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SKELETAL MUSCLE AND EXERCISE |
1 Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA
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Abstract |
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(Received 25 January 2007;
accepted after revision 26 March 2007;
first published online 29 March 2007)
Corresponding author S. G. Hayes: Penn State Heart and Vascular Institute, 500 University Drive, H047, Hershey, PA 17036, USA. Email: shayes1{at}hmc.psu.edu
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Introduction |
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Lactic acid is one of the metabolic products of contraction that has been suggested to be a metabolic stimulus to thin fibre muscle afferents (Victor et al. 1988; Sinoway et al. 1989; Pryor et al. 1990; MacLean et al. 1998; Fadel et al. 2003). For example, injection of lactic acid into the arterial supply of skeletal muscle has been shown to evoke reflex increases in arterial pressure, heart rate and ventilation that approximate those occurring during static exercise (Rotto et al. 1989). In contrast, injection of sodium lactate at a neutral pH failed to evoke any reflex cardiovascular effects (Rotto et al. 1989). Moreover, injection of lactic acid into the arterial supply of skeletal muscle has been shown to increase the discharge of group III and IV muscle afferents as well as to make group III afferents more sensitive to mechanical stimuli (Rotto & Kaufman, 1988; Sinoway et al. 1993).
To demonstrate that a particular metabolite contributes to the elicitation of the exercise pressor reflex, investigators need to show that blockade of a specific receptor to the metabolite prevents or attenuates the expression of the reflex. This demonstration has been difficult to achieve for lactic acid because its receptor on group III and IV afferents was not clearly identified. In particular, lactic acid was thought to activate both the transient receptor potential vanilloid 1 (TRPV 1) receptor as well as the acid sensing ion channel (ASIC). Recently, the TRPV 1 receptor was shown to play little if any role in evoking the metabolic component of the exercise pressor reflex (Kindig et al. 2005). This finding has shifted our attention to acid sensing ion channels in general and to the ASIC3 in particular for two reasons. First, the pH required to activate the ASIC1 and 2 channels is at or below 5.0, a level which is not physiologically relevant in vivo (Alvarez de la Rosa et al. 2002). Second, the ASIC3 is much more sensitive to lactic acid than other acids when compared with the other ASIC channels (Immke & McCleskey, 2001). Although this finding pointed towards the ASIC 3 receptor, there was no known specific antagonist for it.
One possible candidate is amiloride, which has been shown to block ASICs (Waldmann et al. 1997). Unfortunately, amiloride has also been shown to antagonize voltage-gated sodium channels, rendering it able to block impulse conduction in excitable membranes. As a consequence, amiloride may prevent or attenuate the metabolic component of the exercise pressor reflex by blocking impulse conduction in group III and IV muscle afferents as well as by blocking the acid-sensitive ion channel on their endings in the interstitium. In the experiments to be reported, we have searched for a dose of amiloride that attenuated the exercise pressor reflex, but had no effect on the pressor responses to tendon stretch and capsaicin injection into the arterial supply of skeletal muscle. Finding such a dose of amiloride would enable us to examine the role played by ASIC in the generation of the metabolic component of the exercise pressor reflex.
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Method |
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The Institutional Animal Care and Use Committee of the University of California, Davis approved all procedures. Adult cats (n = 51), weighing between 2.5 and 4.6 kg, were initially anaesthetized by inhalation of a mixture of halothane (5%) and oxygen. The trachea was cannulated, and the lungs were ventilated with the anaesthetic gas mixture (1.5-2% halothane). The right common carotid artery and external jugular vein were cannulated for monitoring blood pressure and administering fluids, respectively. The tip of the carotid arterial catheter was located in the thoracic aorta and was pointed towards the leg. Blood pressure was measured by connecting the carotid arterial cannula to a Statham P23XL transducer. Arterial PO2, PCO2 and pH were measured periodically (model ABL 700 Series, Radiometer) and were maintained within normal limits either by adjusting ventilation or by administering sodium bicarbonate (8.5% I.V.). Prior to the decerebration procedure, dexamethasone (4 mg) was injected intravenously to reduce swelling of the brain stem. Additionally, the left common carotid artery was ligated in order to reduce bleeding during the decerebration. The cat was then placed in a Kopf stereotaxic frame and spinal unit and a mid-collicular decerebration was performed. The gaseous anaesthetic was gradually discontinued, and the lungs were ventilated with room air.
The left hind limb was fixed in place at the ankle and knee by clamps, and the left triceps surae muscles, calcaneal tendon and sciatic nerve were exposed. The tendon was severed from the calcaneal bone, attached to a force transducer (model FT-10, Grass Instruments), and stretched with a rack and pinion so that it developed a resting tension of approximately 400 g. Snares were placed around the left common iliac artery and vein in the abdomen for occluding the blood flow to the hind limb. At the conclusion of the experiment the cat was humanely killed with an overdose of pentobarbital (Cardinal) followed by an injection of saturated KCl solution.
Recording activity of muscle spindles, group III and IV afferents
We recorded the impulse activity of individual spindles, group III and IV triceps surae muscle afferents from the distal cut end of the left L7 or S1 dorsal roots. In these cats, a lumbosacral laminectomy was performed to expose the L6 to S2 spinal roots. The left peroneal, sural, gluteal, femoral and obturator nerves, as well as the muscular branch of the sciatic nerve, were cut. The neural signals were passed through a high-impedance probe (Grass HIP511), amplified (Grass P511), and filtered (0.1 to 3 kHz band pass). The action potentials were displayed on a computer monitor (Spike 2) as well as on a storage oscilloscope (Hewlett-Packard). An afferent's receptive field was identified as being in the triceps surae muscles if a burst of impulses were discharged in response to stretch of the muscle in the case of a muscle spindle and by either noxious or non-noxious probing of the muscle in the case of group III and IV afferents. Noxious probing consisted of vigorously pinching the muscles with the fingers, whereas non-noxious probing consisted of either gently stroking the triceps surae with a blunt rod or gently squeezing the muscles with the fingers.
We classified afferents as spindle, group III or group IV by their conduction velocities. Afferents with conduction velocities above 30 m s–1, which were inhibited by twitch, and which were stimulated by muscle lengthening were classified as spindles. Afferents with conduction velocities between 2.5 and 30 m s–1 were classified as group III, and afferents with conduction velocities of < 2.5 m s–1 were classified as group IV. We calculated conduction velocity by measuring the conduction time and distance from a stimulating electrode placed under the tibial nerve close to its exit from the triceps surae muscles and the recording electrode placed under the dorsal root filament. The criterion for a response by an afferent to a manipulation was an increase greater than or equal to 0.2 impulses s–1.
Reflex protocols
To test the effects of amiloride on the exercise pressor reflex we recorded the blood pressure and heart rate responses before, and then 30 and 60 min after one of two doses of amiloride (5 µg kg–1 or 0.5 µg kg–1) to each of four manoeuvers. These were tendon stretch, static contraction of the triceps surae muscles, injection of lactic acid (0.2–0.5 ml; 24 mM) into the popliteal artery, and injection of capsaicin (1–2 µg, 0.25 ml) into the popliteal artery. The concentration of amiloride injected to achieve the large dose (5 µg kg–1) was 200 µM, whereas the concentration injected to achieve the small dose (0.5 µg kg–1) was 20 µM. Only one of the two doses of amiloride was given to each cat.
Tendon stretch was accomplished by stretching the calcaneal tendon with a rack and pinion for 60 s. Static contraction was accomplished by stimulation of the tibial nerve for 60 s at or below twice motor threshold (0.025 ms pulse duration; 40 Hz for reflex experiments and 15–20 Hz for afferent recording experiments). Next, each cat briefly underwent neuromuscular blockade with rocuronium bromide (0.5–0.7 mg kg–1; I.V.) and the tibial nerve stimulated again. In every instance, stimulation after paralysis no longer generated a pressor response. Moreover, no tension was generated by the triceps surae muscles. Injections of lactic acid, capsaicin, as well as a neutral pH saline solution were accomplished by gently inserting a 30-gauge needle into the popliteal artery and then injecting the compounds over approximately 10 s into the vasculature of the triceps surae muscles. The manoeuvers were randomized to eliminate any order effect. Before injecting either capsaicin or lactic acid into the popliteal artery, we paralysed the cat by injecting intravenously rocuronium bromide (0.5–0.7 mg kg–1). Once we identified a muscle spindle, group III or IV afferent with a receptive field in the triceps surae muscles and established its resting level of activity, we recorded the response of the afferent to a variety of manoeuvers, depending on its classification.
Electrophysiological protocols
When a muscle spindle was identified, the cat then underwent neuromuscular blockade. We recorded its responses to two manoeuvers. The first was injection of 1–2 mg of succinylcholine into the catheter placed into the carotid artery, and the second was stretch of the calcaneal tendon. Both manoeuvers were performed before and 30 and 60 min after one of two doses of amiloride (5 µg kg–1 or 0.5 µg kg–1) was injected into the popliteal artery and trapped there for 10 min by tightening the arterial and venous snares. Succinylcholine was used because this agent has been shown to stimulate muscle spindles (Granit et al. 1953; Waldrop et al. 1984). Moreover, succinylcholine has no effect on the discharge of group III and IV muscle afferents (Waldrop et al. 1984).
When a group III or group IV muscle afferent was identified, we recorded its responses to at least one of the four manoeuvers described above (see Reflex protocol). All manoeuvers were performed before, and then 30 and 60 min after one of two doses of amiloride (5 µg kg–1 or 0.5 µg kg–1) was injected into the popliteal artery. The amiloride injectate was trapped in the artery for 10 min. Injections of capsaicin and lactic acid were performed subsequent to neuromuscular blockade of the cat with rocuronium bromide (0.5–0.7 mg kg–1).
Data analysis
Blood pressure, heart rate, muscle tension and impulse activity were all recorded with Spike 2 data acquisition system (CED, Cambridge) and stored on a computer hard drive (Dell). Mean arterial pressure is expressed in mmHg, heart rate in beats per minute, and afferent activity is expressed in impulses per second. The tension–time index was calculated by integrating the area between the tension trace and the baseline level (Spike 2) and is expressed in kgs. Peak developed tension was calculated by subtracting the resting tension from the peak tension and is expressed in kilograms. All values are expressed as the mean ± standard error of the mean (S.E.M.). Two-way repeated measures ANOVA followed by Tukey post hoc tests were used to determine statistical significance, except in the case of tension–time indices and peak developed tension in which case one-way repeated measure ANOVAS were used to determine significance. The criterion for statistical significance was set at P < 0.05.
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Results |
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The reflex pressor responses to arterial injections of lactic acid and capsaicin as well as to tendon stretch and static contraction were measured before, and then 30 and 60 min after popliteal arterial injection of two doses of amiloride (5 µg kg–1 and 0.5 µg kg–1). The effects of the large dose of amiloride (5 µg kg–1) are reported first and are then followed by the small dose (0.5 µg kg–1). The cardioaccelerator responses to the four manoeuvers were, for the most part, modest and are given in Table 1.
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Effects of amiloride (0.5 µg kg–1) on responses to lactic acid and capsaicin. The small dose of amiloride significantly attenuated (P < 0.05) the pressor response to lactic acid injection, but had no effect on the pressor response to capsaicin injection (P > 0.05; Fig. 1). Before amiloride, the pressor response to popliteal arterial injections of lactic acid averaged 36 ± 5 mmHg (P = 0.001; n = 7), whereas 30 and 60 min afterwards it averaged 12 ± 4 mmHg (P = 0.09; n = 7) and 23 ± 6 mmHg (P = 0.005; n = 7). The difference between the pressor response to lactic acid before amiloride and that after 30 min was significant (P = 0.02). Before amiloride the pressor response to popliteal arterial injections of capsaicin averaged 55 ± 11 mmHg, and remained unchanged 30 and 60 min afterwards, averaging 53 ± 10 and 56 ± 10 mmHg, respectively (P = 0.46; n = 7).
Effects of amiloride (0.5 µg kg–1) on responses to static contraction. The small dose of amiloride significantly attenuated (P < 0.05) the pressor response to static contraction (Fig. 2). Before amiloride, the pressor response to static contraction averaged 42 ± 7 mmHg (P = 0.003; n = 7), whereas 30 min afterwards it averaged 15 ± 5 mmHg (P = 0.19; n = 7) and 60 min afterwards it recovered to 31 ± 7 mmHg (P = 0.01; n = 7). Importantly, the difference between the pressor response before amiloride and the pressor response 30 min afterwards was significant (P = 0.009; n = 7). Likewise, the difference between the pressor response 30 min after and 60 min after was also significant (P = 0.01; n = 7). The tension–time indices before, 30 min after and 60 min after amiloride were not significantly different (P = 0.58; n = 7, Table 2).
Effects of amiloride (0.5 µg kg–1) on the responses to tendon stretch. The small dose of amiloride had no effect on the pressor response to tendon stretch (P > 0.05; Fig. 2). Before amiloride the pressor response to stretch of the calcaneal tendon averaged 34 ± 6 mmHg and remained unchanged 30 and 60 min afterwards, averaging 30 ± 6 and 31 ± 5 mmHg (P = 0.59; n = 7), respectively. The tension–time indices before, 30 and 60 min after amiloride were not significantly different (P = 0.79; n = 7, Table 2).
Electrophysiology experiments
We recorded the responses of groups I–IV triceps surae muscle afferents to their effective stimuli before and after the large (5.0 µg kg–1) or small dose (0.5 µg kg–1) of amiloride injected into the popliteal artery.
Spindles. We measured the responses of 10 muscle spindles (conduction velocity: 99 ± 10 m s–1) to tendon stretch and to injection of succinylcholine, both of which evoked repeatable responses. The large dose of amiloride (5.0 µg kg–1) significantly attenuated the responses of each muscle spindle afferent to tendon stretch and to succinylcholine (P < 0.001; n = 10; Fig. 3). The tension–time indices developed during stretch (Table 3, P = 0.56; n = 10) and the baseline tensions (Table 3, P = 0.43, n = 10) were the same before and after the large dose of amiloride.
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Group III afferents. We recorded the activity of 11 group III afferents whose receptive fields were in the left triceps surae muscles (conduction velocity: 14.5 ± 3.2 m s–1; range: 5.4–24.1 m s–1). Each of the 11 responded to non-noxious probing of the triceps surae muscles; 10 of the 11 responded to stretch of the calcaneal tendon. Five of the 11 group III afferents were tested with the large dose of amiloride (5 µg kg–1) and six were tested with the low dose of amiloride (0.5 µg kg–1).
Of the five group III afferents (mean conduction velocity: 12.6 ± 2.1 m s–1; range: 5.4–23.8 m s–1) tested with the large dose of amiloride, four responded to tendon stretch, three responded to popliteal artery injection of lactic acid, and five responded to static contraction. The large dose attenuated the responses of the four group III afferents to tendon stretch (Fig. 4). The tension–time indices developed during stretch were the same before and after amiloride (P = 0.77, n = 4).
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Of the six group III afferents (conduction velocity: 17.9 ± 3.1 m s–1; range: 9.3–24.1 m s–1) tested with the low dose of amiloride (0.5 µg kg–1), each responded to tendon stretch. Four of the six responded to lactic acid, and four responded to static contraction. The low dose of amiloride did not attenuate the responses of group III afferents to tendon stretch. The tension–time indices developed during stretch were the same before and after amiloride (P = 0.87, n = 6).
The small dose of amiloride attenuated the responses of each of the four group III afferents to lactic acid. Likewise, the low dose attenuated the responses of each of the four group III afferents to static contraction. The tension–time indices developed during contraction were the same before and after amiloride (P = 0.44, n = 4). Only 1 of the 11 group III afferents responded to popliteal arterial injection of capsaicin. The low dose of amiloride appeared to have no effect on its response to capsaicin.
Group IV afferents. We recorded the impulse activity of seven group IV afferents whose receptive fields were in the left triceps surae muscles (conduction velocity: 1.1 ± 1.2 m s–1; range: 0.7–2.3 m s–1). Six of the seven responded to noxious probing of the triceps surae muscles. None responded to tendon stretch or to non-noxious probing of the muscles. Four of the seven group IV afferents were tested with the large dose of amiloride (5 µg kg–1) and three were tested with the small dose (0.5 µg kg–1). Three of the four tested with the large dose responded to popliteal arterial injection of lactic acid and capsaicin. Each of the four group IV afferents challenged with the large dose of amiloride responded to static contraction.
The large dose of amiloride prevented the responses of the three group IV afferents to arterial injection of lactic acid (Fig. 5). Similarly, the large dose attenuated each of the responses of the three group IV afferents to arterial injection of capsaicin (Fig. 5). In addition, the large dose of amiloride attenuated the responses of the four group IV afferents to static contraction. The tension–time indices during contraction were the same before and after amiloride (P = 0.34, n = 4).
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Discussion |
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We also found that a second dose of amiloride (5 µg kg–1), which was an order of magnitude higher than the first dose, not only abolished the pressor response to lactic acid, but also attenuated markedly the pressor responses to capsaicin, tendon stretch and static contraction of the triceps surae muscles. Moreover, this higher dose of amiloride attenuated markedly the responses of muscle spindles to both succinylcholine and to tendon stretch, two stimuli which presumably do not activate ASICs (Drew et al. 2004). These findings are consistent with the hypothesis that in our experiments the high dose of amiloride not only blocked ASICs but also blocked voltage-gated sodium channels, thereby impairing impulse conduction in the afferent fibres.
Previous studies in rats have used amiloride to block the pressor responses to injection of acidic solutions into the arterial supply of hind limb muscles. Specifically, these studies have shown that femoral arterial injections of amiloride at a dose of 6 µg kg–1 attenuated by half the reflex pressor responses to diprotonated phosphate (Gao et al. 2006) and to lactic acid (Li et al. 2004). Our findings in cats suggest that the dose of amiloride used in these previous studies (Li et al. 2004; Gao et al. 2006) blocked voltage-gated sodium channels as well as ASICs. If sodium channels were blocked by amiloride, this effect could have impaired impulse conduction in thin fibre afferents stimulated by the acidic solutions.
Amiloride has also been shown to prevent the responses of afferents innervating the lungs, kidneys and carotid sinus (Kopp et al. 1998; Drummond et al. 1998; Carr et al. 2001) to a variety of mechanical stimuli. For example, amiloride attenuated the increases in cytosolic calcium concentrations evoked by a pressure stimulus in cultured baroreceptor cell bodies (Kopp et al. 1998). Likewise, amiloride attenuated the responses to punctate stimulation of vagal myelinated mechanoreceptors innervating the trachea and bronchus (Carr et al. 2001). Patch-clamp studies revealed that the attenuation induced by amiloride was caused by blockade of voltage-gated sodium channels (Carr et al. 2001). This finding led the authors to conclude that amiloride did not selectively block mechanotransduction, but instead reduced excitability in mechanosensitive afferents by blocking voltage-gated sodium channels (Carr et al. 2001).
In our experiments, both doses of amiloride markedly attenuated the exercise pressor reflex. We do not think that a reduction in afferent excitability caused by blockade of voltage-gated sodium channels was the cause of the attenuation of the exercise pressor reflex induced by the low dose of amiloride. If this dose caused a reduction in afferent excitability, then one might expect that low dose would also attenuate the reflex pressor responses to capsaicin injection and to tendon stretch. Moreover, the low dose of amiloride would be expected to attenuate the responses of spindle afferents to succinylcholine and stretch. None of these effects were observed in our experiments, thereby leading us to speculate that the low dose of amiloride blocked ASICs. This speculation is supported by our finding that this low dose of amiloride significantly attenuated the reflex pressor response to lactic acid, a potent stimulant of these channels (Immke & McCleskey, 2001). On the other hand, the attenuation of the pressor reflexes by the high dose of amiloride seems best explained by a reduction in afferent excitability caused by blockade of voltage-gated sodium channels as well as blockade of ASICs.
Three genes and two splice variants encode the four ASICs found in sensory nerves. ASIC3, which has also been termed DRASIC, is unique because it is found, for the most part, only in dorsal root ganglia (Waldmann & Lazdunski, 1998). In addition, in vitro evidence suggests that ASIC3 opens when the pH in the interstitium of muscle decreases from 7.4 to 7.0 (Immke & McCleskey, 2001), a concentration which occurs during exercise. Moreover, ASIC3 is more sensitive to lactic acid than it is to other acids (Immke & McCleskey, 2001). In ASIC3 knockout mice, multiple injections of acid into skeletal muscle failed to cause a long lasting hypersensitivity to mechanical stimuli that was found in their wild type counterparts (Sluka et al. 2003). These findings, considered together, lead us to speculate that the ASIC3 was the channel blocked by the low dose of amiloride in our experiments.
Dorsal root ganglion cells innervating rodent skeletal muscle have been reported to bind antibodies to both ASIC3 and calcitonin gene-related peptide (CGRP), but not to the P2X3 receptor (Molliver et al. 2005). These findings led Molliver et al. (2005) to speculate that during exercise, lactic acid accumulation in the muscle interstitium stimulated thin fibre afferents, thereby evoking the metabolic component of the exercise pressor reflex, while simultaneously releasing CGRP, a vasodilatory peptide, from their sensory endings. There may be, however, more than one substance evoking the metabolic component of the exercise pressor reflex. Likewise, there may be more than one substance causing vasodilatation in exercising muscle. For example, ATP is known to evoke the exercise pressor reflex (Hanna & Kaufman, 2003), and its metabolite, adenosine, is known to cause vasodilatation (MacLean et al. 1998). The possibility that purinergic substances evoke both effects is attractive because ASIC3 and P2X3 receptors have been reported to be found on different thin fibre muscle afferents (Molliver et al. 2005), thereby dilating vessels supplied by thin fibre afferents possessing either ASIC3 or P2X3 receptors.
In humans, the role played by lactic acid in the generation of the metabolic component of the exercise pressor reflex has been controversial (Thomas & Victor, 2003). Most of this controversy has stemmed from studies examining the pressor and muscle sympathetic nerve responses to static exercise in individuals with McArdle's disease. These patients have a myophosphoralase deficiency and as a consequence produce little lactic acid when they exercise. Two studies have shown that the pressor and muscle sympathetic nerve responses to static handgrip are almost non-existent in these patients (Pryor et al. 1990; Fadel et al. 2003), whereas two others have shown that these responses are preserved (Vissing et al. 1998, 2001). Most other studies in humans have found support for a role played by lactic acid in the generation of the exercise pressor reflex. For example, humans display a strong inverse relationship between intracellular pH in statically exercising muscle and either muscle sympathetic nerve activity or calf vascular resistance (Victor et al. 1988; Sinoway et al. 1989). Likewise, blunting lactic acid production by either depleting glycogen in muscle or giving dichloroacetate has been shown to decrease the pressor and muscle sympathetic nerve responses to exercise (Ettinger et al. 1991; Sinoway et al. 1992).
Our report is the first to show that amiloride attenuated the exercise pressor reflex. Although we attribute this attenuation by the low dose to the blockade of ASIC3 on the endings of thin fibre muscle afferents, this blockade was not complete because we found that it did not abolish the reflex pressor response to lactic acid injections. We note with interest that blockade of P2X receptors (Hanna & Kaufman, 2003), bradykinin 2 receptors (Pan et al. 1993) and prostaglandin synthesis (Stebbins et al. 1988) in skeletal muscle have been each shown to attenuate the exercise pressor reflex by at least half. These findings suggest that the ligands to each of these receptors has a role to play in the elicitation of the reflex, the full expression of which must be the result of a complex integration of afferent input in the dorsal horn of the spinal cord or the ventrolateral medulla.
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