclic dinucleotides for treating conditions associated with sting activity such as cancer
SG11201803703UA (en) Anti-complement factor c1q fab fragments and uses thereof
SG11201805166PA (en) Light-mediated polymerase chain reaction amplification and product detection system and methods of use
SG11201805835WA (en) Modified oncolytic virus
SG11201903771XA (en) Binding molecules specific for asct2 and uses thereof
SG11201900773RA (en) Methods for optical micropatterning of hydrogels and uses thereof
SG11201906844RA (en) Biometric feature database establishing method and apparatus
SG11201908240YA (en) Methods for evaluating tumor cell spheroids using 3d microfluidic cell culture device
SG11201809374VA (en) Cd40l-fc fusion polypeptides and methods of use thereof
SG11201903353WA (en) Compositions for reprogramming cells into dendritic cells or antigen presenting cells, methods and uses thereof
SG11201903557SA (en) Methods for screening b cell lymphocytes
SG11201909501TA (en) Personalized 3d neural culture system for generating human oligodendrocytes and studying myelination in vitro
SG11201804144UA (en) High-throughput imaging-based methods for predicting cell-type-specific toxicity of xenobiotics with diverse chemical structures
SG11201806740UA (en) Adaptive sensor sampling of a cold chain distribution system
SG11201808573YA (en) Nucleic acid stabilization reagent, kits, and methods of use thereof