(Stroke. 1997;28:405-411.)
© 1997 American Heart Association, Inc.
Articles |
High Glucose Concentrations Dilate Cerebral Arteries and Diminish Myogenic Tone Through an Endothelial Mechanism
the Department of Surgery, Division of Vascular Surgery, Oregon Health Sciences University (Portland) (M.J.C., J.M.P.), and the Department of Obstetrics and Gynecology, University of Vermont College of Medicine (G.O.), Burlington, Vt.
Correspondence to Marilyn J. Cipolla, Division of Vascular Surgery, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail cipollam@ohsu.edu.
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Abstract |
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Background and Purpose Diabetes is associated with cerebrovascular disease and impaired autoregulation of cerebral blood flow. The purpose of this study was to determine the effect of acute glucose exposure on basal tone and myogenic reactivity of isolated rat cerebral arteries.
Methods Posterior cerebral arteries (PCAs, n=38) were dissected from male Wistar rats and mounted on glass cannulas in a system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were exposed to various concentrations of glucose, and the amount of basal tone and reactivity to TMP was measured. The effect of elevated glucose on cerebral endothelial modulation of basal tone was determined by mechanical denudation and the use of inhibitors of both nitric oxide and prostaglandin synthesis.
Results Arteries exposed to 44 versus 5.5 mmol/L glucose developed significantly less intrinsic tone (percent tone, 2±1% versus 28±2%; P<.01) and responded passively to increases in TMP. Preexisting tone present in 5.5 mmol/L glucose was eliminated on exposure to 44 mmol/L glucose, which decreased tone from 30±5% to 5±4% (P<.01). Glucose-induced dilations were concentration dependent such that half-maximal responses were obtained at 25±2 mmol/L. Endothelial removal abolished this effect, and the amount of tone was similar in 5.5 versus 44 mmol/L glucose (percent tone, 46±6% versus 49±5%; P>.05), as did inhibition of nitric oxide production with 0.3 mmol/L nitro-L-arginine (percent tone, 52±4% versus 46±3%; P>.05); however, blockade of the cyclooxygenase pathway with indomethacin (10-5 mmol/L) only partially inhibited the dilation to glucose (percent tone, 32±3% in 5.5 mmol/L versus 12.4±3% in 44 mmol/L; P<.01).
Conclusions Acute glucose exposure dilates arteries with intrinsic tone and impairs cerebrovascular reactivity to TMP via an endothelium-mediated mechanism that involves nitric oxide and prostaglandins.
Key Words: cerebral arteries • endothelium • glucose • nitric oxide • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Diabetes mellitus is associated with significant cerebrovascular disease,1 including an increased incidence of stroke and cerebral edema.2 3 Impaired autoregulation of CBF has been demonstrated during diabetes and is thought to contribute to the pathogenesis of diabetic cerebrovascular disorders.4 5 6 The arteries and arterioles of the cerebral circulation are different from many other vascular beds in that they possess considerable myogenic tone and respond to increases in TMP by active vasoconstriction.7 These pressure-dependent responses are thought to contribute to CBF autoregulation8 ; therefore, impairment of cerebral artery myogenic behavior during diabetes could have significant effects on cerebrovascular hemodynamics.
Although myogenic reactivity and basal tone are intrinsic to vascular smooth muscle, the ambient level of tone is modulated by endothelial synthesis and release of both vasoconstricting and vasodilating substances.9 It is generally accepted that long-term diabetes is associated with endothelial dysfunction and reduced endothelium-dependent vasodilation.10 11 12 13 14 15 16 17 Hyperglycemia associated with diabetes has also been shown to adversely affect the endothelium of several vascular beds,18 19 20 21 22 23 24 25 including the cerebral circulation,26 and to impair endothelium-dependent vasorelaxation to agonists that release NO.
In the present study, we hypothesized that altered production of endothelial vasodilators such as NO and prostaglandins during periods of high glucose exposure could significantly affect basal tone and myogenic reactivity of isolated and pressurized pial arteries. While previous studies have examined cerebral artery responses to endothelium-dependent agonists during acute and chronic hyperglycemia, this is the first study to directly investigate glycemic effects on basal endothelial function and its influence on myogenic reactivity and intrinsic basal tone.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Preparation of Arteries and Pressurized Arteriograph System
PCAs were obtained from male Wistar rats (n=38) and mounted in a specialized arteriograph chamber. The animals were quickly decapitated as approved by the institutional animal care committee at Oregon Health Sciences University. The cranium was opened, and the whole brain was removed and placed in cold (4°C) oxygenated Ringer's PSS. A third-order branch of the PCA was carefully dissected and placed either directly into one of the two arteriograph chambers or into a special dissecting dish for denudation.
Denudation was accomplished using a technique previously published.27 Briefly, arteries to be denuded were placed in a special dissecting dish containing several human hairs of various diameters (50 to 150 µm) and approximately 1.0 cm in length. The end of the artery to be denuded was grasped with fine forceps and gently pulled two to three times over a hair matched to its size, effectively removing the endothelial cell layer without damaging the surrounding smooth muscle cells. After denudation, arteries were transferred to one of the arteriograph chambers.
The arteriograph (Living Systems Instrumentation) consisted of two 20-mL chambers with inlet and outlet ports for superfusion of the arteries with PSS. The PSS was continually recirculated by a peristaltic pump through a heat exchanger to warm the PSS to 37°C before it entered the arteriograph chambers. Each chamber contained two glass microcannulas to which arteries were mounted and perfused with PSS and each end secured with a strand of nylon suture. TMP was measured and controlled by a servo system that consisted of an in-line pressure transducer, miniature peristaltic pump, and controller connected to the proximal cannulas. The distal cannulas were closed off so that there was no flow through the vessels during an experiment.
Lumen diameter was measured as previously described.28 Once the arteries were mounted and checked for leaks, the arteriograph chambers were transferred to the stage of an inverted microscope with an attached video camera and monitor. Lumen diameter was electronically measured from the transilluminated image of the artery by a video dimension analyzer, the output of which was sent to an IBM-compatible computer via a serial data acquisition system (DATAQ) for visualization of dynamic responses in TMP and lumen diameter, similar to a chart recorder.
Experimental Protocols
Response of Cerebral Arteries to Changes in TMP
To determine the effect of high glucose concentration on pressure-dependent myogenic tone and reactivity, one PCA was mounted in each chamber of the arteriograph filled with PSS containing either 5.5 mmol/L glucose (n=16) or 44 mmol/L glucose (n=13) in both perfusate and superfusate. After a 1-hour equilibration at 25 mm Hg, TMP was increased stepwise from 25 to 100 mm Hg in 25-mm Hg increments, and the diameter at each TMP was recorded. Several vessels were denuded of endothelium before equilibration as described above and equilibrated in either 5.5 mmol/L glucose (n=9) or 44 mmol/L glucose (n=9) PSS. TMP was then increased as in the intact arteries. After pressure steps, acetylcholine (10-5 mol/L) was added to the arteriograph bath to verify successful denudation, ie, lack of vasodilation in the denuded arteries.
Dilation of Preexisting Tone at TMP of 75 mm Hg
The effect of elevated glucose on preexisting tone was investigated in intact (n=6) and denuded (n=4) arteries by equilibrating at TMP of 25 mm Hg in 5.5 mmol/L glucose PSS. TMP was then increased to 75 mm Hg, and spontaneous tone was allowed to develop. The superfusate was then replaced with PSS containing 44 mmol/L glucose, and the diameter responses were recorded. The dose dependency of the glucose dilations was tested in both intact (n=5) and denuded (n=4) arteries by replacing the superfusate with PSS containing increasing concentrations of glucose (5.5, 16.5, 27.5, 35.75, and 44 mmol/L). The diameter was recorded for each concentration after a stable diameter was attained (approximately 10 minutes).
To determine the involvement of the cyclooxygenase pathway in mediating the response to glucose, indomethacin (10-5 mol/L) was added to the arteriograph bath in 5.5 mmol/L glucose before suffusion with 44 mmol/L glucose PSS (n=5). Similarly, the role of NO was tested by adding the NO synthase inhibitor L-NNA (0.3 mmol/L) in 5.5 mmol/L glucose PSS before exposure to 44 mmol/L glucose (n=8). To further investigate the involvement of NO in elevated glucose conditions, L-NNA was also given to intact arteries after dilation in the 44 mmol/L glucose PSS (n=8).
Osmotic Control
The specificity of the responses to glucose was tested in several arteries (n=6) using the metabolically inactive stereoisomer L-glucose in two different protocols. First, the response to TMP was tested by equilibration in 44 mmol/L L-glucose and 5.5 mmol/L D-glucose at 25 mm Hg. TMP was then increased stepwise, similar to intact arteries in D-glucose. Second, the specificity of the glucose dilations was tested by equilibration in 5.5 mmol/L D-glucose at 25 mm Hg. TMP was increased stepwise to 75 mm Hg, and tone was allowed to develop. The superfusate was then replaced with PSS containing 44 mmol/L L-glucose, and the diameter was recorded.
After experimentation, papaverine (0.1 mmol/L) was added to the arteriograph bath, and the relaxed diameter was recorded for each vessel over the entire pressure range.
Drugs and Solutions
All experiments were performed using PSS that both superfused and perfused the vessels; the ionic composition was (mmol/L) NaCl 119.0, NaHCO3 24.0, KCl 4.7, KH2PO4 1.18, MgSO4·7H2O, CaCl2 1.6, and EDTA 0.026. PSS was made each week and stored at 4°C without glucose. The appropriate amount of glucose (either D- or L-) was added to the PSS before each experiment. D-glucose, L-glucose, L-NNA, indomethacin, papaverine, and acetylcholine were purchased from Sigma Chemical Co.
Data Calculations and Statistical Analysis
All results are expressed as mean±SE. The amount of tone (either intrinsic or induced by L-NNA) was calculated as a percent decrease in diameter from the relaxed diameter in papaverine. Differences in percent tone were determined by ANOVA and considered significant at P<.05. The half-maximal concentration of glucose was calculated by first plotting the dose-response curve on a linear scale and extrapolating the value that elicited a 50% dilation off a best-fit line between 20% and 80% of the maximum.
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Results |
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Response of Arteries to Changes in TMP
Increasing TMP caused spontaneous vasoconstriction in arteries at 75 mm Hg in 5.5 mmol/L glucose PSS, which was maintained at 100 mm Hg. A tracing of the diameter response to stepwise increases in TMP in 5.5 mmol/L glucose PSS is shown in Fig 1
, top. At 75 mm Hg, the amount of tone (percent) in arteries in 5.5 mmol/L glucose PSS was 28±2%. Arteries equilibrated in 44 mmol/L glucose PSS, however, developed little or no tone and responded passively to increases in TMP. A tracing of the diameter response to increasing TMP in arteries equilibrated in 44 mmol/L glucose PSS is shown in Fig 1, middle. The average percent tone that developed in arteries in 44 mmol/L glucose was 2±1% (P<.01 versus in 5.5 mmol/L glucose). A graph of the percent tone in 5.5 mmol/L and 44 mmol/L glucose PSS at 75 mm Hg is shown in Fig 1, bottom.
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Denuded arteries in 5.5 mmol/L glucose PSS responded to increasing TMP by constricting and developing significantly more tone than intact arteries: 46.5±5.6% (P<.01 versus intact in 5.5 mmol/L glucose PSS). In contrast to intact arteries, however, denuded arteries equilibrated in 44 mmol/L glucose PSS responded to increases in TMP by active vasoconstriction, developing an amount of tone similar to that of denuded arteries in 5.5 mmol/L glucose PSS. The amount of basal tone present in denuded arteries at TMP of 75 mm Hg was not significantly different in arteries equilibrated in 5.5 mmol/L versus 44 mmol/L glucose: 49.0±4.7% in 44 mmol/L glucose PSS (P>.05 versus denuded in 5.5 mmol/L glucose PSS). A graph showing the percent tone at TMP of 75 mm Hg for denuded and intact arteries in 5.5 mmol/L and 44 mmol/L glucose is shown in Fig 2.
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Glucose Dilation of Preexisting Tone
In this set of experiments, intact arteries in 5.5 mmol/L glucose PSS developed a level of tone at 75 mm Hg similar to that in the previous experiments, with lumen diameter decreasing by 30.2±4.7%. Suffusion of 44 mmol/L glucose PSS dilated basal tone in these arteries, decreasing the amount of tone to 4.6±3.7% (P<.01). A diameter tracing of an intact artery with tone that dilated on exposure to 44 mmol/L glucose PSS is shown in Fig 3, top. Several arteries responded in a biphasic manner to the glucose suffusion, first constricting, then completely dilating. This response appeared to be due to a changing of the bath solution and not to the glucose itself, since cumulative addition of high glucose concentration from a stock solution of 1 mol/L glucose significantly diminished this effect.
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The dilation to elevated glucose exposure was endothelium dependent, since denuded arteries failed to dilate on exposure to the high glucose PSS. A diameter tracing of a denuded artery with tone and exposed to elevated glucose is shown in Fig 3
, bottom. In this artery, myogenic tone developed at 50 mm Hg and was maintained at higher pressures. Effective denudation is evidenced by the lack of dilation to acetylcholine; suffusion of high glucose PSS (44 mmol/L glucose) also failed to elicit a dilation.
Vasodilation to glucose in intact arteries was concentration dependent, with the half-maximal response occurring at 25±2 mmol/L glucose. Fig 4 shows the dose-response relationship of increasing glucose concentrations on inhibition of tone in intact and denuded arteries. Note that exposure to glucose did not elicit any dilation in denuded arteries.
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) and denuded (
) PCAs. Intact arteries dilated in a linear manner to increasing glucose concentrations, whereas denuded arteries did not show altered baseline diameter on exposure to glucose.
Response of Arteries With Indomethacin and L-NNA
Exposure of arteries to 10.0 µmol/L indomethacin before glucose suffusion inhibited a significant portion of the dilation to glucose, decreasing the amount of tone from 32±3% in 5.5 mmol/L glucose to 12±3% in 44 mmol/L glucose with indomethacin present (P<.01). A graph of the percent tone that developed in intact arteries with and without indomethacin is shown in Fig 5.
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Exposure of arteries to 0.3 mmol/L L-NNA before suffusion of 44 mmol/L glucose PSS, however, inhibited the dilation to glucose. L-NNA constricted arteries to a similar degree in both glucose concentrations, reducing lumen diameter by 52±4% in 5.5 mmol/L and 46±3% in 44 mmol/L glucose PSS (P>.05). A graph of the percent tone that developed in arteries with and without L-NNA in both glucose concentrations is shown in Fig 6. Furthermore, addition of 0.3 mmol/L L-NNA to arteries already dilated in 44 mmol/L glucose PSS constricted arteries and decreased lumen diameter by 45±5%. L-NNA did not have any significant effects on arterial diameter in denuded arteries (data not shown), indicating that this effect was due to endothelial production of NO. The restoration of tone by L-NNA after exposure to 44 mmol/L glucose can be seen in the diameter tracing in Fig 7. This artery had developed intrinsic basal tone and dilated on exposure to 44 mmol/L glucose PSS. When L-NNA was added, the artery constricted and tone was restored.
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Osmotic Control
L-Glucose had little effect on basal tone in intact arteries. Arteries equilibrated in 44 mmol/L L-glucose PSS plus 5.5 mmol/L D-glucose developed an amount of tone similar to that of arteries in just 5.5 mmol/L D-glucose, decreasing diameter by 33±4%. Furthermore, addition of 44 mmol/L L-glucose to arteries with tone in 5.5 mmol/L D-glucose failed to cause vasodilation, indicating that osmotic perturbations were not the cause of either the diminished reactivity to TMP or the dilations to glucose. The amounts of tone before and after suffusion of 44 mmol/L L-glucose were 30±5% and 26±6%, respectively (P>.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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The arteries and arterioles of the cerebral circulation operate in a state of partial constriction or tone that allows modulation of local blood flow by increasing or decreasing arterial diameter on demand.7 8 Although myogenic in origin, the level of basal tone can be modulated by endothelial production of vasodilators and vasoconstrictors.9 The most significant finding of the present study is that acute exposure to elevated glucose caused vasodilation and inhibition of arterial tone. This effect was inhibited when the endothelium was removed, indicating that glucose causes vasodilation via an endothelium-mediated mechanism.
The physiological significance of these results is that both cerebrovascular resistance and control of CBF may be impaired during periods of acute hyperglycemia. Impaired cerebrovascular autoregulation and alterations in CBF have been demonstrated during diabetes.4 5 6 29 30 31 32 33 34 35 36 37 Several studies in humans have shown elevated CBF in insulin-dependent diabetes,31 with one study demonstrating a 10% to 20% increase.29 Animal studies using diabetes experimentally induced by streptozotocin, however, are less consistent; some have shown an increase in CBF in rats,4 36 whereas others could detect no change.32 33 34
In nondiabetic rats, acute hyperglycemia (39.3±2.9 mmol/L) caused a small decrease in CBF that was not associated with changes in osmolarity30 and may be a compensatory autoregulatory response that follows vasodilation, as has been previously suggested in the cerebral circulation in response to mannitol.38 In contrast, Sieber et al37 demonstrated in nondiabetic dogs that acute hyperglycemia (14.94±2.52 mmol/L) was associated with elevated CBF and decreased cerebrovascular resistance, a result that is consistent with the findings of the present study.
Isolated arterial preparations and in vivo measurements using a cranial window technique have demonstrated decreased vasodilatory responses to agonists that release NO in both large basilar arteries14 16 and in smaller pial arterioles.15 17 26 However, the present study examined the effect of acute glucose exposure on cerebral artery myogenic tone and responses to TMP, a physiologically important component of autoregulation. It is unclear whether these arteries would have impaired agonist-mediated responses; however, this is the first study to demonstrate impaired myogenic responses to acute glucose exposure to be endothelium dependent.
To determine which endothelial factors may be the cause of the dilations to acute glucose exposure, inhibitors of NO production (L-NNA) and prostaglandin synthesis (indomethacin) were used. Inhibition of NO with L-NNA produced significant vasoconstriction and increased the level of tone in both glucose concentrations, thus demonstrating basal NO production in this circulation. Basal NO production by the endothelium has been shown to contribute to the maintenance of cerebrovascular resistance by providing a continuous vasodilator influence to counteract both neurogenic and myogenic vasoconstriction.39 40 Production of dilator prostaglandins during acute glucose exposure is probably less important than NO production, since blockade of the cyclooxygenase pathway with indomethacin inhibited only a portion of the dilation to glucose, whereas L-NNA inhibited the dilations in a manner similar to endothelial denudation and caused significant vasoconstriction in both glucose concentrations. Furthermore, addition of indomethacin did not significantly alter baseline diameter, indicating that basal prostaglandin synthesis is probably minimal in these arteries. Also, the significant vasoconstriction and the lack of dilation to glucose in the presence of L-NNA demonstrate the importance of the NO pathway in this circulation and in mediating the effects of glucose exposure.
Several studies have suggested augmented endothelial NO production in response to high glucose concentration exposure. Graier et al41 showed that cGMP levels were significantly elevated during agonist stimulation in cultured porcine aortic endothelial cells in response to chronic glucose exposure. In that study, the elevated levels of cGMP were associated with increased intracellular calcium levels. Other investigators have also demonstrated NO production to be strongly glucose dependent. Suschek et al42 measured nitrite and citrulline levels in both cultured islet endothelial cells and aortic endothelial cells. These investigators found that increased glucose in the culture media enhanced NO production in the islet cells but not in cells cultured from the aorta, suggesting a tissue-specific effect of glucose on endothelial cells. Although NO production was not measured in the present study, vasodilation of basal tone was demonstrated to be endothelium dependent and reversed on blockade of NO production.
In summary, exposure of isolated PCAs to elevated glucose concentrations caused vasodilation and loss of intrinsic basal tone. The loss of tone rendered the arteries passive and incapable of responding myogenically to TMP. This effect was endothelium dependent and appeared to involve the NO pathway and to a lesser extent prostaglandin synthesis. The diminished basal tone and impaired reactivity to TMP of pial arteries during periods of acute glucose exposure could impair autoregulation of CBF and diminish vascular resistance to downstream arterioles and capillaries.
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Selected Abbreviations and Acronyms |
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Received September 13, 1996; revision received October 29, 1996; accepted November 14, 1996.
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References |
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Editorial Comment
Department of Physiology and BiophysicsUniversity of Nebraska Medical CenterOmaha, Neb
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Diabetes mellitus produces morphological and functional alterations of cerebrovascular endothelium and appears to contribute to the pathogenesis of stroke.1R 2R 3R The purpose of the present study was to determine the acute effects of glucose on basal tone and myogenic reactivity of cerebral arteries.
PCAs were isolated using in vitro methodologies. The investigators examined the amount of basal tone and reactivity of arteries to changes in TMP during exposure to a physiological level of glucose (5.5 mmol/L) and to a high concentration of glucose (44 mmol/L). In addition, mechanisms for the effects of glucose on basal tone and myogenic reactivity were determined by using inhibitors of cyclooxygenase (indomethacin) and NO (L-NNA). The authors report that exposure to the high concentration of glucose produced relaxation of cerebral arteries and impaired myogenic vasoconstriction. Furthermore, relaxation of cerebral arteries in response to glucose was abolished by endothelial denudation and treatment with L-NNA but only partially inhibited by indomethacin.
The results of the present study may have implications regarding mechanisms that contribute to impaired autoregulation of CBF during hyperglycemia, and perhaps diabetes mellitus.
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Selected Abbreviations and Acronyms |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1R. Kannel WG, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA.. 1979;241:2035-2038.
2R.
Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K. Diabetes and the risk of stroke. JAMA.. 1987;257:949-952.
3R. Wolf PA, Kannel WB, Verter J. Current status of risk factors for stroke. Neurol Clin.. 1983;1:317-343.[Medline] [Order article via Infotrieve]
4R. Mayhan WG, Patel KP. Acute effects of glucose on reactivity of cerebral microcirculation: role of activation of protein kinase C. Am J Physiol.. 1995;269:H1297-H1302.
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  Y.-S. Kim, R. Krogh-Madsen, P. Rasmussen, P. Plomgaard, S. Ogoh, N. H. Secher, and J. J. van Lieshout Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H467 - H473. [Abstract] [Full Text] [PDF]
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M. E. J. Lott, C. Hogeman, M. Herr, R. Gabbay, and L. I. Sinoway Effects of an oral glucose tolerance test on the myogenic response in healthy individuals Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H304 - H310. [Abstract] [Full Text] [PDF]
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S. Lavi, D. Gaitini, V. Milloul, and G. Jacob Impaired cerebral CO2 vasoreactivity: association with endothelial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1856 - H1861. [Abstract] [Full Text] [PDF]
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Z. Bagi, E. Toth, A. Koller, and G. Kaley Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH4 Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H626 - H633. [Abstract] [Full Text] [PDF]
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J. C. Frisbee, K. G. Maier, and D. W. Stepp Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2160 - H2168. [Abstract] [Full Text] [PDF]
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S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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M. J. Cipolla, N. Lessov, E. S. Hammer, and A. B. Curry Threshold Duration of Ischemia for Myogenic Tone in Middle Cerebral Arteries : Effect on Vascular Smooth Muscle Actin Stroke, July 1, 2001; 32(7): 1658 - 1664. [Abstract] [Full Text] [PDF]
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