The first factor to be considered is the moment of time in which the second stimulus is applied, that is, the interval between the first and the second stimulus. If, for example, a weak second stimulus follows very quickly after the first, the stimulus will bring about no response, as the system at the time of its application is in a relative refractory period. (Figure 48.) The stimulus is, therefore, under the threshold. If, however, a stimulus of the same strength is applied somewhat later, when the irritability has already increased to a somewhat greater extent, then at this moment the stimulus is above that of the threshold and a response is obtained which, on account of the state of irritability existing, is summated. (Figure 52.) But further, it is not a question of the _absolute_ interval between the stimuli, but rather to the _relative_ interval to the _specific rapidity of the reaction of the living substance under consideration_. There are living substances, as we have seen, in which the refractory period is unusually short, as, for instance, the nerve. There are other substances wherein this period lasts a considerable time after stimulation, that is, before the irritability returns to the original level, as, for example, the smooth muscle. Indeed, depending upon the specific properties of a system, a short or a long interval is required before a stimulus of a given intensity is again operative. Finally, in one and the same living system the duration of the refractory period can be very different, depending upon the _momentary state of the system_. Above all we know that the refractory period is considerably prolonged in fatigue and likewise after the influence of other agents, as narcotics, lowering of the temperature, etc. In such states a second stimulus remains inoperative when it follows at a definite interval from the first, whereas under normal conditions the same stimulus applied at the same interval would be operative.