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1 School of Kinesiology, University of Western Ontario, London, Ontario N6A 3K7; and 2 Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Arterial hypocapnia has been associated with
orthostatic intolerance. Therefore, we tested the hypothesis that
hypocapnia may be detrimental to increases in muscle sympathetic nerve
activity (MSNA) and total peripheral resistance (TPR) during head-up
tilt (HUT). Ventilation was increased ~1.5 times above baseline for each of three conditions, whereas end-tidal
PCO2 (PETCO2) was clamped at normocapnic (Normo), hypercapnic (Hyper; +5 mmHg relative to
Normo), and hypocapnic (Hypo; 
5 mmHg relative to Normo) conditions. MSNA (microneurography), heart rate, blood pressure (BP, Finapres), and
cardiac output (Q, Doppler) were measured continuously during supine
rest and 45° HUT. The increase in heart rate when changing from
supine to HUT (P < 0.001) was not different across
PETCO2 conditions. MSNA burst
frequency increased similarly with HUT in all conditions
(P < 0.05). However, total MSNA and the increase in
total amplitude relative to baseline (%
MSNA) increased more when
changing to HUT during Hypo compared with Hyper (P < 0.05). Both BP and Q were higher during Hyper than both Normo and Hypo (main effect; P < 0.05). Therefore, the MSNA response
to HUT varied inversely with levels of
PETCO2. The combined data suggest that augmented cardiac output with hypercapnia sustained blood pressure during HUT leading to a diminished sympathetic response.
muscle sympathetic nerve activity; head-up tilt; end tidal CO2; cardiac output; total peripheral vascular resistance
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BOTH CHEMOREFLEXES AND BAROREFLEXES are important modulators of sympathetic outflow (24, 27, 29). Receptors in the cardiac chambers, aorta, and carotid bodies respond to changes in the heart wall or vascular stretch leading to increases in sympathetic outflow during reductions in venous return or pulse pressure (13, 16). Changes in arterial CO2 pressure (PaCO2) also influence autonomic outflow primarily through receptors located on the ventral medullary surface (11, 32). The afferent neural projections from these receptors converge on the nucleus tractus solitaris of the rostral ventrolateral medulla (see Ref. 5 for review) providing an anatomic basis for interactions between chemoreflex and baroreflex cardiovascular control.
Burke et al. (3) first demonstrated the large increase in muscle sympathetic nerve activity (MSNA) during upright posture in humans. This large change in sympathetic outflow underlies the importance of autonomic cardiovascular control during orthostasis. When upright, the baroreflexes are unloaded contributing to the increased sympathetic outflow. In addition, PaCO2 may be reduced when standing upright (19). In hypoxic dogs, levels of PaCO2 directly influenced blood pressure with hypertension during hypercapnia and hypotension during hypocapnia (21). Importantly, hypocapnia has been associated with a greater incidence of orthostatic intolerance (19). Alternatively, elevating PaCO2 by ~10 mmHg above resting values has produced moderate increases in both blood pressure and MSNA (28). In addition, the increase in MSNA with hypercapnia is sustained during baroreceptor loading with phenylephrine (27). These combined observations suggest that chemoreceptor input may directly influence sympathetic responses to orthostatic stress.
However, there is experimental evidence to support the counterhypothesis that the increase in sympathetic outflow during HUT may vary inversely with PaCO2. First, elevated PaCO2 may exert direct vasconstrictor effects (10). In addition, central chemoreceptor activation may increase venous return (6, 11, 23). If so, then hypercapnia may support cardiac output (Q) and blood pressure maintenance during head-up tile (HUT) so that requirements for a sympathetically mediated vasoconstriction are diminished.
The potential for chemoreflex modulation of sympathetic control during postural stress represents an important area of investigation for cardiovascular control mechanisms. Therefore, the purpose of this study was to examine the hypothesis that chemoreceptors modulate sympathoexcitation during postural stress. The MSNA and cardiovascular responses to 45° HUT were examined under conditions where end-tidal CO2 pressure (PETCO2) was clamped at ±5 mmHg of normocapnic levels and where tidal volume and breathing frequency were also clamped to normalize lung stretch receptor modulation of sympathetic outflow (24, 28, 30) across all conditions. In addition, we measured cardiac stroke volume (SV) and heart rate to determine the contributions of Q versus total peripheral resistance (TPR) in blood pressure control.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Ten health individuals (6 male and 4 female) volunteered for the study. All females were in the early follicular phase of the menstrual cycle. The subjects were 176 ± 8 cm in height and 73.6 ± 12 kg in weight (means ± SD). The mean age was 24.8 yr (range = 22-34 yr). Each volunteer provided signed consent for the experimental procedures that had been approved by the institutional Office of Research Ethics.Measurements
Heart rate was determined by standard electrocardiogram methods. Arterial pressure was measured continuously from the finger of the left hand by photoplethysmographic methods (Finapres, Ohmeda 2300; Englewood, CA). Baseline blood pressures from the Finapres device were corrected against manually obtained systolic and diastolic measures before the onset of the data collection.Sympathetic activation was assessed by microneurographic (33) measures of MSNA in the common peroneal nerve. A 200-µm diameter, 35-mm long tungsten microelectrode that tapered to an uninsulated 1- to 5-µm tip was inserted transcutaneously into the peroneal nerve just posterior to the fibular head. A reference electrode was positioned subcutaneously 1-3 cm from the recording site. Neuronal activity was amplified 1,000 times by a preamplifier and 50-100 times by a variable gain isolated amplifier. The signal was band-pass filtered with a bandwidth of 700-2,000 Hz and was then rectified and integrated to obtain a mean voltage neurogram (0.1-s time constant). A MSNA site was confirmed by manually manipulating the microelectrode until the characteristic pulse-synchronous burst pattern was observed that did not produce skin paresthesias and that increased in frequency during a voluntary apnea but not in response to arousal (7).
Cardiac SV and aortic dimensions were obtained to calculate Q on a continuous basis. Aortic diameter was obtained using echo Doppler ultrasound (3.75 MHz, phased array probe, Toshiba model SSH-140A) with a longitudinal view of the aorta from the third intercostal space. Our preliminary studies indicated that aorta diameters ranged from 2.7 ± 0.1 to 2.8 ± 0.1 cm between supine and HUT during each PETCO2 level (n = 6; not significant). Therefore, the aortic measurements obtained during the study were made during the supine phase of each PETCO2 condition. SV velocity was obtained from the suprasternal notch using a hand-held 2-MHz continuous wave probe (Exerdop, Quintin Instrument). The quadrature output from the Exerdop device was demodulated to provide a mean velocity tracing of the SV velocity.
Respiratory excursions were assessed by a Respitrace plethysmograph (Respitrace). PETCO2 was assessed by a breath-by-breath gas mass spectrometer (MGA-1100 Medical Gas Analyzer, Perkin-Elmer). The analog signal for each variable was stored using a TEAC RD-111T data recorder (Teac). Offline analysis of the heart rate (from the electrocardiogram sampled at 1,000 Hz), blood pressure, and blood flow data were performed with customized data analysis software. The MSNA data were sampled at 100 Hz and stored on computer for subsequent analysis (PowerLab 8S, AD Instruments).
Experimental Design
Upon arrival at the laboratory each subject voided his/her bladder and was measured for height and weight. After instrumentation, baseline respiratory rate, tidal volume, and PETCO2 levels were obtained over at least a 10-min period of spontaneous breathing with the subject in supine rest. This baseline period was used to identify the PETCO2 associated with normocapnia.Controlled breathing. A controlled-breathing protocol was used to normalize the effects of lung stretch receptors on sympathetic outflow (10) across all conditions. An auditory signal was used to control respiratory frequency at 15 breaths/min (0.25 Hz) by cueing subjects to inhale and exhale over 4 s with an inspiratory-to-expiratory ratio of 1:1. Tidal volume was then adjusted so that total ventilation was increased ~50% above baseline control levels. Tidal volume was held at this level by the subjects who watched an oscilloscope that displayed tidal volume excursions. The breathing pattern was monitored closely by the experimenters to ensure adherance to the protocol. This breathing protocol caused a reduction in PETCO2 to ~8-10 mmHg below control levels. Thereafter, PETCO2 was clamped at one of three levels representing normocapnia, hypocapnia, and hypercapnia using a computerized gas-mixing system (22). Hypocapnia and hypercapnia levels were 5-mmHg below and above control levels, respectively. The hypocapnia level was chosen to reflect the range of PETCO2 typically observed during HUT (18, 26). These levels were maintained during each condition while the subject maintained the same breathing frequency and tidal volume. The order of the conditions was varied across subjects.
Each of the three PETCO2 conditions included supine and HUT collection periods. After a 7-min supine collection period, the subject was tilted to a 45° HUT position for an additional 7 min before returning to supine. The 45° HUT angle was chosen to elicit a moderate orthostatic stress while diminishing the risk of electrode displacement during the tilt transition. During the HUT phase the subjects supported their weight on the left leg with the foot planted firmly on a footplate attached to the tilt table. MSNA data were obtained from the right leg, which was slightly bent and supported at the knee. Between each tilt session the mask was removed and the subject was allowed to breathe spontaneously for 5-10 min. The mask was then replaced, the hyperventilatory breathing sequence was started, and the next level of PETCO2 condition was initiated. Data were collected continuously during the supine and HUT positions.Data Analysis
Muscle sympathetic nerve activity was analyzed by identifying each burst (2:1 signal-to-noise ratio) and then determining the amplitude of each burst over the final 5 min of supine and HUT positions. Burst frequency per minute was determined as the total burst count during the 5-min period of analysis divided by 5 min. The total MSNA per minute during the different baseline or HUT periods was then calculated as the sum of analog-integrated MSNA burst amplitudes divided by 5 min. More than one MSNA recording site was required in three subjects, but in no case was a nerve recording site lost on going from supine to HUT positions. To account for possible effects of altered electrode position and PETCO2 on baseline MSNA levels and to determine the MSNA response during each condition, the percent increase in total MSNA amplitude over supine levels was calculated. In addition, average values of heart rate, blood pressure, and cardiac SV were obtained during the final 2 min of each collection period.SV was calculated as the product of cross-sectional area
(
r2) and mean SV velocity over a given R-R
duration. Q (in l/min) was then determined as the SV × HR, where
HR is heart rate. TPR was calculated from mean arterial pressure (MAP)
and Q as TPR = MAP/Q.
Statistics
The effects of PETCO2 level and posture on all measured variables were assessed using a repeated measures two-way analysis of variance (ANOVA) procedure with a Mixed-Effects Linear Model (SAS) and Tukey's post hoc analysis. The level of probability for statistical significance was P < 0.05. All data are represented as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Ventilatory Responses
PETCO2 was maintained at ~40 mmHg in the normocapnic trials and ±5 mmHg in the hypercapnic and hypocapnic conditions, respectively (Table 1). Tidal volume was maintained across conditions (Table 1). Breathing frequency was maintained for all test conditions at ~16 breaths/min except HUT during hypercapnia, where respiratory rate increased by ~2 breaths/min (P < 0.05) above the desired levels leading to a concurrent increase in total ventilation (P < 0.05; Table 1).
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Hemodynamic and MSNA Responses
Original blood pressure, heart rate, and MSNA responses from a representative subject obtained while supine and in HUT during hypocapnia and hypercapnia are illustrated in Fig. 1. These tracings demonstrate that in contrast to hypocapnia, blood pressure was maintained with HUT during hypercapnia but with a diminished orthostatic MSNA response.
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In a similar manner, the averaged systolic blood pressure was not
altered between supine and HUT postures in any test condition. However,
systolic blood pressure was significantly elevated during hypercapnia
compared with normocapnia and hypocapnia (Fig.
2, main effect; P < 0.05). Diastolic blood pressure did not change with HUT but was greater
during hypercapnia compared with hypocapnia (main effect of
PETCO2) (P < 0.05; Fig.
2).
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Supine heart rate was not altered with the changing
PETCO2 levels (Fig.
3). Heart rate increased ~15-17
beats/min when changing from supine to HUT (P < 0.0001). The increase in heart rate with HUT was not different
across PETCO2 conditions. SV was reduced during HUT in each experimental condition (P < 0.05;
Fig. 3). Importantly, overall SV was greater during hypercapnia
compared with hypocapnia (main effect of
PETCO2, P < 0.01).
Subsequently, Q was greater during hypercapnia compared with hypocapnia
(main effect of PETCO2, P < 0.01). The increase in heart rate with each HUT compensated for the
reductions in SV so that Q was maintained close to the supine levels
(P = 0.1). However, supine Q was elevated in
hypercapnia compared with hypocapnia (P < 0.05).
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Compared with supine (16 ± 2 mmHg · l
1 · min1) TPR was
greater during HUT (23 ± 4 mmHg · l1 · min1) in
hypocapnic (P < 0.05) but not in any other HUT
condition (Fig. 3). Overall, TPR was less during hypercapnia compared
with hypocapnia (main effect of PETCO2,
P < 0.01). When comparing HUT levels only, TPR during
the hypercapnic trial was less than during the hypocapnic trial
(P < 0.05; statistical indicators not shown on Fig.
3).
Sympathetic nerve amplitude is affected by electrode placement within the nerve fascicle. Recording sites were maintained in all transitions from supine to HUT allowing direct comparisons of total MSNA amplitude within each condition. In three subjects, nerve recording sites were altered during the transition from HUT back to supine. Therefore, the effect of altered PETCO2 on baseline MSNA amplitude was not tested.
Sympathetic nerve burst frequency while supine was not affected by the
altered ventilatory patterns or by increasing or reducing PETCO2 (Fig.
4). In addition, the increase in MSNA
burst frequency on going from supine to HUT (P < 0.0001) was not different between the different
PETCO2 levels.
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The total MSNA response to HUT varied inversely with the level of PETCO2. During hypocapnia total amplitude increased from 1,504 ± 503 units while supine to 4,535 ± 1,640 units during HUT (P < 0.005) (Fig. 4). In normocapnia total MSNA amplitude increased from 1,274 ± 521 units while supine to 3,038 ± 1,283 units in HUT (P < 0.05). During hypercapnia total MSNA was 1,567 ± 621 units while supine and 2,867 ± 1,136 units in HUT (P < 0.1). The diminished increase in total MSNA with HUT in hypercapnia despite similar changes in burst frequency across conditions was due to a smaller relative increase in average burst amplitude in hypercapnia (11 ± 7%) compared with hypocapnia (31 ± 13%; P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The primary finding of the current study was that mild alterations in PETCO2 were related inversely to the sympathetic response to postural stress in humans. Thus, when compared with the hypocapnic condition, MAP during HUT in hypercapnia was maintained by elevated Q while the increase in MSNA was attenuated and TPR was diminished. Thus it appears that the augmented Q during hypercapnia led to elevated blood pressures that diminished the sympathetic vasoconstrictor response to HUT. The current findings are consistent with recent reports that severe hypercapnia (70-80 mmHg) elevated Q and diminished TPR in supine sedated patients with acute respiratory distress syndrome (35). However, the current data indicate that the hemodynamic effects of hypercapnia may be evident with much smaller changes in PETCO2, and that these effects are sustained during postural stress.
Medullary and peripheral chemoreceptors respond to changes in
PaCO2. The primary assumption of the current study was
that manipulation of PETCO2 would result
in similar changes in PaCO2. It has been shown during
physical exercise that PETCO2 varies as a
function of PaCO2 and tidal volume
(PaCO2 = 5.5 + 0.9 PETCO2 0.0021 tidal volume)
(14). Therefore, under the current conditions where tidal
volume was controlled, PaCO2 should vary solely as a
function of PETCO2 and thereby reflect
accurately any changes in arterial CO2 levels
(36).
Muscle Sympathetic Nerve Responses
Chemoreceptor activation results in increased ventilation that, in turn, may inhibit sympathetic outflow (4, 29) at least during conditions of supine rest. In addition, PaCO2 is reduced on going from the supine to head-up postures (19, 25). The subsequent modifications to ventilatory control may then affect maintenance of PaCO2 and MSNA. Furthermore, lung inflation, or other factors associated with diaphragmatic activation, modulate within-breath sympathetic outflow (24, 28). To diminish the effects of these ventilatory factors to the MSNA response during HUT, PETCO2 was clamped between supine and HUT postures, and tidal volume excursions were maintained at similar levels throughout the study. Evidence that even large changes in breathing frequency do not affect total MSNA averaged over time (24) suggests that the ~2 breaths/min greater ventilatory rate in HUT with hypercapnia did not interfere with the current analysis.In humans, baseline MSNA increased modestly by ~50% when PETCO2 was increased by ~10 mmHg with 6-7% inspired CO2 (27). These observations contrast with the current data where baseline MSNA was not altered by either 5 mmHg hypercapnia or hypocapnia. It is possible that MSNA might have changed with a greater modification of PETCO2, but this was not investigated.
Hypercapnia and Q
Heart rate responses to HUT were similar across the three PETCO2 conditions, and the changes in Q during hypercapnia were primarily the result of augmented SV. The improved SV in hypercapnia suggests that cardiac function was improved under this condition by an unknown mechanism. Improved left ventricular contractility during hypercapnia is unlikely because current evidence indicates that cardiac inotropy is reduced in hypercapnia (34, 35). Moreover, increases in peripheral and central sympathetic outflow appear to occur concurrently (15). Therefore, enhanced sympathetically mediated cardiac contractility seems an unlikely explanation of the augmented SV because, in hypercapnia, the MSNA response was diminished. Increased ventilation may affect venous return through intrathoracic pressure excursions (17). However, ventilatory tidal volumes were maintained at levels that were ~50% above spontaneous levels throughout the study thereby minimizing any effect of varying intrathoracic pressure oscillations on venous return. Finally, the higher systolic afterload during hypercapnia would not have facilitated increased SV. Therefore, it does not appear that the respiratory pump or changes in cardiac contractility or afterload can explain the observed increase in SV during hypercapnia.On the basis of earlier evidence, we propose that the improved SV during hypercapnia was mediated by improved cardiac filling resulting from increases in venous return. Specifically, severe hypercapnia and hypoxic hypercapnia have been associated with diminished vascular capacitance, increased venous return, and increased Q in anesthetized dogs (1, 11, 23). In these earlier studies the improved central circulation was related to a redistribution of volume from splenic and splanchnic capacitance vessels (11). Thus it appears that elevated PaCO2 may enhance venous return through a translocation of blood to a less compliant vascular bed (6).
Although enhanced venous return may explain the current data, the mechanism of CO2-mediated changes in venous return remains speculative. The improved venous return, combined with observations of elevated sympathetic outflow during increased PaCO2 (6, 11, 27), suggests that a redistribution of blood flow may be occurring during hypercapnia due to a sympathetically mediated constriction of capacitance organs. However, MSNA directed to skeletal muscle was not augmented during the mild hypercapnia in the current study, and the reflex response to HUT was smaller than that observed during hypocapnia. Yet improvements in Q and mean systemic blood pressure were observed in hypercapnia. Thus CO2 may act on flow distribution by a nonsympathetic mechanism (11), by differentially affecting the efferent sympathetic signals to skin, muscle, and visceral vascular beds, and/or by eliciting venoconstriction (31).
Data from patients with autonomic failure support the idea of direct vasoactive effects of CO2. Specifically, Onrot et al. (20) reported that in the absence of a functioning autonomic nervous system, hyperventilation leads to a large reduction in blood pressure. In contrast, these patients demonstrate a hypertensive response when PETCO2 is increased. Similarly, blood pressure was directly related to PETCO2 in hypoxic dogs (21). Therefore, arterial CO2 levels appear to exert a constrictor effect on some level of the peripheral vasculature.
The level of peripheral vasculature affected by CO2 has not been examined, but indirect evidence implicates the involvement of the veins. Canine capacitance vessels are under chemoreceptor (8) and baroreceptor (9) control. Moreover, distinct populations of sympathetic neurons innervating mesenteric veins and arterioles have been observed (2). Furthermore, the combined increase in Q with concurrent reductions in TPR with hypercapnia observed in the current and earlier (35) studies supports the hypothesis that CO2 may exert constrictor responses that are isolated to capacitance rather than resistance vessels. One interesting aspect of the current study is that these vasoactive effects of CO2 might be evident at even moderate levels of hypercapnia, which do not appear to affect baseline sympathetic outflow. This is consistent with in situ observations that capacitance vessels show a greater degree of responsiveness at lower neural discharge frequencies of stimulation than arterioles that require higher stimulation frequencies to produce the same degree of constriction (12).
In summary, blood pressure regulation during postural stress requires complex contributions from cardiovascular, neural, and respiratory control mechanisms. The current data provide evidence of this interaction in conscious humans. The finding that PETCO2 inversely affected the sympathetic response to HUT due to effects on SV pointed to the potential role of a CO2 influence on venous return. Importantly, the effect of PaCO2 on Q was observed at levels that did not modulate baseline MSNA. Therefore, it is possible that CO2 may have direct actions on veins or may alter distribution of sympathetic outflow following chemoreceptor and postural sympathoexcitatory stimuli.
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ACKNOWLEDGEMENTS |
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The authors are grateful for the expert technical assistance of David Northey, Tim Wilson, Derek Kimmerly, and Mike Edwards during data collection and analysis.
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FOOTNOTES |
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This research was supported by the Natural Sciences and Engineering Research Council of Canada (to K. Shoemaker) and by the cooperative activities program grant from National Sciences and Engineering Research Council and the Canadian Space Agency Grant 216758-98 (to R. L. Hughson).
Address for reprint requests and other correspondence: J. K. Shoemaker, Neurovascular Research Laboratory, School of Kinesiology, Rm. 3110, Thames Hall, Univ. of Western Ontario, London, Ontario, Canada N6A 3K7 (E-mail: kshoemak{at}uwo.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 November 2000; accepted in final form 27 April 2001.
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TOP
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RESULTS
DISCUSSION
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