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which they are named; eNOS in vascular cells, nNOS in the CNS and peripheral nerves, and iNOS within the immune cells, although these divisions are not so strict as first thought and some cells therefore can produce two different types of the enzyme (Nathan 1992). The enzymes are coded for on differing chromosomes; chromosome 7 for eNOS (Zl-22 kb,26 exons), chromosome l2for nNOS (150kb, 29 exons) and chromosome 17 foriNOS (37kb,26 exons) (Marsden, Heng et al. 1993). The characteristics of the NOS enzymes are listed in Table 3.3 (Byrnes, Bush et al. 1996). Table 3.3: The characteristics of the nitric oxide synthase isoenzymes Enzyme nNOS Constitutive/ inducible constitutive Type NO oroduclion picomoles Galcium/ calmodulin dependent Ghromosome location 7: 26 exons span 21 kb eNOS constitutive ill picomoles dependent 12i 28 exons span >100 kb iNOS inducible tl nanomoles independsnt 17: 26 exons span 37 kb a CNS' central nervous system; PNS, peripheral nervous system; |NANC, inhibitory noradrenergic noncholinergic b TNF, tumor necrosis factor; lL, interleukin. This table is taken from Byrnes CA, Bush A, Shinebourne EA "Measuring expiratory nitric oxide in humans" Methods in Enzymology 1996; 26g:45g-413 (Byrnes, Bush et d. rbsoi. 3.4.1 Constitutive nitric oxide wnthases Activation of the two constitutive isoenzymes (nNOS and eNOS) depends on the levels of calmodulin and calcium. The NOS enzyme lies dormant until an increase in cellular calcium in the presence calmodulin occurs. A calcium concentration of 200 to 400 nanomoles allows half the maximum activity of the enzyme. This results in a sustained release of NO over several minutes, with picomole amounts of NO released, and this acts locally. The enzymes are stimulated by a number of mediators, depending on where they are situated, and these include bradykinin, acetylcholine, calcium ionophore, histamine, leukotriene, platelet activating factor (serotonin/thrombin) and exercise. In this way these enzymes participate in maintaining physiological balance within systems as discussed in the previous Chapter 2.3.4. The nNOS was the first of the isoenzymes to be purified and cloned (Bredt, Hwang et al. l99l; Schmidt, Pollock et al. 1991). There is wide expression and high activity of nNOS isoenzyme in the brain and throughout the peripheral nervous system in the NANC nerves, 81 Gells" in which enzvme is found cNS: especially cerebellum PNS: gut, bladder, reproductive organs iNANC neruac endothelial cells, mast c€lls, platelets, smooth muscle cells. neutroohils macrophages, neutrophils, airway epithelial cells, fibroblasts, mast cells Enzyme. stimulationo acetylcholine, bra)kinin, Ca'* ionophore histamins, leukotrieng, PAF serotonin, thrombin, shear stress ilpoporysacnand e, y-interferon, TNFq, TNFp, tll, tL2, leptochoic acid, picolinic acid
providing NO as a neurotransmitter (Forstermann, Closs et al. 1994). However it has also been found in the spinal cord @un, Dun et al. 1992), in sympathetic ganglia and adrenal glands @un, Dun et al. 1993; Sheng, Gagne et al. 1993), in the epithelial cells of the lung, uterus and stomach (Schmidt, Gagne et al.1992), in pancreatic islet cells (Schmidt, Warner et al. 1992) and in human skeletal muscle (Forstennann, Closs et al. 1994). While in the main nNOS NO production functions mostly in neurotransmission, it is also utilised to maintain muscle tone, for example, in the gastrointestinal tract and skeletal muscle. These enzymes are involved in homeostasis throughout the body from memory, behaviour, circadian rhythms, to the gastroenterology tract, renal function and reproductive activity. It is likely that this isoenzyme form is the largest proportion of constitutive NOS in humans (Forstermann, Closs et al. 1994; Knowles and Moncada 1994). The eNOS isoenzyme within arteries give a basal level of NO production continuously, which maintains the vascular blood flow and blood pressure. This isoenzyme is largely responsible for the NO which inhibits platelet aggregation and platelet adhesion. 3.4.2 Inducible nitric oxide svnthase The main method of activation, the amount of NO produced and the regulation of this form of the enzyme is very different from the constitutive forms. The iNOS isoform is regulated at transcriptional level with activation requiring both a primary and a secondary signal before the mRNA for the enzyme is produced. The priming agent is interferon gamma (IFNI) or an interferon inducing agent like bacterial lipopolysaccharide (LPS) (Weinberg, Chapman et al. 1978; Stuehr and Marletta 1985; Drapier, Wietzerbin et al. 1988; Sherman, loro et al. 1991; Munoz-Fernandez, Fernandez et al. 1992). The category of factors which can act as the secondary agent continues to be enlarged by every new study. These include interleukin 1 (n-l), IL2, TNFo, tumor necorsis factor p (TNFp), muramyl dipeptide, lipoteichoic acid, picolinic acid (metabolite of l-tryptophan), ozone, cAMP elevating agents, ultravoilet light, ozone and trauma (Ding, Nathan et al. 1988; Drapier and Hibbs 1988; Lorsbach, Murphy et al. 1993; Bastian and Hibbs 1994; Nathan and Xie 1994).In addition, a number of viral and antimicrobial products from mycobacteium tuberculosis, salmonella typhimuium and protozoan parasites have also been found to stimulate this form of the enzyme (MacMicking, North et ^1. 1997; Shoda, Kegerreis et al. 2001; Thoma-Uszynski, Stenger et al. 2001). Some food components are also capable of inducing NO and may be the mechanism of action of some food carcinogens, og soybean trypsin inhibitor, beta amylase (Nathan 1997). For example, nitrites and nitrates are important antimicrobial, flavouring and colouring agents in meat and fish products (Chow and Hong 2W2). 82
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UNIVERSITV OF AUCKI'AND Abstract -
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There was no significant difference
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This is Dedicated: Dedication To th
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New Zealand The Paediatric Departme
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Contents Abstract ........tr Dedica
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6.5.4 The subjects............... .
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XIV
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List of Figures Figure l.l: Top l0
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List of Abbreviations ABPA allergic
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LADA N*N* dimethyl L-arginine LFA1
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t}ryem(eNoS)Typeltrendothelialnifti
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area, some of it has been expanded
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In addition, both of these groups a
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studies conducted throughout the Un
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Video clips of infants with a varie
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the Paediatric Society of New 7*ala
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inhaled anti-cholinergic agents and
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ecommended to monitor asthma at hom
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improvement to 70Vo PEF would have
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Furthermore, investigators have als
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poorer predictor of a diagnosis of
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Bronsky et al. 1998), and a long-te
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SIGN guideline (SIGN 2005) stated "
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In brief, the human airway can be d
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The ability to biopsy has led to st
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Page 55 and 56: methodology of sputum induction and
Page 57 and 58: et al. 1999; Giannini, Di Franco et
Page 59 and 60: over a six month treatment prograrn
Page 61 and 62: There are other studies suggesting
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Page 67 and 68: onchial hyper-responsiveness (Reich
Page 69 and 70: led to research which looked for le
Page 71 and 72: analyser machines. This thesis pres
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Page 77 and 78: levels compared to those children l
Page 79 and 80: More recently 'Air Quality Indexes'
Page 81 and 82: acetylcholine. These were known to
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Page 93 and 94: 3.1 Chapter 3: The synthesis, react
Page 95 and 96: BHa = tetrahyrobiopterin, FAD = fla
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Page 103: Figure 3.3: The nitric oxide syntha
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Page 109 and 110: inappropriate production from comme
Page 111 and 112: Nicotinamide adenosine dinucleotide
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Page 115 and 116: 4.1 Introduction Chapter 4: Methods
Page 117 and 118: 4.4 Nitrite and nitrate The measure
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Page 121 and 122: A group of instruments have been de
Page 123 and 124: The original group demonstrated tha
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Page 127 and 128: helium for 30 minutes to remove Oz.
Page 129 and 130: (Postlethwait and Bidani 1990; Post
Page 131 and 132: is set at 5ppm (AIHA 1966) based on
Page 133 and 134: 5.1 Chapter 5: Methodological asses
Page 135 and 136: wanted to compare the patterns of e
Page 137 and 138: in different colours that became th
Page 139 and 140: an advisor for this work and main s
Page 141 and 142: Delay time: the time between turnin
Page 143 and 144: led to an increased water content t
Page 145 and 146: Chapter 6: Methodological studies o
Page 147 and 148: pulmonary circulation appeared to c
Page 149 and 150: al found levels of 10.3ppb compared
Page 151 and 152: Authors and Pap€r Sublect numbers
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6. Check that the pens work. Fill w
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keys but it is currently in the mid
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Calibration pressures: the test por
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T-piece: tO The first figure shows
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the rotameter. Tracings of each par
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Figure 6.6: Mean exhaled NO levels
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NO and COz results from single exha
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6.6.4 (iii) Comparison of exhaled n
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Figure 6.11b: COz levels at peak NO
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I also considered whether the diffe
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the direct to the indirect method l
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need for methodological experiments
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The exhalations were carried out in
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Figure 7.2: Example of the tracing
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7.4.4 Results There was an increase
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Table 7.3: NO, COz and duration of
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The second set of exhalations invol
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Figure 7.6: Photographs of the chan
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Table 7.5: Exhaled NO results with
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the NO concentrations taken pre and
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Figure 7.10: Hyperbolic relationshi
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pressure over the likely range enco
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subjects with respiratory disease,
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8.1 Chapter 8: Exhaled nitric oxide
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standard error of the mean (SEM), s
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T-piece sampling system to analyser
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Figure 8.2a: Comparison of peak exh
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if yes who? if yes who? if yes who?
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There are limitations with regard t
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significantly between research grou
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controls. Kharitinov et al reported
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direct method in asthmatic children
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Figure 8.4a: The eftect of commenci
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had last used her p2 agonist inhale
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higher level of exhaled NO at 4.9pp
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9.1 Introduction Chapter 9: Exhaled
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For the oral measurements options i
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Table 9.1: The recommended standard
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taken from the available literature
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compartment correlated with the ser
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measurement with variable expirator
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to settle. We may have been measuri
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9.5 Off-line measurement NO determi
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(Hyde, Geigel et al. 1997; Tsoukias
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9.6 Nasal nitric oxide measurement
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measured over two 24 hour periods,
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women who coincidently experienced
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While these cross-sectional and the
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symptoms. Steroid response was sign
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'difficult asthma' also had higher
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season and then reduced down to bas
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of cross sectional studies with a t
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Ciabattoni et al. 2004; Petersen, A
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FEV9.5, symptom score and airways r
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Indomethacin - This medication alte
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89Vo for PCD, and above that exclud
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This low NO occurs despite higher t
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patients were followed through one
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differences noted based on filter,
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9.L6 Nitric oxide levels in exercis
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another study of 111 school childre
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Almost all studies used sedation, w
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peak exhaled NO production in the f
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flow and to minimize nasal contamin
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ecruit blood vessels in the lung. S
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Chapter 10: Reflections The outcome
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and I enrolled 52 asthmatic childre
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Edwards EA, Douglas C, Broome S, Je
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o Cass Byrnes & Nicky Holt. "Drugs
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o Byrnes CA. Paediatric fibreoptic
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Appendix 2: Questionnaire for enrol
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Al-Ali, M. K. and P. H. Howarth (20
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Archer, S. L., P. J. Shultz, et al.
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Baraldi, E., N. M. Azzolin, et al.
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Belda, J., P. Hussack, et al. (2001
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Bongers, T. and B. R. ODriscoll (20
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Brown, G. C. and C. E. Cooper (1994
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Castro-Rodriguez, J. A., C. J. Holb
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Cockcroft, D. W., D. N. Killian, et
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de Blic, J., V. Marchac, et al. (20
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Donaldson, S. H., W. D. Bennett, et
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Emi-Miwa, M., A. Okitani, et al. (1
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Frey, U., J. Stocks, et al. (2000).
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Gershman, N. H., H. Liu, et al. (19
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Grasemann, H., E. Michler, et al. (
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Hashimoto, T., K. Minoguchi, et al.
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Holgate, S. T., D. E. Davies, et al
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Iriso, R., P. M. Mudido, et al. (20
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Jones, A. W., M. Fransson, et al. (
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Kercsmar, C. M. (2006). Wheezing in
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Kleinert, H., T. Wallerath, et al.
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Lamblin, C., P. Gosset, et al. (199
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Li, X. and J. W. Wilson (1997). "In
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Lymar, S. V. and J. K. Hurst (1996)
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Massaro, A. F., S. Mehta, et al. (1
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Miyabara, Y., R. Yanagisawa, et al.
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contribute to impaired endothelium-
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ODell, T. J., R. D. Hawkins, et al.
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Panza, J. A., C. E. Garcia, et al.
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Peters, S. P. (2006). "Safety of in
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Prieto, L., L. Bruno, et al. (2003)
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Ribbons, K. A., X. J. Zhang, et al.
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Sacco, O., R. Sale, et al. (2003).
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Sessa, W. C., K. Pritchard, et al.
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Silvestri, M., F. Sabatini, et al.
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Stamler, J. S. (1994). "Redox signa
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Stuehr, D. J., N. S. Kwon, et al. (
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Tierney, W. M., J. F. Roesner, et a
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Upchurch, G. R., G. N. Welch, et al
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Wadsworth, R., E. Stankevicius, et
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Williams, O., R. Y. Bhat, et al. (2
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Yates, D. H., S. A. Kharitonov, et
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