3. Electrophysiology

STZ was injected in rats on 28th day of experiment; as a result, blood glucose level was increased by 4.4 times (p ≤ 0.001). On the 14th and 28th day of development of diabetes, the threshold of pain sensitivity increased by 26.4% (p < 0.05) and 95.86% (p < 0.01), accordingly, by comparison to an initial level (before STZ injection). Therefore, pain sensitivity in diabetic rats was suppressed, indicating the development of peripheral neuropathy.

Force response of musculus gastrocnemius in rats with diabetic polyneuropathy caused by single stimulation pool with frequency of 50 Hz showed that time of the force response beginning increased by 119.34% with stimulation through the nerve (Figures 2 and 3). It should be noted that time of force response in the condition of direct stimulation though the muscle did not change.

The time of force response beginning increased from 121.25% at the first run till 142.27% at the tenth run in case of 10 consecutive stimulation pools usage (Figures 1 and 3). It was concluded the presence of neuropathic changes associated with the impossibility of generation of 10 consecutive stimulation pulses without significant physiological disturbances of myopathy origin.

It was shown that the diabetic polyneuropathy leads to significant dysfunctions during stimulation signal transfer to effector. When the parameters of stimulation signal approach to the physiological level, the dysfunction of neuromuscular activity increases till the level that is

Figure 3. The change in time of muscle force response in rats with diabetic neuropathy caused by 10 consecutive irritation pools by modulated electrostimulation with 50 Hz frequency. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct

Figure 2. The change in time of muscle force response in rats with diabetic neuropathy caused by 10 consecutive irritation pools by modulated electrostimulation with 50 Hz frequency. The relaxation time is 10 s. Cont—control; Δt1—time between two consecutive stimulation pools; Δt2—time of muscle force response beginning; a—direct stimulation of the

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muscle, rat with diabetic neuropathy; b—stimulation through the nerve, rat with diabetic neuropathy.

capable to disturb the overall dynamics of the contractile process.

stimulation of the muscle; b—stimulation through the nerve.

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2.2.10. Analysis of fusion index

126 Pathophysiology - Altered Physiological States

by the whole muscle.

3. Electrophysiology

muscle did not change.

origin.

To analyze the dynamics of real movements, we considered the peculiarities of the transformation of segmental and descending activity during the development of polyneuropathy. An important role in the realization of the motor function belongs dedicated to asymmetric nature of the muscle reactions as a result of increase in the level of incoming efferent activity. In our work, almost all movements are relatively simple and are provided with straight pattern of motor neuron populations. Since motor neurons directly control muscle contraction, the nature of the transformation of activity coming to them from multiple sources is largely predetermined by the peculiarities of muscle dynamics. The significant inertia of muscle contraction during the development of the pathological process requires motor neurons to have such dynamic properties that could compensate for the insufficiently high-speed parameters of muscle contraction. Thus, the slowdown of smooth tetanus appearance can be used as another parameter to describe the dynamics of pathologies development. We investigated the transition of active muscle force response from the state of the unfused tetanus to the fused one. We had also analyzed the time variation between the peaks of the force response and their maximum force. Two above-described parameters are important for the transition of the active muscle from the state of unfused tetanus to the fused one. The analysis of their changes shows us the peculiarities of dysfunction generation by individual motor units, and the consistent nature of their activation provides the possibility of smooth regulation of the force developed

STZ was injected in rats on 28th day of experiment; as a result, blood glucose level was increased by 4.4 times (p ≤ 0.001). On the 14th and 28th day of development of diabetes, the threshold of pain sensitivity increased by 26.4% (p < 0.05) and 95.86% (p < 0.01), accordingly, by comparison to an initial level (before STZ injection). Therefore, pain sensitivity in diabetic

Force response of musculus gastrocnemius in rats with diabetic polyneuropathy caused by single stimulation pool with frequency of 50 Hz showed that time of the force response beginning increased by 119.34% with stimulation through the nerve (Figures 2 and 3). It should be noted that time of force response in the condition of direct stimulation though the

The time of force response beginning increased from 121.25% at the first run till 142.27% at the tenth run in case of 10 consecutive stimulation pools usage (Figures 1 and 3). It was concluded the presence of neuropathic changes associated with the impossibility of generation of 10 consecutive stimulation pulses without significant physiological disturbances of myopathy

rats was suppressed, indicating the development of peripheral neuropathy.

Figure 2. The change in time of muscle force response in rats with diabetic neuropathy caused by 10 consecutive irritation pools by modulated electrostimulation with 50 Hz frequency. The relaxation time is 10 s. Cont—control; Δt1—time between two consecutive stimulation pools; Δt2—time of muscle force response beginning; a—direct stimulation of the muscle, rat with diabetic neuropathy; b—stimulation through the nerve, rat with diabetic neuropathy.

Figure 3. The change in time of muscle force response in rats with diabetic neuropathy caused by 10 consecutive irritation pools by modulated electrostimulation with 50 Hz frequency. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

It was shown that the diabetic polyneuropathy leads to significant dysfunctions during stimulation signal transfer to effector. When the parameters of stimulation signal approach to the physiological level, the dysfunction of neuromuscular activity increases till the level that is capable to disturb the overall dynamics of the contractile process.

Thus, the use of streptozotocin increases time of force response, which is an adequate criterion for the presence of neuropathy in rats with diabetic neuropathy.

The change in time of maximum force reach (Figure 5) caused by 10 consecutive stimulation pools modulated by electrostimulation with 50 Hz frequency and duration of 2 s was 183.41% at the first and 213.27% at the tenth run, respectively. When stimulation time was increased till 4 and 6 s, the data were 188.49% (1), 243.47% (10), 188.49% (1) and 243.47% (10), respectively.

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Figure 5. The change in time of maximum force reach by musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 3 and 4 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

As a result, amplitude-force changes in the muscle response were revealed (Figure 4), both compared to control or to direct muscle stimulation. It should be noted that the presence of clearly expressed fluctuation changes in the phase of stationary state retention in rats with diabetic polyneuropathy with stimulation through the nerve.

Figure 4. The changes in the dynamic parameters of musculus gastrocnemius contraction in rats with diabetic polyneuropathy, stimulated by modulated electrostimulation with 50 Hz frequency and duration of 2, 4 and 6 s. The relaxation time is 10 s. a—direct stimulation of the muscle; b—stimulation through the nerve; 1, 2, 3—stimulation time 2, 4 and 6 s, respectively; Cont—control, Δt1—phase of the maximum force response, Δt2—phase of stationary state of contraction.

The change in time of maximum force reach (Figure 5) caused by 10 consecutive stimulation pools modulated by electrostimulation with 50 Hz frequency and duration of 2 s was 183.41% at the first and 213.27% at the tenth run, respectively. When stimulation time was increased till 4 and 6 s, the data were 188.49% (1), 243.47% (10), 188.49% (1) and 243.47% (10), respectively.

Thus, the use of streptozotocin increases time of force response, which is an adequate criterion

As a result, amplitude-force changes in the muscle response were revealed (Figure 4), both compared to control or to direct muscle stimulation. It should be noted that the presence of clearly expressed fluctuation changes in the phase of stationary state retention in rats with

Figure 4. The changes in the dynamic parameters of musculus gastrocnemius contraction in rats with diabetic polyneuropathy, stimulated by modulated electrostimulation with 50 Hz frequency and duration of 2, 4 and 6 s. The relaxation time is 10 s. a—direct stimulation of the muscle; b—stimulation through the nerve; 1, 2, 3—stimulation time 2, 4 and 6 s, respectively; Cont—control, Δt1—phase of the maximum force response, Δt2—phase of stationary state of

contraction.

for the presence of neuropathy in rats with diabetic neuropathy.

128 Pathophysiology - Altered Physiological States

diabetic polyneuropathy with stimulation through the nerve.

Figure 5. The change in time of maximum force reach by musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 3 and 4 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

The time of stationary state reach by musculus gastrocnemius in rats with diabetic neuropathy by stimuli for 2 s showed that the time increased from 211.34% at the first till 249.14% at the tenth run corresponding (Figure 6). When stimulation time was increased till 4 and 6 s—215.64% (1), 253.78% (10) and 234.12% (1) 297.66% (10), respectively. At the same time, the time of stationary state retention also decreased linearly as with the increase in the number of stimulating pools and with an increase in the stimulation longevity (Figure 7).

Figure 6. The change in time of stationary state reach by musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 4 and 6 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

The changes in the maximum and minimum force of muscle contraction in rats with diabetic neuropathy caused by 10 consecutive stimulation pools with modulated electrostimulation with 50 Hz frequency and duration 2, 4 and 6 s were analyzed. The decrease in the maximum force was found from 99.34% at first run till 91% at tenth run, as well as decrease in the minimum force response was found from 99% (1) till 90.78% (10). The changes in these indicators with increasing stimulation duration up to 4 s were as follows: 98.71% (1) to 78.58% (10) and 97% (1) to 51.8% (10) for the maximum and minimum force, respectively. Increase in stimulation up to 6 s: 97% (1) to 51.8% (10) and 91.18% (1) to 65.34% (1) for the

2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

Figure 7. The change of integrated power of musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 3 and 4 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values;

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maximum and minimum force, respectively.

The time of stationary state reach by musculus gastrocnemius in rats with diabetic neuropathy by stimuli for 2 s showed that the time increased from 211.34% at the first till 249.14% at the tenth run corresponding (Figure 6). When stimulation time was increased till 4 and 6 s—215.64% (1), 253.78% (10) and 234.12% (1) 297.66% (10), respectively. At the same time, the time of stationary state retention also decreased linearly as with the increase in the number of

Figure 6. The change in time of stationary state reach by musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 4 and 6 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

stimulating pools and with an increase in the stimulation longevity (Figure 7).

130 Pathophysiology - Altered Physiological States

Figure 7. The change of integrated power of musculus gastrocnemius in rats with diabetic polyneuropathy caused by 10 consecutive stimulation pools with electrostimulation with 50 Hz frequency and duration 2, 3 and 4 s. The relaxation time is 10 s. The meanings are represented as percentages from control values considered as 100%. 1—control values; 2–11—consecutive irritation pools; a—direct stimulation of the muscle; b—stimulation through the nerve.

The changes in the maximum and minimum force of muscle contraction in rats with diabetic neuropathy caused by 10 consecutive stimulation pools with modulated electrostimulation with 50 Hz frequency and duration 2, 4 and 6 s were analyzed. The decrease in the maximum force was found from 99.34% at first run till 91% at tenth run, as well as decrease in the minimum force response was found from 99% (1) till 90.78% (10). The changes in these indicators with increasing stimulation duration up to 4 s were as follows: 98.71% (1) to 78.58% (10) and 97% (1) to 51.8% (10) for the maximum and minimum force, respectively. Increase in stimulation up to 6 s: 97% (1) to 51.8% (10) and 91.18% (1) to 65.34% (1) for the maximum and minimum force, respectively.

Integrated power in rats with diabetic polyneuropathy showed a slight decrease from 100% at the first run to 92.37% at the tenth run with stimulation duration of 2 s. More significant changes were recorded at 4 and 6 s stimulation from 98.7% (1) to 71.16% (10) and from 94.71% (1) to 49.6% (10), respectively.

Based on the obtained data, it could be concluded that with the development of diabetic neuropathy for all 10 consecutive stimulation pools, the formation of a stable muscle response in the phases of the maximum force retention (and stationary state) does not occur. The dynamics of amplitude-force formation had a clear tendency to reduce the stabilization time of the constant power characteristics.

Biomechanical curves showed that prolonged stimulation with 1 and 2 Hz frequency (Figure 8) decreased the maximum force response of the muscle throughout the period of stimulation. Stimulation of 2 Hz caused the development of rapid fatigue processes, and the maximum change in muscle power productivity occurs on 1 min of force parameters registration (Figures 8 and 9). If we continue stimulation in the same way, after 150 s, the muscle passes into a state of complete nonexcitability (Figure 10).

The time of muscle contraction force reduction during diabetic polyneuropathy by 50% was 55 and 39 s, respectively. The time of muscle contraction force reduction by 30% was 165 s at 1 Hz

Figure 9. Time of musculus gastrocnemius force reduction in rats with diabetic neuropathy by 50% (1) and 30% (2) compare to initial level caused by unrelaxed stimulation by electrostimulation with frequency 1 Hz and 2 Hz. a—control; b—direct stimulation of the muscle; c—stimulation of the muscle through the nerve; 1—time of force reduction by 50%

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compared to the initial level; 2—time of force reduction by 30% compared to the initial level.

Thus, it can be assumed that the conversion of the depolarization current to the impulse frequency of the outgoing motor neuron during the development of these pathological processes is a linear process of the development of fatigue with the absence of rapid adaptation by a constant frequency stimulus. The registered parameters during fatigue process development were similar to the processes of motor neuron impulse frequency changing caused by severe pathological disorders of the neuromuscular preparation. The transformation of depolarization current into the pulse frequency in this case is a nonlinear process, most likely connected with numerous pathological processes in organism. The absence of both initial and subsequent adaptation of the induced fatigue process can be associated with processes of inactivation of

and 82 s at 2 Hz (Figure 9).

Ca channels located in the initial axon segments.

Figure 8. Curves of musculus gastrocnemius force generation caused by unrelaxed stimulation by electrostimulation with 1 Hz (a) and 2 Hz (b) frequency. Δt1—time of force reduction by 50% compared to the initial level; Δt2—time of force reduction by 30% compared to the initial level.

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Integrated power in rats with diabetic polyneuropathy showed a slight decrease from 100% at the first run to 92.37% at the tenth run with stimulation duration of 2 s. More significant changes were recorded at 4 and 6 s stimulation from 98.7% (1) to 71.16% (10) and from

Based on the obtained data, it could be concluded that with the development of diabetic neuropathy for all 10 consecutive stimulation pools, the formation of a stable muscle response in the phases of the maximum force retention (and stationary state) does not occur. The dynamics of amplitude-force formation had a clear tendency to reduce the stabilization time

Biomechanical curves showed that prolonged stimulation with 1 and 2 Hz frequency (Figure 8) decreased the maximum force response of the muscle throughout the period of stimulation. Stimulation of 2 Hz caused the development of rapid fatigue processes, and the maximum change in muscle power productivity occurs on 1 min of force parameters registration (Figures 8 and 9). If we continue stimulation in the same way, after 150 s, the muscle passes into a state of complete

Figure 8. Curves of musculus gastrocnemius force generation caused by unrelaxed stimulation by electrostimulation with 1 Hz (a) and 2 Hz (b) frequency. Δt1—time of force reduction by 50% compared to the initial level; Δt2—time of force

94.71% (1) to 49.6% (10), respectively.

132 Pathophysiology - Altered Physiological States

of the constant power characteristics.

reduction by 30% compared to the initial level.

nonexcitability (Figure 10).

Figure 9. Time of musculus gastrocnemius force reduction in rats with diabetic neuropathy by 50% (1) and 30% (2) compare to initial level caused by unrelaxed stimulation by electrostimulation with frequency 1 Hz and 2 Hz. a—control; b—direct stimulation of the muscle; c—stimulation of the muscle through the nerve; 1—time of force reduction by 50% compared to the initial level; 2—time of force reduction by 30% compared to the initial level.

The time of muscle contraction force reduction during diabetic polyneuropathy by 50% was 55 and 39 s, respectively. The time of muscle contraction force reduction by 30% was 165 s at 1 Hz and 82 s at 2 Hz (Figure 9).

Thus, it can be assumed that the conversion of the depolarization current to the impulse frequency of the outgoing motor neuron during the development of these pathological processes is a linear process of the development of fatigue with the absence of rapid adaptation by a constant frequency stimulus. The registered parameters during fatigue process development were similar to the processes of motor neuron impulse frequency changing caused by severe pathological disorders of the neuromuscular preparation. The transformation of depolarization current into the pulse frequency in this case is a nonlinear process, most likely connected with numerous pathological processes in organism. The absence of both initial and subsequent adaptation of the induced fatigue process can be associated with processes of inactivation of Ca channels located in the initial axon segments.

Figure 10. Musculus gastrocnemius maximum force reduction in rats with diabetic neuropathy compared to the initial level caused by unrelaxed stimulation by electrostimulation with 1 Hz and 2 Hz frequency and duration of 200 s. The meanings are represented as percentages from control values considered as 100%. a—control; b—rat with diabetic neuropathy; 1–21—consecutive irritation pools.

Maximum force contraction during diabetic neuropathy decreased from 97% till 30% with stimulation of 1 Hz and duration of 200 s (Figure 11).

With stimulation of 2 Hz and duration of 200 s, the maximum force contraction of musculus gastrocnemius in rats with diabetic neuropathy decreased significantly from 95 to 5%, respectively (Figure 10).

Time between the development of the maximum force response decreased by 65 min during first unfused tetanus till 53 min during the fifth contraction (Figures 10). The change in peaks force is 311 mN at the first contraction and 331 mN at the fifth contraction of the unfused tetanus. The time for establishing of fused tetanus caused with stimulation of 20 Hz and 6 s duration was 4789 ms. In control this time was 3456 ms (Figure 12).

4. Conclusions

musculus gastrocnemius.

(cont) and diabetic (diabete) rats. 1–5—consecutive irritation pools.

To form macroindicators of neuromuscular activity during the development of diabetic polyneuropathy numerous complex, nonlinear nonstationary processes occur. The influence of

Figure 12. The changes in time between the development of the maximum force response (a), force (b), during the first five contractions of unfused tetanus and the time of its establishment (c), stimulation with 20 Hz frequency of the control

Figure 11. The changes in musculus gastrocnemius maximum force response development at five first peaks of the unfused tetanus caused by stimulation with 20 Hz frequency in rats with diabetic neuropathy. a—it is the general view of the muscle force response caused by stimulation with 20 Hz frequency, for 6 s control (1), rats with diabetic neuropathy (2); b—five consecutive peaks of the tetanus; \*—indicated parameters of the investigated rats; Δt1–Δt5—time of force response development 1–5 consecutive reductions; Δf1–Δf5—the force of consecutive peaks of the first contractions of

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Figure 11. The changes in musculus gastrocnemius maximum force response development at five first peaks of the unfused tetanus caused by stimulation with 20 Hz frequency in rats with diabetic neuropathy. a—it is the general view of the muscle force response caused by stimulation with 20 Hz frequency, for 6 s control (1), rats with diabetic neuropathy (2); b—five consecutive peaks of the tetanus; \*—indicated parameters of the investigated rats; Δt1–Δt5—time of force response development 1–5 consecutive reductions; Δf1–Δf5—the force of consecutive peaks of the first contractions of musculus gastrocnemius.

Figure 12. The changes in time between the development of the maximum force response (a), force (b), during the first five contractions of unfused tetanus and the time of its establishment (c), stimulation with 20 Hz frequency of the control (cont) and diabetic (diabete) rats. 1–5—consecutive irritation pools.

#### 4. Conclusions

Maximum force contraction during diabetic neuropathy decreased from 97% till 30% with

Figure 10. Musculus gastrocnemius maximum force reduction in rats with diabetic neuropathy compared to the initial level caused by unrelaxed stimulation by electrostimulation with 1 Hz and 2 Hz frequency and duration of 200 s. The meanings are represented as percentages from control values considered as 100%. a—control; b—rat with diabetic

With stimulation of 2 Hz and duration of 200 s, the maximum force contraction of musculus gastrocnemius in rats with diabetic neuropathy decreased significantly from 95 to 5%, respec-

Time between the development of the maximum force response decreased by 65 min during first unfused tetanus till 53 min during the fifth contraction (Figures 10). The change in peaks force is 311 mN at the first contraction and 331 mN at the fifth contraction of the unfused tetanus. The time for establishing of fused tetanus caused with stimulation of 20 Hz and 6 s

stimulation of 1 Hz and duration of 200 s (Figure 11).

neuropathy; 1–21—consecutive irritation pools.

134 Pathophysiology - Altered Physiological States

duration was 4789 ms. In control this time was 3456 ms (Figure 12).

tively (Figure 10).

To form macroindicators of neuromuscular activity during the development of diabetic polyneuropathy numerous complex, nonlinear nonstationary processes occur. The influence of pathological factors on these processes leads to either complete dysfunction of these parameters or their desynchronization. As a result, the whole muscle as a dynamic system is not able to adequately implement the pool of neural activity getting from the central nervous system. The nature and level of these dysfunctions is linearly related to the level of pathological processes development, the analysis of which at present can be carried out exclusively at the phenomenological level. Despite new experimental approaches in studying microlevel of neuromuscular regulation, traditional electro-physiological models with usage of neuromuscular preparation in vivo are still important. Such studies should be conducted not only to obtain accurate quantitative analysis of the pathologies of muscle dynamics but also to study the totality of the central processes involved in the regulation of muscle contraction.

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In condition of diabetic polyneuropathy development, differences in the response of the muscle to frequency changes indicate that to determine the contractile properties of the muscle, it is important to know not only the current values of the force response and activation intensity but also the history of changes in these parameters. The consequence of above-described dysfunction of the neuromuscular complex is the need of motor neurons to generate powerful dynamic discharge components to resume the error-free operation of the muscular system. Thus, at the same levels of the stationary state of the efferent command, an increase in the duration of the preceding dynamic component not only slows down the transition to a new equilibrium force but also leads to decrease in the maximum force response. The mechanokinetic curves showed the changes in the implementation of complex stimulation programs during the development of polyneuropathy. The analysis of dynamic properties of various parts of the motor system gives an idea of the presence of changes in the dynamics of complex movements associated with the precision positioning of joints and the ability of the system to correct the descending motor commands by adaptation processes in the central neurons.

Usage of static characteristics "stimulation signal-reduction force" to analyze the pathological processes during diabetic polyneuropathy development will lead to incomplete picture of pathology development. For an adequate understanding and analysis of these changes, a multifaceted experimental approach is needed with the possibility of simultaneous monitoring of various biomechanical parameters with different amplitude-time intervals and a labile system of external stimulation. Only in this case it becomes possible to trace the changes in the reaction of neuromuscular preparation to stimulation that are responsible for the development of ballistic precision positional movements, the analysis of which will be a critical factor in concluding the level of development of pathologies in diabetic polyneuropathy.
